Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:7]=2[O:6][C:5]=1[C:16]([O:18]CC)=[O:17])(=[O:3])N.[OH2:21]>S(=O)(=O)(O)O>[OH:15][C:13]1[CH:12]=[CH:11][C:8]2[C:9](=[O:10])[C:4]([C:1]([OH:3])=[O:21])=[C:5]([C:16]([OH:18])=[O:17])[O:6][C:7]=2[CH:14]=1
Reactant: O
Reactant: CCOC(=O)c1oc2cc(O)ccc2c(=O)c1C(N)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1oc2cc(O)ccc2c(=O)c1C(=O)O

Procedure:
A mixture of 2.0 g (7.2 mmol) of ethyl 3-carbamoyl-7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate in 10 ml of 80% sulfuric acid was heated over a steam bath for 1 hr. and then poured into 50 ml of water. This was filtered and the filtrate evaporated in vacuo. The gummy residue was triturated with a minimum amount of water, the solid filtered and dried, mp 255°-257°C.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[Li]CCCC.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Br:22])[CH:16]=1.Cl>C1COCC1.O>[Br:22][C:17]1[CH:16]=[C:15]([C:14]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:13])[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: Cc1cncs1
Reactant: COC(=O)c1cc(Cl)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)c2cc(Cl)cc(Br)c2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
To a stirring mixture of 5-methylthiazole (4.37 g, 44.1 mmol) in dry THF (30 L) under was added n-BuLi (44.1 mmol, 17.64 ml solution in hexanes) drop wise over 10 minutes at −78° C. under nitrogen atmosphere. The mixture was stirred between −78° C. and −60° C. for 30 minutes and then cooled to −78° C. A solution of 3-Bromo-5-chloro-benzoic acid methyl ester (11.0 g, 44.1 mmol) in THF (20 mL) was added drop wise over 10 minutes. The resulting mixture was stirred at −78° C. for 30 minutes and warmed to room temperature with stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL). The resulting mixture was adjusted to pH around 6 with HCl (1N) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc mixtures to afford (3-Bromo-5-chloro-phenyl)-(5-methyl-thiazol-2-yl)-methanone (14 g, yield=100%) as a solid.
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)[C:17]2[NH:26][C:27]4[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=4[C:16]=2[CH2:15][CH2:14]3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[CH3:34][O:33][C:31]1[CH:32]=[C:27]2[C:28]([CH2:16][CH2:15][C:14](=[O:3])[N:26]2[CH3:17])=[CH:29][CH:30]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccc2c(c1)N(C)C(=O)CC2

Procedure:
Under nitrogen, combined 3.2 g of 7-Hydroxy-3,4-dihydro-1H-quinolin-2-one (0.0196 mol) with 25 ml of THF. Added 5.1 g of potassium t-butoxide (0.0451 mol) and stirred for 1.25 hours. Added 4.3 ml of dimethyl sulfate (0.0451 mol), followed by 10 ml of THF and stirred overnight. The reaction mixture was diluted with EtOAc and extracted three times with H2O, dried (MgSO4), and evaporated under reduced pressure. Purified by chromatography on Biotage Flash 40, eluting with 3:1 Hexanes/EtOAc to give 1.7 g of white solid (45%). 1H NMR (400 MHz, CDCl3) δ 2.62 (2H, q, J=5.39 Hz), 2.83 (2H, q, J=6.85 Hz), 3.32 (3H, s), 3.81 (3H, s), 6.53 (1H, d, J=2.49 Hz), 6.54 (1H, d, J=1.87 Hz), 7.05 (1H, d, J=7.68 Hz). M/z (APCI+) 192.1 (M+1). HPLC (aqueous 200 mM ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 uM, 125×4 mm column) 4.068.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:5]([NH:6][CH3:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1.C1CCCCC=1.C(=O)([O-])[O-].[Na+].[Na+].[N:28]([C:31]1[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=1[CH3:39])=[C:29]=[S:30]>C(O)C.[Pd]>[NH2:10][C:8]1[C:5]([NH:6][CH3:7])=[C:4]([NH:13][C:29]([NH:28][C:31]2[C:32]([CH3:39])=[CH:33][C:34]([CH3:38])=[CH:35][C:36]=2[CH3:37])=[S:30])[CH:3]=[C:2]([F:1])[CH:9]=1
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Reactant: CNc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CNc1c(N)cc(F)cc1NC(=S)Nc1c(C)cc(C)cc1C
Yield: 32.4 %

Procedure:
In 75 mL of ethanol was mixed 1.30 g (6.04 mmol) of 4-fluoro-N-methyl-2,6-dinitroaniline, 3.7 mL (36 mmol) of cyclohexene and 5.1 g (2.4 mmol, 40 mol %) of 10% palladium on carbon (50% water, Degussa type). The mixture was refluxed for 2.5 h and filtered into a flask containing 0.77 g (7.3 mmol) of sodium carbonate and 1.07 g (6.04 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The resulting slurry was refluxed for 4 h, concentrated and slurried in dichloromethane. The slurry was filtered, concentrated and purified by flash chromatography eluting with a 70% hexanes/ethyl acetate mixture to give 0.65 g (32%) of the title compound as an off-white solid.
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#N.S(=O)(=O)(O)O.O.[C:32]([OH:35])(=[O:34])[CH3:33]>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:33]([C:32]([OH:35])=[O:34])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
Quantities: compound 57 (17.00 g, 0.051 mol), concentrated sulphuric acid (40 ml), water (40 ml), glacial acetic acid (200 ml).
Reaction SMILES: C([Li])CCC.[OH:6][C:7]([C@@H:10]1[C@@H:13]([CH2:14][CH:15]=[CH2:16])[N:12]([C:17](=[C:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:11]1=[O:25])([CH3:9])[CH3:8].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(O)(=O)C>O1CCCC1>[CH3:23][C:22]([CH3:24])=[C:17]([N:12]1[C@H:13]([CH2:14][CH:15]=[CH2:16])[C@@H:10]([C:7]([CH3:9])([O:6][C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:28])[CH3:8])[C:11]1=[O:25])[C:18]([O:20][CH3:21])=[O:19]
Reactant: C=CC[C@@H]1[C@@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@H](C(C)(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
A solution of n-butyl lithium (0.42 ml of 1.55M solution in hexane) was added to a solution of methyl 2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (150 mg) in tetrahydrofuran (3 ml) during 3 minutes at -70° C. and the mixture was stirred for 5 minutes at -70° C. A solution of p-nitrobenzyl chloroformate (161 mg) in tetrahydrofuran (1.6 ml) was added to the mixture during 5 minutes at -70° C. and the mixture was stirred for 15 minutes at -70° C. The mixture was allowed to warm to 0° C. during 30 minutes and stirred for 2 hours at 0° C. Acetic acid (0.037 ml) was added to the mixture at 0° C. and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate ( 50 ml), and the sodium was washed with water (10 ml), 10% phosphoric acid (10 ml), phosphate buffer (pH 7.0) (10 ml×2), aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of hexane and ethyl acetate (5:1-1:1) to give methyl 3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate (135 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN(C)C=O.C(O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH:27]1[CH2:28][CH2:29][N:30]([CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)[CH2:31][CH2:32]1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: Clc1cccc(OC2CCNCC2)c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Oc2cccc(Cl)c2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(3-chlorophenoxy)-piperidine (Table No.1, SM 7) in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=497.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:18])[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:18][C:8]1[C:7](=[O:19])[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[CH:9]=1
Reactant: CSc1ncc2cc(C)c(=O)n(C3CCCC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ncc2cc(CBr)c(=O)n(C3CCCC3)c2n1
Reaction time: 3 h
Yield: 32 %

Procedure:
8-Cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.5 g, 12.7 mmol) and N-bromosuccinimide (2.6 g, 14.6 mmol) in carbon tetrachloride (100 ml) were irradiated with ultraviolet light allowing the temperature to reach 45° C. over 3 hours. The mixture was filtered, washed with dilute sodium sulfite solution, then brine, and dried over anhydrous magnesium sulfate. The crude product was chromatographed on silica gel eluting with 1:1 ethyl acetate:hexane to provide 6-bromomethyl-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a crystalline solid yielding (1.46 g, 32% yield), mp 103–105° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[N:8]=2)=[CH:5][C:4]([CH3:15])=[N:3]1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[C:12]([O:13][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=[C:9]([CH3:14])[N:8]=2)=[CH:5][C:4]([CH3:15])=[N:3]1
Reactant: Cc1ccc(O)c(-c2cc(C)nn2C)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cc(C)nn3C)c2cc1OC
Temperature: 140 °C
Reaction time: 4 h
Yield: 23.7 %

Procedure:
2-(2,5-Dimethyl-2H-pyrazol-3-yl)-6-methyl-pyridin-3-ol (33 mg), 4-chloro-6,7-dimethoxyquinoline (109 mg), and 4-dimethylaminopyridine (66 mg) were dissolved in dimethyl sulfoxide (5 ml) to prepare a solution. Cesium carbonate (165 mg) was added to the solution, and the mixture was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (15 mg, yield 23%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C[O-].[Na+].C(NC1C=CC(S)=CC=1)(=O)C.[Na].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Cl)[N:29]=1>CS(C)=O>[Cl:27][C:28]1[N:29]=[C:30]([S:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(Sc2cccc(Cl)n2)cc1
Temperature: 100 °C

Procedure:
4-Acetamidothiophenol (16.8 grams; 0.1 mole) was mixed with a solution of sodium methylate (prepared by mixing sodium metal (2.3 grams; 0.1 mole) in 90 ml. of methanol) and the resulting sodium 4-acetamidothiophenol solution added over a period of about 1 hour to a well-stirred solution of 2,6-dichloropyridine (14.8 grams; 0.1 mole) in 100 ml. of dimethylsulfoxide. The reaction mixture was distilled during the addition and the reaction temperature maintained at about 100° C. for this period and for a period of about 2 hours thereafter. The reaction mixture was then poured into 350 ml. of water and the resulting product precipitate recovered by filtration, washed several times and taken up in 300 ml. of hot benzene and dried and treated with Norite. About 350 ml. of hexane was added to precipitate the product from the benzene solvent which was recovered by filtration. As a result of such operations, the desired N-(4-((6-chloro-2-pyridinyl)thio)phenyl)acetamide compound was recovered as a crystalline solid which was found to have carbon, hydrogen, nitrogen, chlorine and sulfur contents of 56.2, 4.3, 9.9, 11.4 and 11.63 percent, respectively, as compared with the theoretical contents of 56.0, 3.96, 10.05, 12.7 and 11.45, respectively, calculated for the named structure.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][C:24]=1[N+:37]([O-:39])=[O:38]>CN(C=O)C.CCOCC>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][O:12][C:3]2[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])=[C:24]([N+:37]([O-:39])=[O:38])[CH:25]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1OCCBr
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1OCCOc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 70 °C
Yield: 69.4 %

Procedure:
2,3-Difluoro-6-nitrophenol (0.7 g, 3.7 mmol) was stirred with K2CO3 (0.5 g, 3.7 mmol) in DMF (10 mL) for 10 min. Bromoethane 6 (1.1 g, 3.1 mmol) was added to the reaction mixture and heated at 70° C. for 24 hrs. The reaction mixture was diluted with ether (30 mL) and washed with water (20 mL) and then brine (20 mL). The ether layer was dried (MgSO4) and concentrated under reduced pressure. Fractionation of the crude product by flash chromatography with 4:1 hexane/ethyl acetate provided 7 as a yellow oil (960 mg, 63%). 1H NMR: 4.45 (t, J=5 Hz, 2H), 4.71 (t, J=5 Hz, 2H), 5.05 (s, 2H), 7.0-7.7 (m, 10H)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:9]([C:13]([F:16])([F:15])[F:14])=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].Br[CH2:18][C:19]([NH:21][C:22]1[S:26][C:25]2[CH2:27][CH2:28][CH2:29][CH2:30][C:24]=2[C:23]=1[C:31]([NH2:33])=[O:32])=[O:20].O>CN(C=O)C>[C:31]([C:23]1[C:24]2[CH2:30][CH2:29][CH2:28][CH2:27][C:25]=2[S:26][C:22]=1[NH:21][C:19](=[O:20])[CH2:18][N:11]1[CH:12]=[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])[C:9]([C:13]([F:15])([F:16])[F:14])=[N:10]1)(=[O:32])[NH2:33]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 120 °C
Yield: 19 %

Procedure:
NaH (60% [w/w] suspension in oil, 10 mg, 0.25 mmol) was added to a solution of ethyl-3-(trifluoromethyl)pyrazole-4-carboxylate (25 mg, 0.056 mmol) in DMF (2 mL). The reaction mixture was stirred at RT for 60 min before the addition of 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide. The reaction mixture was heated at 120° C. for 10 min in the microwave. Water (5 μL) was added and the reaction mixture extracted with EtOAc (3×10 mL). The combined EtOAc layers were washed with water (5×5 mL), brine (5 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure to give the crude reaction mixture as a yellow solid (44 mg, 0.01 mmol). Purification by preparative reverse phase HPLC gave the desired product (10 mg, 0.024 mmol, 19%).
Reaction SMILES: [CH2:1]([C:5]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:43](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:8]2[CH:9]([C:21]([O:23][CH3:24])=[O:22])[N:10]([C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1>C(O)=O>[CH2:1]([C:5]1[N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[CH:31][CH:32]=2)[C:8]2[CH:9]([C:21]([O:23][CH3:24])=[O:22])[N:10]([C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2
Solvent: O=CO
Solvent: C1CCOC1
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a mixture of methyl (+)-2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (395 mg) and tetrahydrofuran (4 ml) is added 90% formic acid (8 ml) under ice-cooling, and the mixture is stirred at-room temperature for 30 minutes, and evaporated under reduced pressure to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give methyl (+)-2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (270 mg) as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[N:22]1([CH2:27][C:28](O)=[O:29])[CH:26]=[N:25][N:24]=[N:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:28](=[O:29])[CH2:27][N:22]3[CH:26]=[N:25][N:24]=[N:23]3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)Cn1cnnn1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1cnnn1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 57.4 %

Procedure:
Preparation of example 12 from the title compound of Example 7 (15 mg, 0.054 mmol), tetrazol-1-yl-acetic acid (8 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Additional tetrazol-1-yl-acetic acid acid (1.0 mg, 0.008 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.0 mg, 0.008 mmol) were added after c.a. 18 hours to drive the reaction to completion. Filtration, concentration and recrystallization afforded the title compound (12 mg, 0.031 mmol) as a yellow powder in 58% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)[C:9]=2[F:34])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=3)[C:22]#[N:23])(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:24][NH:25][CH3:26])[C:9]=2[F:34])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2Cl)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.8 %

Procedure:
To a solution of tert-butyl ({5-(2-chloropyridin-3-yl)-1-[(3-cyanophenyl)sulfonyl]-4-fluoro-1H-pyrrol-3-yl}methyl)methylcarbamate (489 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give a free base of the title compound as a pale-yellow oil (yield 152 mg, 39%). A solution of the obtained free base in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (44 mg) in ethanol (4 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 127 mg, 28%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[OH:24].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[O:24][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.59 g (0.0525 moles) of 2-chloro-5-nitrobenzonitrile, 9.96 g (0.0541 moles) of 2,3,4,5,6-pentafluorophenol, 7.56 g (0.0541 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of deionized water. The product separated as a crystalline solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from 200 ml of absolute ethanol to give 9.91 g (57% yield) of purified 2-(2,3,4,5,6-pentafluorophenoxy)-5-nitrobenzonitrile, mp 127.5°-129° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[Cl:14])[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1OCC)C=[O:20]>>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:20])=[O:11])=[CH:8][C:7]=1[Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C=O)cc1Cl
Reactant: CCOc1ccc(C=O)cc1Cl
Product: CCCCOc1ccc(C(=O)O)cc1Cl
Yield: 85 %

Procedure:
When the product of Step A was substituted for 3-chloro-4-ethoxybenzaldehyde in Example 49, Step A the identical process afforded the title compound in 85% yield. 1H-NMR (CDCl3) 0.96 (tr, 3H, J=7.38 Hz); 1.46-1.57 (m, 2H); 1.59-2.77 (m, 2H); 4.1 (tr, 2H, J=6.45 Hz); 6.93 (d, 1H, J=8.67 Hz); 7.96 (dd, 1H, J=8.64, 2.1 Hz); 8.1 (d, 1H, J=2.07 Hz).