Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30]SC)[C:23]4=[O:33])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:34]O.O[O:37][S:38]([O-:40])=O.[K+]>O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][S:38]([CH3:34])(=[O:40])=[O:37])[C:23]4=[O:33])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CO
Reactant: CSCCOc1cccn(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)CCOc1cccn(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 48 in a 2:1 mixture of methanol and water was added 3 equivalent of oxone. The mixture was stirred at room temperature for 1 hr and directly subjected to reverse phase HPLC to isolate the title compound as a white powder after lyophilization. MS found for C22H20ClN5O5S2 (M+H)+ 534.1, 536.1 (Cl pattern).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27](Cl)=[O:28])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[N:1]1([C:27]([O:26][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl piperidine-2-carboxylate (15 g, 95 mmol), triethylamine (27 ml, 191 mmol) and 4-dimethylaminopyridine (0.58 g, 4.8 mmol) in dichloromethane (100 ml) at 0° C. is added a solution of benzyl chloridocarbonate (17 g, 100 mmol) dropwise. The reaction is allowed to warm slowly to room temperature. It is stirred at room temperature overnight (16 h), then allowed to stand for 2 days. The crude product is extracted with dichloromethane, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine. The organic phase is dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography over silica gel 60 (300 g) with cyclohexane/ethyl acetate as eluent to afford a pale yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:14]([NH:15][OH:16])=[CH:13][C:11](=[O:12])[N:10]([CH3:17])[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([O-])([O-])OCC>CN(C)C=O>[CH3:17][N:10]1[C:11](=[O:12])[C:13]2=[CH:18][O:16][N:15]=[C:14]2[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:9]
Reactant: Cn1c(=O)cc(NO)n(-c2ccccc2)c1=O
Reactant: CCOC([O-])[O-]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2conc2n(-c2ccccc2)c1=O

Procedure:
A mixture of 2 g of 1-phenyl-3-methyl-6-hydroxyaminouracil, 100 ml of dimethylformamide and 10 ml of ethyl orthoformate is reacted in the same manner as Example 11 to obtain 0.93 g of the captioned compound. melting point: 219°-221° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([OH:9])[CH:8]=1)#[N:2].Cl.N#[C:12][NH2:13].C(=O)([O-])O.[Na+].[CH2:19]([OH:22])[CH2:20][CH3:21]>C(#N)C>[C:12]([N:2]=[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([OH:9])[CH:8]=1)[O:22][CH2:19][CH2:20][CH3:21])#[N:13]
Reactant: N#CN
Reactant: CCCO
Reactant: N#Cc1cncc(O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCOC(=NC#N)c1cncc(O)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a solution of 3-cyano-5-hydroxypyridine (0.42 g, 3.50 mmol) in 1-propanol (40 ml) was passed hydrogen chloride gas under ice-cooling for 30 minutes. The reactor was tight sealed, and the mixture was stirred at room temperature for 20 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. To the solution of the residue in acetonitrile (20 ml) was then added an aqueous solution (30 ml) of cyanamide (0.88 g, 20.9 mmol), Na2HPO4 (1.5 g, 10.6 mmol) and NaH2PO4 ·2H2O (3.27 g, 21.0 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was adjusted to pH 7.0 with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform (50 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl N-cyano-5-hydroxy-3-pyridinecarboximidate (0.26 g).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].CO.C(S)[CH2:40][S:41]([O-])(=O)=O.[Na+]>C1COCC1.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([S:41][CH3:40])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(Cl)nc2ccccc2c1-c1ccccc1
Reactant: O=S(=O)([O-])CCS
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CSc1nc2ccccc2c(-c2ccccc2)c1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Example 269 (100 mg) in THF (6 ml)-methanol (2 ml) was added 15% MeSNa in water (4 ml), and the mixture was stirred for 8 hours with heating under reflux. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and evaporated to yield the title compound as colorless crystals (55 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:12]([CH3:13])[CH2:11][CH:10](O)[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.S(Cl)([Cl:24])=O>C1C=CC=CC=1.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:12]([CH3:13])[CH:11]([CH2:10][Cl:24])[CH2:9][N:8]=[C:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6]=2[CH:21]=1
Reactant: O=S(Cl)Cl
Reactant: CN1CC(O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1c2ccc(Cl)cc2C(c2ccccc2)=NCC1CCl
Product: Cl

Procedure:
A solution of 1 g of 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine in 50 ml benzene was heated under reflux for 1 hour with 1 ml thionylchloride. The solution was reacted with a few drops of triethylamine, washed with water and concentrated by evaporation to dryness in a vacuum. The residue was dissolved in isopropanol and reacted with an ether solution of hydrogen chloride. There was obtained 7-chloro-1-methyl-2-chloromethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine hydrochloride. The product was also identical with the product obtained in Example 10 of application Ser. No. 335,986; m.p. 110°-112° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([CH2:14][CH:15]([NH2:17])[CH3:16])[CH:5]=1.[Br:18]Br>ClCCl>[ClH:1].[Br:18][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[CH:5][C:6]=1[CH2:14][CH:15]([NH2:17])[CH3:16]
Reactant: BrBr
Reactant: COc1cc(CC(C)N)cc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: COc1cc(CC(C)N)c(Br)c2ccccc12

Procedure:
To a cold heterogeneous solution (ice bath) of 2-(4-methoxy-naphthalen-2-yl) 1-methyl-ethylamine hydrochloride (0.10 g, 0.39 mmol, Example 11) in dichloromethane, was added bromine (0.07 g, 0.43 mmol) via syringe. After 1 h the volatiles were evaporated and the residue was partitioned in a mixture of ethyl acetate (20 mL) and a saturated aqueous solution of bicarbonate (20 mL). The organic layer was separated, dried (MgSO4), and concentrated in vacuo. The residue was dissolved in ethyl ether (20 mL) and the free amine was transformed to its correspondent hydrochloride salt by adding 1 M solution of hydrogen chloride in ethyl ether. The solid formed was collected by filtration (80 mg): 1H NMR (DMSO-d6) δ 1.21 (d, 3H, CH3), 3.24 (m, 2H), 3.60 (m, 11H), 3.66 (m, 1H), 4.02 (s, 3H, OCH3), 7.03 (s, 1H, Ar—H), 7.48–7.75 (m, 2H, Ar—H), 7.96 (m, 3H, NH3+), 8.17 (m, 2H, Ar—H); MS 296 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 250-mL round-bottom flask was placed a mixture of 4-bromoaniline (6.90 g, 40.1 mmol), triethylamine (16.8 g, 166 mmol), 4-dimethylaminopyridine (200 mg, 1.64 mmol), and 2-phenylacetyl chloride (6.50 g, 42.1 mmol) in dichloromethane (150 mL). The resulting mixture was stirred for 12 hours at 25° C. The reaction was then quenched by the addition of 50 mL of water. The organic layer was separated, and the aqueous layer was extracted with 2×50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel column, 100:1 to 10:1 CH2Cl2/MeOH) to provide the title compound as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19](OCC)=[O:20].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C1(C)C=CC=CC=1>[NH2:34][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:19]([C:3]1[C:4](=[O:18])[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])=[O:20])(=[O:32])=[O:33]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCCC1(CCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCCC1(CCC)C(=O)C(C(=O)Nc2ccccc2S(N)(=O)=O)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A suspension of the product of Example 1F (490 mg, 1.55 mmol) and 2-aminobenzenesulfonamide (Aldrich) (267 mg, 1.55 mmol) in toluene (25 mL) was stirred at reflux for 18 hours, cooled to 25° C. and concentrated in vacuo. The residue was recrystallized from ether-hexane solution to afford the title compound (410 mg, 60%). 1H NMR (300 MHz, CDCl3): δ 17.76 (d, J=12.13 Hz, 1 H), 12.67 (s, 1 H), 8.34 (m, 1 H), 8.09 (dd, J=8.09, 1.47 Hz, 1 H), 7.63 (m, 1 H), 7.38 (m, 3 H), 6.83 (m, 1 H), 5.57 (s, 2 H), 4.85 (s, 1 H), 2.32 (m, 2 H), 1.93 (m, 2 H), 0.97 (m, 2 H), 0.68 (m, 8 H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[N:9]=[C:8]([CH3:10])O[C:6]1=[O:11])(=O)[CH3:2].[NH3:12]>C(#N)C>[CH3:2][C:1]1[NH:12][C:6](=[O:11])[N:5]([N:9]=[CH:8][C:10]2[CH:6]=[N:5][CH:4]=[CH:1][CH:2]=2)[CH:4]=1
Reactant: CC(=O)Cn1nc(C)oc1=O
Reactant: N
Solvent: CC#N
Product: Cc1cn(N=Cc2cccnc2)c(=O)[nH]1
Reaction time: 1 h

Procedure:
A solution of 156 g of 3-acetylmethyl-2,3-dihydro-5-methyl-2-oxo-1,3,4-oxadiazole in 600 ml of acetonitrile is treated with 170 g of aqueous ammonia solution (30%), and the mixture is stirred for one hour at 80° in an autoclave. A pressure of approximately 8 bar is in this case established. The resulting suspension is evaporated, the residue is dissolved in 500 ml of methanol, and 40 g of gaseous HCl are passed into the solution at 50°. The reaction mixture is stirred for 30 minutes at 50°, and 107 g of 3-formylpyridine are then added dropwise at the same temperature. The reaction mixture is stirred for a further 30 minutes at 50°, then cooled to 0°, and filtered with suction. The filter cake, consisting of 2,3-dihydro-2-oxo-1-pyrid-3-ylmethyleneamino-4-tert-butyl-1H-imidazole hydrochloride (compound no. 4.1.1 in table 4), is dissolved in water at room temperature. The pH of the solution is brought to approximately 7 using aqueous sodium hydroxide solution (30%), during which process a precipitation of crystals is observed at a pH of approximately 3. The crystals are filtered off with suction and dried in vacuo, yielding the title compound melting at 200°-202°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: [O-][n+]1ccc(Br)cc1
Product: COc1cc(-c2cc[n+]([O-])cc2)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxyphenylboronic acid (2.49 g) and 4-bromopyridine-N-oxide (2.25 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:27]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:28])[CH2:10][N:9]=2)=[C:18]([C:22]2(O)[CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2].CCN(S(F)(F)[F:35])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:27]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:28])[CH2:10][N:9]=2)=[C:18]([C:22]2([F:35])[CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C4(O)CCC4)C3=C2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C4(F)CCC4)C3=C2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
Example 113. A solution of 2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxycyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (120 mg, 0.32 mmol) in DCM was cooled to 0° C. under N2 and treated with DAST (0.42 mL, 3.19 mmol) dropwise. The mixture was stirred for 20 min at 0° C., and the allowed to warm to RT. The reaction mixture was then slowly poured onto a cooled saturated aq. solution of NaHCO3 and extracted with DCM. The combined org layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product obtained was purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 9:1) and SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton; eluent: isocratic 6% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm) to afford the title compound (42 mg) as a beige solid. UPLC-MS: MS 379.2 (M+H+); UPLC rt 0.95 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.10-1.19 (m, 3 H); 1.46-1.64 (m, 1 H); 1.88-2.09 (m, 1 H); 2.47 (m, 2 H); 2.51-2.79 (m, 4 H); 2.95 (t, J=5.28 Hz, 2 H); 3.73 (t, J=6.06 Hz, 2 H); 4.22 (br. s., 2 H); 7.07 (s, 1 H); 7.33-7.48 (m, 2 H); 7.58-7.67 (m, 1 H); 7.95 (d, J=8.21 Hz, 1 H); 8.13 (s, 1 H).
Reaction SMILES: [CH:1]1([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(OO)(=[O:16])C.O>C(Cl)Cl>[CH:3]12[O:16][CH:4]1[CH2:5][CH2:6][CH:1]([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2]2
Reactant: CC(=O)OO
Reactant: CCCCCC(=O)C1CC=CCC1
Solvent: O
Solvent: ClCCl
Product: CCCCCC(=O)C1CCC2OC2C1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 8.42 g (0.0668 mol) 1-(3-cyclohexen-1-yl)-1-hexanone, and 80 mL of methylene chloride. Peracetic acid (14.5 g, 35 wt. % in acetic acid; 0.0668 mol) in methylene chloride (60 mL) was added dropwise to above mixture over 20 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 200 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×100 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×100 mL), then with water (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Li][N:19]([Si](C)(C)C)[Si](C)(C)C.Cl>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]([NH2:19])=[NH:15])=[CH:12][CH:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(OCCN2CCOCC2)cc1
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: N=C(N)c1ccc(OCCN2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-(2-Morpholin-4-yl-ethoxy)-benzonitrile (Maybridge CC 42116)(2.7 g; 11.64 mmol) in THF (10 ml) is combined with LiN(TMS)2 (30 mmol; 30 ml of a 1M solution in THF) and stirred for 30 minutes at 55° C., kept at room temperature for 30 minutes and cooled to 5° C., while 3N HCl (28 ml) is added slowly. After 10 minutes the reaction mixture is washed with TBME and the aqueous phase is adjusted to pH ˜11 with solid NaOH, saturated with solid K2CO3 and extracted with TBME/MeOH (˜10:1) several times. The combined organic phases are dried over Na2SO4, filtered and evaporated to yield the title compound as yellow crystals (2.7 g; 93%). 1H-NMR (400 MHz; DMSO-d6): 7.72 (d, 2H); 6.96 (d, 2H); 6.31 (bs, 3H); 4.13 (t, 2H); 3.59 (m, 4H); 2.71 t, 2H); 2.49 (m, 4H). MS (m/z) ES+: 250 (MH+).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C>C(#N)C>[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][O:12][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1ccccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)OCCOc1ccccc1Cl
Yield: 58 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride solution prepared in (a) was reacted as in Example 4 with 17.3 g (0.100 mole) of 2-(2-chlorophenoxy)ethanol and 40.4 g (0.400 mole) of triethylamine in 100 ml of acetonitrile followed by extraction, washing and concentration procedures of Example 4 through the first evaporation. The viscous, oily residue was partitioned between 500 ml of water and 500 ml of ethyl ether. The organic layer was washed with four 300 ml portions of water (pH of wash finally neutral to pH paper), dried over magnesium sulfate and the solvent evaporated under reduced pressure to give a white solid. The solid was recrystallized from ethyl ether-petroleum ether (bp 30°-60° C.) to give 14.5 g (58%) of title compound as white solid, mp 84.5°-86° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[OH:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1
Reactant: CC1CC(=O)NN=C1c1ccc(O)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(OCCCO)cc1
Temperature: 100 °C

Procedure:
A solution of 361 mg (1.62 mmol) of the THP-derivative of 3-bromo-1-propanol prepared above, 220 mg (1.08 mmol) of 6-(4-hydroxyphenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 298 mg (2.15 mmol) of powdered anhydrous potassium carbonate in 3 ml of DMF is heated at 100° C. for 2 hr. After cooling the reaction mixture is diluted with 25 ml of water and extracted with EtOAc (3×25 ml). The combined organic extracts are washed once with water, dried (MgSO4), filtered, and the solvent removed under vacuum. The residue is taken up in 5 ml of methanol, about 200 mg of pyridinium p-toluenesulfonate added, and the mixture heated at 60° C. for 2 hr under N2. solvent is removed under vacuum and the residue is flash chromatographed on silica gel (95:5 CHCl3 :CH3OH) to give 252 mg of 6-[4-(3-hydroxypropyloxy)phenyl]-5-methyl-4,5-dihydro-3 (2H)-pyridazinone as a white solid. 1H-NMR (CDCl3): δ1.18 (d, 3H); 1.83 (t, 1H); 2.00 (quintuplet, 2H); 2.40 (d, 1H); 2.63 (d pair, 1H); 3.25 (m, 1H); 3.80 (m, 2H); 4.10 (t, 2H); 6.90 (d, 2H); 7.63 (d, 2H); 8.65 (s, 1H).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:8][CH2:9][OH:10])=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:42]([O:44][C:45](=[O:58])[C@@H:46]([O:55][CH2:56][CH3:57])[CH2:47][C:48]1[CH:53]=[CH:52][C:51](O)=[CH:50][CH:49]=1)[CH3:43]>>[CH2:42]([O:44][C:45](=[O:58])[C@@H:46]([O:55][CH2:56][CH3:57])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:10][CH2:9][CH:8]=[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:6][CH:5]=2)[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:50][CH:49]=1)[CH3:43]
Reactant: OCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2)cc1)OCC
Yield: 76.4 %

Procedure:
Reaction of 3,3-bis-biphenyl-4-yl-prop-2-en-1-ol (363 mg, 1.0 mmol), tributylphosphine (303 mg, 1.5 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (262 mg, 1.1 mmol) and azodicarboxylic dipiperidide (378 mg, 1.5 mmol) in an identical manner to example 3 gave the title compound (445 mg, 76%) containing 0.8 equivalents of ethyl acetate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:23]/[O:24][CH2:25][C:26]([O:28]C)=O)/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH3:30]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:23]/[O:24][CH2:25][C:26]([NH2:30])=[O:28])/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: N
Product: C/C(=N\OCC(N)=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 13.4 %

Procedure:
To a solution of (E)-methyl 2-(1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)acetate (example 31) (70 mg, 0.179 mmol) was added ammonia (2 N, 0.268 mL, 0.537 mmol). The reaction was heated at reflux for 12 h. The reaction mixture was concentrated in vacuo to give a crude product which was purified by prep-HPLC to afford 9 mg (16%) of the title compound. 1H-NMR (400 MHz, DMSO-d6+D2O) δ ppm 9.32 (s, 1H), 8.88 (d, 1H), 8.34 (d, 1H), 8.01 (m, 2H), 7.81 (d, 1H), 7.52 (dd, 1H), 7.33 (br, 2H), 6.20 (s, 2H), 4.67 (s, 2H), 2.27 (s, 3H). LCMS (method B): [MH]+=377, tR=1.06 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[C:4](/[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:5]\[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[H-].[Na+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])/[C:4](/[C:16]1[CH:17]=[CH:18][C:19]([O:22][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1)=[CH:5]\[C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)/C(=C\c1cc(OC)cc(OC)c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C(=C\c1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Yield: 156.7 %

Procedure:
Under argon, 20 (0.60 g, 0.9-mmol) was dissolved in dry DMF (4 mL) and to this sodium hydride (60% in oil, 0.09 g, 2.28 mmol) was added. To the resulting orange solution, 4-fluorobenzaldehyde (0.25 mL, 2.28 mmol) was added and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The crude product obtained after evaporation was purified by chromatography over silica gel and elution with a mixture of hexane-ethyl acetate (4:1) to yield 21 as white solid (0.59 g, 74%): 1HNMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.10 (overlapped d, J=8.8 Hz, 2H), 7.08 (overlapped d, J=8.8 Hz, 2H), 6.96 (s, 1H), 6.53 (dd, J=2.8 Hz, 2H), 6.43 (t, J=2.0 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 6H).