Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Cl.O>CN(C)C=O>[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Reactant: Fc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4ccccc4F)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Sodium hydride (60%, oily, 36.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (360 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 2-Fluorobenzyl chloride (0.119 ml) was added to this mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[6-(2-fluorobenzyloxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (404 mg, yield: 88%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([NH:11][S:12]([CH2:15][CH2:16][CH2:17][N:18]=[N+]=[N-])(=[O:14])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([NH:11][S:12]([CH2:15][CH2:16][CH2:17][NH2:18])(=[O:13])=[O:14])[C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:10]
Reactant: CCOC(=O)C(NS(=O)(=O)CCCN=[N+]=[N-])C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(NS(=O)(=O)CCCN)C(=O)OCC
Yield: 105.3 %

Procedure:
A solution of 3-azidopropanesulfonamidomalonate diethyl ester (27.60 g, 0.086 mol,) in ethanol (70 mL) and 1 g of Pd/C (10%) were placed in a Parr hydrogenation apparatus under 60 psi H2 for 8 hours. The hydrogen was replenished every 2 hours. The mixture was filtered through a pad of Celite and a solution of 1 N HCl in ethanol (10 mL) was added to the filtrate. The solvent was removed in vacuo and the residue was purified by column chromatography on Al2O3 using CH2Cl2/MeOH (4/1, v/v) to give 26.84 g of the title compound as the hydrochloride salt: 1H NMR (CDCl3) δ 1.30 (t, 6, CH3), 2.12 (m, 2, OCH2CH3), 3.21 (t, 2, CH2), 3.50 (t, 2, CH2), 4.26 (m, 4, OCH2CH3), 4.84 (d,1, CH), 6.09 (d, 1, NH), 8.29 (br.s, 2, NH3). 13C NMR (CDCl3) 613.6, 26.3, 42.5, 51.2, 58.5, 62.7, 165.9.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[C:20]([C:24](O)=O)=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][NH:22][N:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
4-Morpholin-4-ylmethyl-benzene-1,2-diamine (1 mol. eq.) and 4-nitro-1H-pyrazole-3-carboxylic acid (1 mol. eq.) were dissolved in dimethylformamide (DMF) (10 vol.). O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (1.2 mol. eq.) was added and the mixture was stirred at ambient temperature for 24 hours. The mixture was concentrated in vacuo until no further solvent was seen to distil. The residue was then dissolved in glacial acetic acid (10 vol.) and heated at 65° C. for ˜12 hours. The mixture was concentrated in vacuo and then dissolved in water (6 vol.) at 75° C. The black solution was cooled to 0-5° C. over 2 hours during which time a solid was formed. The solid was removed by filtration and the aqueous filtrate was diluted with ethyl acetate (4 vol.) and tetrahydrofuran (2 vol.). Solid NaHCO3 was added slowly to the stirred mixture until no further effervescence was observed and a pH of 6.8 was reached. The mixture was then stirred until a precipitation was observed. After standing the mixture at 0-5° C. for 2 hours, the solid was collected by filtration and washed with water (2 vol.) and ethyl acetate (2 vol.) and dried to give 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl)1H-benzimidazole as a brown solid (40%). (LC/MS (basic method): Rt 1.93, [M−H+]− 327).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1.C([SnH2][C:18]1[CH:23]=[CH:22][N:21]=[N:20][CH:19]=1)(C)(C)C.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:20]1[CH:19]=[CH:18][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=3[CH:12]=2)=[CH:22][N:21]=1
Reactant: CC(C)(C)[SnH2]c1ccnnc1
Reactant: OCc1cc2cc(Br)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1cc2cc(-c3ccnnc3)ccc2o1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a solution of (5-bromo-benzofuran-2-yl)-methanol (1.6 g, 3.7 mmol) and 4-tert-butylstannanyl-pyridazine (1 g; 4.4 mmol) in 15 mL dry toluene, was added tetrakis(triphenylphosphine)palladium (0) (130 mg). The mixture was stirred at 95° C. overnight. After allowing the mixture to come to room temperature, the solution was poured into water, extracted, dried over MgSO4, and filtrated to afford 2.4 g of crude product that was further purified by chromatography to afford (5-pyridazin-4-yl-benzofuran-2-yl)-methanol.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5](C2C=CC=CC=2)[C:4](=O)[C:3]=1CCO.[OH-].[Na+]>S(=O)(=O)(O)O>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][N:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: O=c1c(CCO)c(O)c2cccnc2n1-c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCNc2ncccc21
Reaction time: 8 h

Procedure:
A solution of 4-hydroxy-3-(2-hydroxyethyl)1-phenyl-1,8-naphthyridin-2-(1H)-one (10 g.) in 30% (v/v) sulfuric acid (200 ml.) was heated to reflux, in an atmosphere of nitrogen, and was held at reflux until no further reaction occured (ca. 5-8 hrs.). After cooling, the solution was added slowly and carefully to an icecooled solution of sodium hydroxide (50% solution; 200 ml.). The mixture was allowed to stand overnight and was then filtered. The product was washed with water, dried in air and recrystallized from dimethylformamide/water, with charcoal treatment, to yield the product, m.p. 276°-277.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C:8]1([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13](=[O:14])[O:12]C(C)(C)[O:10][C:9]1=[O:17])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:22]([O:21][C:19](=[O:20])[CH2:18][C:8]([C:13]([OH:14])=[O:12])([C:9]([OH:17])=[O:10])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:26])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)OC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CC(CC(=O)OC(C)(C)C)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound of Example 165 (200 mg, 0.54 mmol) was dissolved in a mixture of THF (10 mL) and water (2 mL). Lithium hydroxide monohydrate (46 mg, 1.07 mmol) was added and the mixture was stirred for 24 h at room temperature. The solvent was evaporated and the residue was dissolved in water (5 mL) and extracted with ether. The water phase was acidified by HCl to pH1 and extracted with ethyl acetate. After drying over sodium sulfate, filtration and evaporation, the solvent was evaporated to dryness. 1H NMR(CDCl3, 300 MHz): 1.43(s, 18H); 3.10(s, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[C:9](=[O:12])[C:10]#[CH:11])[CH:5]=[CH:4][CH:3]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]2[C:6]([CH:5]=[CH:4][CH:3]=1)=[C:8]([C:13]1[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=1[Cl:19])[C:9](=[O:12])[CH:10]=[CH:11]2
Reactant: C#CC(=O)C(c1cccc(Cl)n1)c1c(Cl)cccc1Cl
Solvent: c1ccncc1
Product: O=c1ccn2c(Cl)cccc2c1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of 1-(6-chloropyridin-2-yl)-1-(2,6-dichlorophenyl)but-3-yn-2-one (Step A above, 102 mg) in pyridine (7 mL) was heated to 90° C. for about 1½ hr and cooled to room temperature. The mixture was evaporated and purified by silica gel (methylene chloride/acetone=3/1) to give desired product as a yellowish solid (90 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.[CH3:23][CH2:24][C:25]([C:27]1[CH:32]=[C:31]([F:33])[C:30](O)=[C:29]([F:35])[CH:28]=1)=[O:26]>>[F:33][C:31]1[CH:32]=[C:27]([C:25](=[O:26])[CH2:24][CH3:23])[CH:28]=[C:29]([F:35])[C:30]=1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:8])[C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])[CH2:3]1
Reactant: CCC(=O)c1cc(F)c(O)c(F)c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Product: CCC(=O)c1cc(F)c(OC2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)C2)c(F)c1
Yield: 21 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone and 3,5-difluoro-4-hydroxypropiophenone. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 21%). MS (m/e): 496.5 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1.Cl>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:14]1[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:13]1=[O:21])[CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCC2=O
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Nc1ccc2c(c1)CCC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Yield: 5 %

Procedure:
A mixture of 0.5 g 5-amino-1-indanone, 1.3 g oxindole and 3 ml piperidine in 5 ml of dimethylforamide was heated in a sealed tube at 130° C. for 3 days to yield a reddish-black suspension. The mixture was added to 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate and concentrated. Chromatography afforded 45 mg of 3-(5-aminoindan-1-ylidene)-1,3-dihydroindol-2-one as a brown solid.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:14])=[C:11]([F:13])[F:12])(=O)=O.[N:15]1[S:19][N:18]=[C:17]2[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:16]=12.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[N:15]1[S:19][N:18]=[C:17]2[CH:20]=[C:21]([C:24]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:14])=[C:11]([F:13])[F:12])=[O:25])[CH:22]=[CH:23][C:16]=12
Reactant: O=C(O)c1ccc2nsnc2c1
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCCCOC(=O)c1ccc2nsnc2c1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To 30 ml of ethanol was dissolved 2.0 g (10 mmol) of methyl benzo[1,2,5]thiadiazole-5-carboxylate, followed by the addition of 3.3 g of a 25% aqueous solution of sodium hydroxide and stirring at room temperature for 3 hours. To the reaction liquid was added 50 ml of water and a dilute hydrochloric acid to make pH of 2. Crystal precipitated was filtered off and dried under reduced pressure to obtain 1.7 g (yield: 92%) of benzo[1,2, 5]thiadiazole-5-carboxylic acid. In a separate reactor, 0.50 g (2.2 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.43 g (2.4 mmol) of benzo[1,2,5]thiadiazole-5-carboxylic acid were dissolved in 7 ml of N,N-dimethylformamide, followed by the addition of 0.37 g (4.4 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 0.44 g (yield: 64%) of 6,6-difluoro-5-methyl-5-hexenyl benzo[1,2,5]thiadiazole-5-carboxylate.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>O.C(#N)C>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@:11]([CH2:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH3:23])([OH:12])[CH2:10]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: Cc1ccccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1C[C@]1(O)C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1CO
Yield: 20.4 %

Procedure:
A 1.14 g quantity of potassium hydroxide was dissolved in a mixture of 33 ml of water and 16 ml of acetonitrile. To the solution were added 1.00 g of 2'-deoxy-5-fluorouridine and 1.50 g of 2-methylbenzyl bromide at room temperature with stirring. Then the same subsequent procedures as in Examples 4 and 5 were conducted, giving 0.29 g of the title compound in a yield of 20%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.CC(C)=[O:24]>O.[N+]([O-])([O-])=O.[Ag+]>[OH:24][CH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: FC(F)(F)c1cccc(-c2ccc3nnc(CCl)n3n2)c1
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: OCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A 1.0 g. sample of 3-(chloromethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine is heated (50°-60° C.) in a mixture of acetone and water in the presence of silver nitrate. The mixture is filtered and the filtrate concentrated to give the product of the Example.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][C:9]2[S:10][C:11]([CH3:16])=[CH:12][C:13]=2[C:14]#[N:15])[CH:7]=1.Cl.[Sn](Cl)[Cl:22]>CCO>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:14]([NH2:15])[C:13]3[CH:12]=[C:11]([CH3:16])[S:10][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: Cc1cc(C#N)c(Nc2cc(F)ccc2[N+](=O)[O-])s1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(s1)Nc1cc(F)ccc1N=C2N
Temperature: 85 °C
Yield: 87.2 %

Procedure:
Stir 2-(5-fluoro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile (113 g, 0.408 mol) as a suspension in EtOH (1.1 L) at ambient temperature. Add aqueous 6N HCl (1.1 L) and tin (II) chloride (232 g, 1.22 mol) with stirring. Heat to gentle reflux (85° C.) for 3-4 hours, and then allow cooling to ambient temperature. Filter the crude product and rinse with 1:1/EtOH:6N HCl, then deionized water, and dry in a vacuum oven at 50° C. to constant weight. Stir the crude product (139 g) as a suspension in aqueous 1N HCl (6 L) at gentle reflux (95° C.) for 2 hours, and then allow cooling to ambient temperature. Filter the product and rinse with 1N HCl and water, then dry at 50° C. to give 101 g (87%) the title compound: 1H NMR (400 MHz, DMSO-d6) δ 11.33 (bs, 1H), 9.80 (s, 1H), 9.16 (bs, 1H), 8.88 (bs, 1H), 6.99 (m, 1H), 6.89 (m, 1H), 6.84 (s, 1H), 2.28 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H11ClFN3S 248.0658; found 248.0657.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:42][C:43]1[N:47]([CH2:48][CH2:49][CH3:50])[CH:46]=[N:45][N:44]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH2:42][C:43]5[N:47]([CH2:48][CH2:49][CH3:50])[CH:46]=[N:45][N:44]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCn1cnnc1CCl
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CC(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(OCc4nncn4CCC)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-(4-hydroxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g), 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (0.22 g) and potassium carbonate (0.4 g), N,N-dimethylformamide (10 ml) was added, and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-4H-1,2,4-triazol-3-yl)methoxy]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 26) (0.47 g) as pale yellow amorphous.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]=12.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O.C(Cl)Cl>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([Cl:16])=[O:12])[CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc2nonc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 0.84 g (5.0 mmoles) benzofurazan-5-carboxylic acid and 1 drop dimethylformamide in 20 ml methylene chloride cooled in an ice-bath was added 0.70 g (5.5 mmoles) oxalyl chloride. The solution was warmed to room temperature, stirred for 3 hours, and the solvent was removed in vacuo. The residual oil was extracted with 3×15 ml warm hexane. The combined extract was evaporated to dryness, the resulting solid was stirred under 2 ml cold hexane, the hexane was decanted, and the solid was dried to give 0.895 g (98%) crude benzofurazan-5-carbonyl chloride.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:29][C@@H:30]([CH2:49][CH3:50])[C@H:31]([N:35]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[C:36]1=[O:48])[C:32](O)=[O:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][C:32](=[O:33])[C@@H:31]([N:35]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[C:36]1=[O:48])[C@@H:30]([CH3:29])[CH2:49][CH3:50])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
A solution of the product from Example 6A (0.046 g, 0.119 mmol) in THF (0.9 mL) was treated with the product from Example 7B (0.050 g, 0.119 mmol), EDAC (0.035 g, 0.183 mmol), HOBT (0.025 g, 0.185 mmol), and NMM (0.040 mL, 0.364 mmol) at 0° C., stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, dilute sodium bicarbonate solution, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.080 g, 100% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([O:26][C:27]1[C:28]([C:41](Cl)=[O:42])=[N:29][N:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[CH:31]=1)[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41]([C:28]2[C:27]([O:26][CH2:24][CH3:25])=[CH:31][N:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=3)[N:29]=2)=[O:42])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCOc1cn(-c2cccc([N+](=O)[O-])c2)nc1C(=O)Cl
Product: CCOc1cn(-c2cccc([N+](=O)[O-])c2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X3 was prepared from A2 and 4-ethoxy-1-(3-nitrophenyl)-1H-pyrazole-3-carbonyl chloride, which was prepared similar to Preparative Example 16 step 1-4. MS (ES) C29H24N5O7 requires: 573. Found: 574 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:12][CH3:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:23]([O:22][C:20]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[S:3][C:4]([NH:12][CH3:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)[CH2:16][CH2:15]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1nc(Br)sc1NC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1NC
Temperature: 100 °C
Yield: 35.2 %

Procedure:
To a solution of ethyl 2-bromo-5-methylamino-thiazole-4-carboxylate (401 mg, 1.512 mmol) and tert-butyl piperazine-1-carboxylate (1.06 g, 5.69 mmol) in anhydrous dioxane (15 ml) was added DIPEA (2 ml, 11.5 mmol) and the reaction was heated at 100° C. in a sealed flask for 23 hours. The mixture was cooled to room temperature, partitioned between DCM and sat. sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted twice with DCM and the combined organic layers were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by column chromatography (silica, gradient from 10 to 70% ethyl acetate in n-heptane) to yield 197 mg of a white solid (0.532 mmol, yield 35%) MS (multi-mode) m/z=371.2 [M+1]+.