Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C1(C)C=CC=CC=1>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]\[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(/C=C\N(C)C)c([N+](=O)[O-])cn1
Temperature: 90 °C
Yield: 63 %

Procedure:
To a solution of N-(4-methyl-5-nitropyridin-2-yl)acetamide (1 g, 5 mmol, Step a) in dry dimethylformamide (10 mL), dimethylformamide dimethyl acetal (1.5 mL, 11 mmol) was added and the resulting reaction mixture was heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, toluene was added and evaporated under vacuum followed by triturating with diethyl ether and filtration to afford N-{4-[(Z)-2-(dimethylamino)ethenyl]-5-nitropyridin-2-yl}acetamide (0.8 g, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][OH:17])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60](O)=[CH:59][CH:58]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][O:17][C:60]3[CH:61]=[CH:62][C:57]([O:56][CH3:55])=[CH:58][CH:59]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)[C@H]3SC2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 21.2 %

Procedure:
5.00 g (10.1 mmol) of Diphenylmethyl 7-tert-butoxycarbonylamino-3-hydroxymethyl-3-cephem-4-carboxylate, 7.93 g (30.2 mmol) of triphenylphosphine, and 7.28 g (60.2 mmol) of p-methoxyphenol were dissolved in 25 ml of tetrahydrofuran under argon atmosphere, and the reaction solution was cooled to -40°-35° C., and 4.76 ml (30.2 mmol) of diethyl azodicarboxylate were added dropwise, and then the stirring was effected for 6 hrs. at the same temperature. This solution was added to a suspension of 300 ml of ice cold 1N hydrochloric acid and 300 ml of ethyl acetate, and stirred, and then separated, and the layer of ethyl acetate was washed with water and saturated saline solution, and dried over anhydrous magnesium sulfate. Benzene was added to a caramel obtained by evaporating off the solvent so that the insoluble material was removed by filtering off, and the residue obtained by evaporating off the benzene filtrate was dissolved in diethyl ether. This ether solution was washed with 20% potassium carbonate aqueous solution until unreacted p-methoxyphenol was removed, and further washed with saturated potassium dihydrogen phosphate aqueous solution, water, and saturated saline solution. The layer of ether was dried over anhydrous magnesium sulfate, and then, ether was evaporated off to give 2.80 g of a caramel. The caramel was column chromatographed on silica gel by eluting with benzene-acetone (V:V;100:1), and then, powdered with ether-hexane to give 1.29 g of diphenylmethyl 7-tert-butoxycarbonylamino-3-(4-methoxyphenoxymethyl)-3cephem-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1.[H-].[Na+].[CH3:21][CH:22]([CH3:37])[CH:23](OS(C(F)(F)F)(=O)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:23]([CH:22]([CH3:37])[CH3:21])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: CCOC(=O)C(OS(=O)(=O)C(F)(F)F)C(C)C
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
3.50 g (13.4 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile in the presence of 1.5 eq. of sodium hydride and 5.60 g (20.1 mmol, 1.5 eq.) of ethyl 3-methyl-2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) were reacted at RT according to General Method 4E. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 3.70 g (66% of theory)
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:12][CH:13]([CH3:14])[N:9]3[C:10]=2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]3)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=O>CN(C)P(=O)(N(C)C)N(C)C>[N:20]1([C:2]2[C:11]3[CH2:12][CH:13]([CH3:14])[N:9]4[C:10]=3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]4)=[CH:4][C:3]=2[F:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCN1
Reactant: CC1Cc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1Cc2c(N3CCCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 39.8 %

Procedure:
A mixture of 56 g of 9-chloro-8-fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid, 71 g of pyrrolidone and 60 ml of hexamethylphosphoric triamide in a stainless steel autoclave was reacted at 150° C. for 8 hours. After completion of reaction, hexamethylphosphoric triamide was distilled off under reduced pressure and the residue was recrystallized repeatedly from dimethylformamide to give 25 g of 9-(1-pyrrolidinyl)-8-fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid. m.p. not lower than 300° C., pale yellow rhombic crystals.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C(=O)(O)[O-].[Na+].Br[CH2:11][C:12]([CH2:14][C:15]([NH:17][CH:18]1[C:28](=[O:29])[N:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]12)=[O:16])=O.Cl>O1CCCC1.O>[NH2:1][C:2]1[S:3][CH:11]=[C:12]([CH2:14][C:15]([NH:17][CH:18]2[C:28](=[O:29])[N:20]3[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]23)=[O:16])[N:4]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 51.1 %

Procedure:
Thiourea (663 mg), sodium bicarbonate (732 mg) and water (20 ml) were added to a stirred solution of 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylic acid (2.11 g) in tetrahydrofuran (20 ml) under ice-cooling and stirred at the same temperature for an hour. After the resultant solution was adjusted to pH 4.0 with dilute hydrochloric acid, the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (1.01 g).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([NH:19][NH2:20])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC2N(O)N=NC=2C=1.[CH3:31][O:32][C:33]1[C:42]2[C:37](=[C:38]([O:43][CH3:44])[CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([C:45]([N:47]2[CH2:52][CH2:51][C:50]3([CH2:61][C:60](=[O:62])[C:59]4[C:54](=[CH:55][CH:56]=[C:57]([C:63](O)=[O:64])[CH:58]=4)[O:53]3)[CH2:49][CH2:48]2)=[O:46])[CH:34]=1>C(OCC)(=O)C.CN(C=O)C>[CH3:31][O:32][C:33]1[C:42]2[C:37](=[C:38]([O:43][CH3:44])[CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([C:45]([N:47]2[CH2:52][CH2:51][C:50]3([CH2:61][C:60](=[O:62])[C:59]4[C:54](=[CH:55][CH:56]=[C:57]([C:63]([NH:20][NH:19][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:64])[CH:58]=4)[O:53]3)[CH2:49][CH2:48]2)=[O:46])[CH:34]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)O)ccc2O3)nc2c(OC)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)NNC(=O)OC(C)(C)C)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.5 %

Procedure:
50.6 mg of EDCI was added to a mixture of 29.1 mg of Boc-hydrazine, 33.7 mg of HOBT, 105 mg of 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(carboxy)spiro[chroman-2,4′-piperidin]-4-one and 2.2 mL of DMF, and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with 15 mL of ethyl acetate, washed with water and aqueous saturated NaHCO3 solution, and dried over sodium sulfate. The residue was purified through silica gel chromatography (2% MeOH/CHCl3) to obtain 119 mg of tert-butyl 2-({1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}carbonyl)hydrazinecarboxylate. 2 mL of 4 N HCl in dioxane was added to 59.1 mg of the product, and stirred at room temperature for 1 hour, and then concentrated. The residue was suspended in 2.5 mL of THF, and 0.049 μL of triethylamine and 24.3 mg of CDI were added thereto at 0° C., and stirred at room temperature for 14 hours. Water was added to the reaction solution, and extracted with chloroform, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified through silica gel thin-layer chromatography (17% MeOH/CHCl3) to obtain the intended compound. 1H-NMR (CDCl3) δ: 8.85 (1H, br s), 8.38 (1H, d, J=2.2 Hz), 7.97 (1H, dd, J=2.2, 8.8 Hz), 7.77 (1H, dd, J=8.5, 1.0 Hz), 7.47 (1H, dd, J=7.8, 8.5 Hz), 7.20 (1H, s), 7.13 (1H, d, J=8.8 Hz), 7.08 (1H, dd, J=1.0, 7.8 Hz), 4.64-4.56 (1H, m), 4.24-4.16 (1H, m), 4.09 (3H, s), 4.03 (3H, s), 3.67-3.58 (1H, m), 3.43-3.34 (1H, m), 2.87 (1H, d, J=16.8 Hz), 2.81 (1H, d, J=16.8 Hz), 2.26-2.18 (1H, m), 2.11-2.04 (1H, m), 2.01-1.87 (2H, m). MS [M+H]+=517.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]2[O:43][CH2:44][O:45][C:39]=2[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]4[O:43][CH2:44][O:45][C:39]=4[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc3c(c2)OCO3)CC1
Yield: 50.6 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.88 g) as starting compound, potassium carbonate (2.0 g) and 6-bromo-1-(3,4-methylenedioxyphenyl)-1-hexanone (0.80 g) were reacted and treated in the same manner as in Example 172 to give 0.62 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(3,4-methylenedioxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([Si:20]([O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].CN([CH:36]=[O:37])C>C1COCC1>[Si:20]([O:23][CH2:24][CH2:25][C:26]1[C:27]([F:32])=[C:28]([CH:29]=[CH:30][CH:31]=1)[CH:36]=[O:37])([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:21])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(C=O)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (11.0 g) in anhydrous THF (200 mL) was cooled to −78° and treated with butyllithium (37.5 mL), added steadily over 5 minutes via a syringe. The solution was stirred at −78° for 15 minutes and then treated with a solution of tert-butyl(2-fluorophenethoxy)dimethylsilane [Aromatic Intermediate 5, step a] (9.9 g) in THF (25 mL), added dropwise over 15 minutes. The solution that was stirred at −78° for 2 hours, then treated with a solution of DMF (9.0 mL) in THF (25 mL), added dropwise over 10 minutes. The solution was stirred at −78° for 1 hour, then the cooling bath was removed and the solution was allowed to warm to room temperature overnight. The reaction mixture was poured into aqueous HCl (0.5 M) and extracted three times with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the titled compound. Yield 10.1 g.
Reaction SMILES: C[O-].[Na+].[CH:4]([O:6][CH3:7])=[O:5].[Cl:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24](OC)=[O:25])[CH:12]=[CH:11][CH:10]=1.O>C1(C)C=CC=CC=1>[Cl:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:24]\[OH:25])/[C:4]([O:6][CH3:7])=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)Cc1ccccc1COc1cccc(Cl)n1
Reactant: COC=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C(=C/O)c1ccccc1COc1cccc(Cl)n1
Yield: 98.6 %

Procedure:
Sodium methoxide (0.39 g, 6.9 mmol) and methyl formate (1 ml, 16 mmol) were added portionwise to a stirred solution of methyl 2-(6-chloropyrid-2-yloxymethyl)phenylacetate (1.0 g, 3.3 mmol) in dry toluene (15 ml) under a nitrogen atmosphere at room temperature. After 3 hours at room temperature the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried and the ethyl acetate removed to give (E)-methyl 2-[2-(6-chloropyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (1.04 g, 95%) as a brown gum which was used in the final stage without further purification; 1H NMR(270 MHz)δ: 3.75(3H,s), 5.29(2H,s), 6.65(1H,d), 6,90(1H,d), 7.15-7.60(6H,m), 11.98(1H,d) ppm.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=2[CH3:17])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([S:20][CH2:21][CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH2:18]([S:20][CH2:21][CH2:22][O:16][C:12]1[CH:11]=[C:10]([CH3:17])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)=[C:14]([CH3:15])[CH:13]=1)[CH3:19]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Reactant: CCSCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Temperature: 95 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a solution of 3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol (1.83 g, 8.00 mmol) and 2-chloroethyl ethyl sulfide (1.07 mL, 12.0 mmol) in N,N-dimethylformamide (15 mL) were added potassium carbonate (1.33 g, 9.60 mmol) and potassium iodide (0.132 g, 0.800 mmol), and the mixture was stirred at 95° C. for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50) to give the title compound (1.19 g, yield 47%) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1.[F:20][C:21]([F:28])([F:27])[C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:9][O:8][C:7]1[C:3]([CH2:2][N:24]2[CH:25]=[CH:26][C:22]([C:21]([F:28])([F:27])[F:20])=[N:23]2)=[N:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:6]=1
Reactant: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1Cn1ccc(C(F)(F)F)n1
Temperature: 55 °C
Reaction time: 1.25 h

Procedure:
To a solution of 4-(bromomethyl)-5-methoxy-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole (i.e. the product of Example 1, Step D) (0.25 g, 66 weight %, 0.5 mmol) in N,N-dimethylformamide (2 mL total), was added 3-(trifluoromethyl)pyrazole (0.082 g, 0.6 mmol) and anhydrous potassium carbonate (0.21 g, 1.5 mmol). The mixture was heated to 55° C. and stirred for 75 min. The reaction mixture was cooled to 23° C., diluted with water (20 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0 to 40% ethyl acetate in hexanes to afford the title compound (0.098 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)Cc1ccc(N)cc1Cl
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of methyl 2-(2-chloro-4-nitrophenyl)acetate (step 3, 3.6 g, 15.6 mmol) in ethanol/water (4/1) were added Fe (4.4 g, 78.0 mmol) and NH4Cl (409 mg, 7.8 mmol). The mixture was stirred for 1 h under reflux temperature. The solvent was removed and the residue was diluted with CH2Cl2. The mixture was washed with brine, dried (MgSO4) and concentrated to give 2.59 g (83%) of title compound as orange oil.
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH3:10])[CH2:3][NH:4][C:5]([NH:7][CH2:8][CH3:9])=O.S(Cl)(Cl)=O>C(Cl)Cl>[CH2:8]([NH:7][C:5]1[O:11][C:2]([CH3:1])([CH3:10])[CH2:3][N:4]=1)[CH3:9]
Reactant: CCNC(=O)NCC(C)(C)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCNC1=NCC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of N-(2-methyl-2-hydroxypropyl)-N′-ethylurea (7.2 g, 45 mmol) in CH2Cl2 (100 mL) at 0° C. was added a solution of thionyl chloride (5.4 g, 45 mmol) in CH2Cl2 (20 mL). The mixture was warmed to ambient temperature. After 2 hours, the mixture was concentrated in vacuo, and the resulting solid triturated with boiling water. The mixture was cooled to ambient temperature and made basic by addition of saturated aqueous K2CO3. The mixture was extracted with methylene chloride, dried over K2CO3, and concentrated in vacuo to afford 3.2 g (50% yield) of 2-ethylamino-5,5-dimethyloxazoline; NMR (DMSO-d6/TFA) 3.2 (s, 2), 3.0 (q, 2), 1.3 (s, 6), 1.0 (t, 3) ppm.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.C(O)=O.C([NH2:16])=O.Cl>C(O)C>[Br:10][C:6]1[CH:5]=[C:4]([CH:2]([NH2:16])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: NC=O
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cl
Solvent: CCO
Solvent: O=CO
Product: CC(N)c1cccc(Br)c1
Temperature: 220 °C

Procedure:
A mixture of commercially available 3-bromoacetophenone (30 g, 0.1508 mol), formic acid (47 ml) and formamide (70 ml) was heated to 220° C. for 5 h. The brown liquid obtained was cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated to provide a brown liquid. Ethanol (375 ml) and conc.HCl (75 ml) were added to the brown liquid and the reaction mixture refluxed over night. Ethanol was removed completely under reduced pressure and the aqueous layer was washed with ether and ethyl acetate to remove all non-basic impurities. The aqueous layer was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, and concentrated to provide 26 g (86.65%) of A1.13a This compound was taken to the next step with out further purification. 1H NMR (CDCl3, 300 MHz) δ 1.38 (d, 3H), 4.1 (q, 1H), 7.2 (m, 1H), 7.27 (m, 1H), 7.37 (m, 1H), 7.51 (s, 1H). LS-MS (M−H)+=200.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:18])=[O:19]
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1ccc(C)c(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 81 %

Procedure:
2,5-Dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,5dimethylbenzenesulfonyl chloride according to the procedures described in Example 40b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give off-white crystals, m.p. 102°-104° C., yield 81%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1)[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.CO>CS(C)=O>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:18]([C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[Cl:15])[NH:13][C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1ccc(N)c(N)c1
Reactant: O=Cc1ccccc1Cl
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)Nc1ccc2nc(-c3ccccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A freshly prepared solution of (3,4-diamino-phenyl)-carbamic acid ethyl ester in DMSO (0.2 M, 0.10 mL) was placed in a vial. To it was added 2-chloro-benzaldehyde (0.2 M in toluene, 0.12 mL), followed by FeCl3 (0.02 M in THF, 0.050 mL). The mixture was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give [2-(2-chloro-phenyl)-3H-benzoimidazol-5-yl]-carbamic acid ethyl ester: MS (m/z) 315.97 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][CH:10]=1.[Br:16]N1C(=O)CCC1=O>O1CCCC1>[Br:16][C:9]1[CH:10]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[NH:7][C:8]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1csc(-c2ccc(-c3cccs3)[nH]2)c1
Solvent: C1CCOC1
Product: Brc1cc(-c2cccs2)[nH]c1-c1cccs1
Reaction time: 4 h
Yield: 46.6 %

Procedure:
To a solution of 2,5-dithienylpyrrole (130 mg, 0.56 mmol) in 2.5 mL of anhydrous tetrahydrofuran cooled to -78° C. was added N-bromosuccinimide (99.68 mg, 0.56 mmol). After addition was complete the cooling bath was removed and the reaction mixture was allowed to stand in a -20° C. freezer for 4 hours, during which the solution became a brown color. The reaction mixture was concentrated under reduced pressure, carbon tetrachloride was added to precipitate the succinimide, and this mixture was filtered. The filter cake was washed with additional chloroform, the combined filtrates were concentrated, and the resulting oil was chromatographed on silica gel (50 g). Elution with hexane-ethyl acetate, 4:1, furnished 81 mg (46%) of 3-bromo-2,5-dithienylpyrrole.