Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:36][O:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:36][O:37][CH2:38][CH2:39][OH:40])=[O:6]
Reactant: NOCCO
Reactant: CS(=O)(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CS(=O)(=O)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 52 %

Procedure:
The title compound was prepared from reaction of the product of Example 28, Step A, 3,4-difluoro-2-[[2-fluoro-4-(methylsulfonyl)phenyl]amino]benzoic acid, with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E. Then, after workup, the crude solid purified by dry flash column chromatography on silica (5% isopropanol/hexanes as eluant) to afford 3,4-difluoro-2-[[2-fluoro-4-(methylsulfonyl)phenyl]amino]-N-(2-hydroxyethoxy)benzamide as a white solid (52%); m.p. (Et2O) 85–88° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.78 (br s, 1 H), 8.88 (br s, 1 H), 7.72 (dd, J=11.1, 2.1 Hz, 1 H), 7.55 (ddd, J=8.8, 2.1, 0.6 Hz, 1 H), 7.48–7.35 (m, 2 H), 6.87 (td, J=8.8, 4.0 Hz, 1 H), 4.68 (br s, 1 H), 3.81 (t, J=4.6 Hz, 2 H), 3.54 (td, J=4.9, 4.2 Hz, 2 H), 3.18 (s, 3 H). Anal. Calcd for C16H15F3N2O5S: C, 47.5; H, 3.6; N, 6.9. Found: C, 47.3; H, 3.8; N, 6.6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=[N:14][OH:15]
Reactant: NO
Reactant: O=C1CCOc2c(F)cccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: ON=C1CCOc2c(F)cccc21
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 8-fluorochroman-4-one (8.2 g), hydroxylamine hydrochloride (3.78 g) and sodium acetate (4.46 g). A reflux condenser was added, the flask was purged with argon, dry EtOH (20 mL) was added, and the mixture was stirred at reflux for 18 hours. The solution was cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried, and evaporated to give the intermediate 8-fluorochroman-4-one oxime, which was reduced with Raney Nickel in EtOH at 50 PSI to yield the titled amine (4.69 g, 57%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)ccc1NS(C)(=O)=O
Temperature: 160 °C
Yield: 31.8 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 25 mg, 0.075 mmol), N-(4-hydroxy-2-methyl-phenyl)methanesulfonamide (ChemBridge Corporation, San Diego, Calif., USA; 15 mg, 0.075 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide was heated in the microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture and the precipitate was filtered through a silica plug, washing with methanol. The solvent was removed and the residue was purified by HPLC to afford 4-[4-(4-methanesulfonylamino-3-methyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (12 mg, 33%) as an off white solid. Mass Spec MH+=503.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH:6]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:8]=2[O:7]1)C.Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=1[CH2:33][CH2:34][CH3:35]>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][O:16][C:14]2[CH:13]=[CH:12][C:9]3[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:3])=[O:17])[O:7][C:8]=3[CH:15]=2)=[C:24]([CH2:33][CH2:34][CH3:35])[C:25]=1[OH:32])(=[O:31])[CH3:30]
Reactant: CCOC(=O)CC1CCc2ccc(O)cc2O1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCOc2ccc3c(c2)OC(CC(=O)O)CC3)ccc(C(C)=O)c1O
Yield: 40.5 %

Procedure:
A 0.9 g sample of racemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester was alkylated with 3 g of 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone using the procedure described in Example 31. The crude product (2.6 g) was chromatographed on 50 g of silica gel giving 1.2 g of the desired ester as a pale-yellow oil (eluted with 19:1 toluene-ethyl acetate). This material was saponified with 2.0 g of lithium hydroxide monohydrate using the procedure described in Example 31. The crude acid (1.1 g) was chromatographed on 50 g of silica gel. Elution with 2:1 and 1:1 toluene-ethyl acetate afforded 682 mg (40.5%) of racemic-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-acetic acid as a pale-yellow solid, mp 107°-109.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[CH3:30].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:26]4[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=4)[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(-c4ccccc4)n3)CC2)cc1C

Procedure:
99 mg (84%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (70 mg, 0.225 mmol), 1-(3,4-dimethylphenyl)piperazine (61 mg, 0.225 mmol), DIPEA (0.059 mL, 0.338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[N:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)=[C:9](O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=[N:11][C:10]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1
Reactant: Oc1cc(-c2ccccc2)nnc1N1CCN(c2ncccn2)CC1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc(-c2ccccc2)nnc1N1CCN(c2ncccn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
6-phenyl-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazin-4-ol (22.0 g, 66 mmol) was suspended in 75 ml phosphorus oxychloride and heated with stirring at 100° C. for 3 h. After cooling to room temperature the mixture was poured onto crushed ice. The mixture was then neutralized with NaOH solution to give white suspension. The precipitation was filtered off, washed with water, dried over fitter funnel to provide white solid (21.3 g, 60.3 mmol, 91.4%). ESI-MS: m/z 353.4 (M+H+). 1H NMR (CDCl3): d 8377 (d, J=4.5, 2H), 8.036 (d, J=7.5, 2H), 7.833 (s, 1H), 7.508 (m, 3H), 6.564 (t, J=4.5, 1H), 4.073 (t, J=4.5, 4H), 3.672 (t, J=4.5, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[C:19](S(C)(=O)=O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:28]#[N:29].[Na+].O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:28]#[N:29])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cc(Cl)nc(S(C)(=O)=O)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOc2cc(Cl)nc(C#N)n2)CC1
Reaction time: 10 h

Procedure:
To a solution of the crude 4-[2-(6-chloro-2-methanesulfonylpyrimidin-4-yl oxy)ethyl]-piperidine-1-carboxylic acid tert-butyl ester (4.9 g) and NaCN (14 mmol) in CH2Cl2:H2O (50 mL, 4:1) is added TBAB (tetrabutylammonium bromide) (0.06 mmol) at room temperature. After stirring at the same temperature for 10 h, TBAB (0.19 mml) is added to the reaction mixture. The reaction mixture is stirred at room temperature for 2 h and H2O is added. The organic layer is separated, dried over MgSO4 and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give 4-[2-(6-chloro-2-cyanopyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester; 1H-NMR (CDCl3), δ: 1.14-1.28 (2H, m), 1.45 (9H, s), 1.56-1.78 (7H, m), 2.69 (2H, t), 4.11 (2H, m), 4.49 (2H, t), 6.93 (1H, s).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)#[N:11]>O.C(O)C>[OH:3][NH:2][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[NH:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
Into a mixture of hydroxylamine hydrochloride (52 g, 748.30 mmol, 3.00 equiv) and potassium carbonate (55.5 g, 402.47 mmol, 1.60 equiv) in water (125 mL) was added a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (52.5 g, 249.68 mmol, 1.00 equiv) in ethyl alcohol (625 mL) dropwise with stirring. The resulting mixture was stirred overnight at 90° C. in an oil bath, cooled down to room temperature, filtered and concentrated under reducing pressure. The residue was diluted with 2000 mL of ethyl acetate, washed with 1×800 mL of water and dried over anhydrous sodium sulfate. Filtration and concentration under reducing pressure gave 60 g of tert-butyl 4-(N-hydroxycarbamimidoyl)piperidine-1-carboxylate as a white solid, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 245.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]=[C:3]1[S:9][CH3:10].[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3]([S:9][CH3:10])=[N:4][CH:5]=1
Reactant: CSc1nccc(=O)n1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CSc1ncc(Br)c(=O)n1C
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
3-Methyl-2-methylthio-3H-pyrimidin-4-one (Step 2, 3.31 g, 21.2 mmol) was dissolved in CHCl3 (50 mL) and cooled to 0° C. under Ar. Br2 (1.25 mL, 25.4 mmol) was added via syringe, and the reaction was stirred at 0° C. for 35 min, at which time TLC analysis indicated complete consumption of starting material. The reaction was quenched with 40 mL saturated NaHCO3, warmed to RT, and stirred overnight. The reaction was extracted with CH2Cl2 (3×25 mL), and the organic extracts were combined, dried over Na2SO4, filtered, and concentrated to give the title compound, which did not require further purification. MS (ESI pos. ion) m/z: 236. Calc'd for C6H7BrN2OS: 233.95.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[CH3:36]>N.CO>[F:29][C:30]1[CH:31]=[C:32]([S:37]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.8 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 3-Fluoro-4-methylbenzenesulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.4 mg). MS m/z 361 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH3:30])=[CH:24]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25]([CH3:30])=[CH:24]4)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(Oc3ncnc4cc(OCc5ccccc5)ccc34)ccc2[nH]1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A solution of 7-benzyloxy-4-chloroquinazoline (2 g, 7.4 mmol), 5-hydroxy-2-methylindole (1.3 g, 8.9 mmol), (prepared as described for the starting material in Example 48), in DMF (20 ml) containing potassium carbonate (1.53 g, 11.1 mmol) was stirred at 80° C. for 3 hours. After cooling, the mixture was poured in portions into ice/water. The precipitate was filtered and washed with water and dried under vacuum. The solid was dissolved in methylene chloride and was purified by column chromatography eluting with ethyl acetate and methylene chloride (1/1) to give 7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline (2.28 g, 81%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[NH:13][C:9]=2[CH:8]=[CH:7][N:6]=1.[C:15]1([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH2:23]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:21]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:13]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([O:4][CH3:3])[C:10]=2[CH:11]=[C:12]1[CH3:14]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: COc1nccc2[nH]c(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of NaH (98 mg, 2.5 mmol, 60% in mineral oil) in THF (10 mL), 4-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine 3 (280 mg, 1.72 mmol) in THF (3 mL) was added. The mixture was stirred at room temperature for 30 min, and then 2-phenylbenzyl bromide (0.40 mL, 2.2 mmol) was added, stirring was continued for 18 h. The reaction mixture was quenched with saturated NH4Cl (20 mL), extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water (40 mL), brine (40 mL), dried over Na2SO4 and evaporated. Flash chromatography of the residue over silica gel, using 10% EtOAc in hexanes to 25% EtOAc in hexanes) gave product 4 as a yellow foam. Yield: 375 mg (66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=1)=[N:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:26]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:6](/[CH:7]=[CH:8]/[C:3]3[O:10][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=4)=[N:11][N:4]=3)=[N:24][N:25]=2)=[N:36][CH:37]=1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Reactant: NNC(=Nc1ccccc1Cl)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(Cl)cn4)n3-c3ccccc3Cl)o2)ccn1
Temperature: 25 °C

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 4 (0.2 g, 0.75 mmol) in CH3CN was added POCl3 (0.37 g, 2.4 mmol). The mixture was stirred under reflux for 16 hours, cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in CH3CN, treated with a solution of N-amino-5-chloro-N′-(2-chlorophenyl)pyridine-2-carboxamidine 8 (0.38 g, 1.2 mmol) in CH3CN and K2CO3 (0.38 g, 1.2 mmol). The mixture was stirred at ambient temperature for 1 hour, refluxed for 2 hours, and filtered. The filtrate was concentrated. The residue was subjected to FCC (50-60% EtOAc/hexanes) to afford the title compound 5-chloro-2-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)pyridine as a white solid. Yield: 0.11 g, 28%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14]C(C)(C)C)(=[O:13])=[O:12]>FC(F)(F)C(O)=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: COCCc1ccccc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCCc1ccccc1S(N)(=O)=O
Yield: 39.6 %

Procedure:
A solution of the crude ether from Example 2 (35.0 g) and 80 ml trifluoroacetic acid was stirred at room temperature for 16 hours. The trifluoroacetic acid was removed in vacuo and methylene chloride added to the residue. The organic phase was washed twice with cold saturated sodium bicarbonate, once with water and dried (Na2SO4). Concentration gave a viscous brown oil which was triturated with hexane. The resulting sticky solid was recrystallized from chloroform/hexane (1:1) to provide 11.0 g of pure 2-(2-methoxyethyl)benzenesulfonamide as a white solid; m.p. 79-81.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[C:18]([Mg]Cl)([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+]>C1COCC1>[CH3:19][C:18]([C:13]1[CH:14]=[C:9]2[CH2:8][CH2:7][C:6]3[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:15](=[O:16])[C:10]2=[N:11][CH:12]=1)([CH3:21])[CH3:20]
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Reactant: CC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cnc2c(c1)CCc1cc(Cl)ccc1C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 20.05 grams (82.28 mmol) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 400 ml of dry THF at -72° C. and under an atmosphere of nitrogen was added dropwise over 40 minutes 66.0 ml of 2.7M t-butyl magnesium chloride in THF. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was then poured into 10% aqueous ammonium chloride and extracted four times with CH2Cl2. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound, along with 8-chloro-11-(1,1-dimethyl-1-ethyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol. These compounds were separated via flash chromatography to give the title compound, which was recrystallized from isopropyl ether to give 4.37 grams (18%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([S:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=3)=[N:19][C:18]=2[CH3:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[Li+].[OH-].O.Cl>C1COCC1>[CH3:1][C:2]1[CH:14]=[C:13]([S:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[C:24]([F:32])[CH:23]=3)=[N:19][C:18]=2[CH3:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(SCc2sc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Example 2a (1 mmol) in THF (10 mL) was treated with 1N LiOH in water (2 mL, 2 mmol), and stirred 16 h at room temperature (when reactions were slow, the temperature was elevated to 50° C.). The solution was neutralized with 1N HCl (2 mL, 2 mmol) and the organic solvent evaporated to afford an aqueous solution with an insoluble product. If the insoluble was a solid, it was filtered and dried to afford the final product. If the insoluble was an oil, it was extracted with EtOAc (30 mL). The organic solution was separated, washed with water (2×30 mL), dried, filtered, and evaporated to afford the final product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=[N:6][C:7]=1S(C)(=O)=O.Cl.[OH-:29].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:7](=[O:29])[NH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2[nH]c(=O)c(N)nc2-c2ccccc2)ccc1=O

Procedure:
A solution of 6-[5-amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (200 mg) in a mixture of 1N aq. NaOH (1 ml) and dioxane (2 ml) was refluxed for 6 hours. After cooling, the mixture was adjusted to pH 4 with 1N HCl to give a precipitate. The precipitate was collected by filtration and crystallized from DMSO and water to give 6-(5-amino-6-oxo-3-phenyl-1,6-dihydro-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (123 mg).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][O:14][CH2:15][CH2:16][OH:17].[OH-].[K+].C(O)(=O)C>O>[CH3:1][O:2]/[N:3]=[C:4](/[C:5]1[O:17][CH2:16][CH2:15][O:14][N:13]=1)\[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6]
Reactant: CON=C1C(=NOCCO)Oc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CO/N=C(/C1=NOCCO1)c1ccccc1O
Temperature: 10 °C
Yield: 69.1 %

Procedure:
A solution of 25.6 g (0.1084 mol) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-(O-methyl-oxime) and 14.2 g (0.216 mol) of potassium hydroxide pellets in 250 ml of water is stirred at 60° C. for 195 minutes. The solution is cooled to 10° C. and acidified to pH 5-6 with glacial acetic acid. The crystalline product is filtered off with suction, washed with 200 ml of water a little at a time and dried at 45° C. in a vacuum drying oven. 17.7 g (67.7% of theory) of E-(5,6-dihydro-[1,4,2]dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime are obtained.