Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[F:12][C:13]([F:21])(S(F)(=O)=O)C(O)=O.O>C(#N)C.[Cu]I>[Br:1][C:2]1[C:7]([O:8][CH:13]([F:21])[F:12])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: CC(=O)c1cccc(O)c1Br
Agent: [Cu]I
Solvent: O
Solvent: CC#N
Product: CC(=O)c1cccc(OC(F)F)c1Br
Temperature: 55 °C
Reaction time: 3 h
Yield: 18 %

Procedure:
1-(2-Bromo-3-hydroxy phenyl)ethanone (6.50 g, 30.2 mmol), which had been obtained in Reference example 3 (3c), and copper (I) iodide (2.51 g, 13.2 mmol) were dissolved in acetonitrile (150 mL), followed by addition of a solution of difluoro(fluorosulfonyl)acetic acid (50.0 g, 281 mmol) dissolved in acetonitrile (50 mL) over 1 hour and 30 minutes under heating at 55° C. Upon the completion of the dropwise addition, the reaction solution was stirred at 55° C. for 3 hours, cooled to room temperature, added with water, and then extracted with ethyl acetate/hexane (2:1, V/V). The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (neutral silica gel, hexane:ethyl acetate, 100:0-75:25, V/V and basic silica gel, hexane:ethyl acetate, 100:0-50:50, V/V) to give the title compound as a colorless oily substance (1.53 g, yield 18%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH2:10][S:11][CH2:12][C:7]=2[CH:6]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=O)C=1>C(OCC)(=O)C.C(=O)=O>[S:9]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]2=[CH:12][S:11][CH:10]=[C:8]12
Reactant: COC(=O)c1cc2c(s1)CSC2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cscc2s1
Reaction time: 8 h

Procedure:
A solution of 2.0 g (10 mmol) (3) in 30 mL ethyl acetate was stirred and cooled down in dry ice bath. MCPBA (1.75 g, 10 mmol) in 30 mL ethyl acetate was added dropwise to the reaction solution. After the addition, the mixture was kept stirring for overnight. Then the solvent was removed by evaporation and the residue contained a crude product of (4) and 3-chlorobenzoic acid.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[N:17]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.O=[Mn]=O>[C:1]1([C:7]([C:9]2[N:17]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)c2ccccc2)cc2ccncc21
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc2ccncc2n1S(=O)(=O)c1ccccc1
Reaction time: 20 h
Yield: 66.1 %

Procedure:
A mixture of phenyl[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanol (2.6 g, 7.1 mmol) and MnO2 (9.3 g, 110 mmol) in THF (125 mL) was heated to reflux. After 20 h, the reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure. Purification by column chromatography (silica gel, CH2Cl2 to 99:1 CH2Cl2/MeOH) gave phenyl[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanone (1.7 g, 68%) as an off-white solid: mp 145-146° C.; 1H NMR (500 MHz, DMSO-d6) δ7.32 (1H, s), 7.60-7.63 (2H, m), 7.66-7.69 (2H, m), 7.73-7.77 (3H, m), 7.93-7.95 (2H, m), 8.07-8.09 (2H, m), 8.50 (1H, d, J=5.3 Hz), 9.35 (1H, s); ESI MS m/z 363 [C20H14N2O3S+H]+; HPLC (Method A) 99.0% (AUC), tR=18.2 min.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[N:4][N:3]=1.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+].[C:26]([O:30][C:31](=[O:40])[N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>O>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:36]2[CH2:35][CH2:34][CH:33]([N:32]([CH3:39])[C:31](=[O:40])[O:30][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:38][CH2:37]2)=[N:3][N:4]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Brc1nnc(Br)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(Br)c3ccccc23)CC1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
Combine 1,4-dibromophthalazine (0.70 g, 2.38 mmol), N-methylpyrrolidone (7.0 mL), potassium carbonate (395 mg, 2.86 mmol), and methyl-piperidin-4-yl-carbamic acid tert-butyl ester (532 mg, 2.38 mmol). Heat at 80° C. overnight. Cool and pour into water. Collect the solid and dry in a vacuum oven at ambient temperature overnight to obtain the final product (0.96 g, 95%). ES/MS m/z (81Br) 421.0 (M+1).
Reaction SMILES: [OH-].[Na+].CO[C:5](=O)[C:6]([C:24]#[N:25])(C)[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10]2>C(O)C>[CH3:5][CH:6]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10]2)[C:24]#[N:25]
Reactant: COC(=O)C(C)(C#N)c1ccc2nc(-c3ccccc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C#N)c1ccc2nc(-c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
36.4 ml of 1 N sodium hydroxide solution are added dropwise to a solution of 10.4 g of α-cyano-α-methyl-2-phenyl-6-quinolineacetic acid methyl ester in 580 ml of ethanol at room temperature. The reaction mixture is stirred for 16 hours at room temperature and evaporated to dryness, the residue is treated with water and the suspension thereby produced is filtered off. After drying in vacuo at 40°C, crude α-methyl-2-phenyl-6-quinolineacetonitrile is obtained, which is directly processed further.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:23](Br)[CH:24]=[CH2:25]>ClCCl.Cl>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([O:19][CH2:25][CH:24]=[CH2:23])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reactant: C=CCBr
Agent: Cl
Solvent: ClCCl
Product: C=CCOc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.017 g, 0.045 mmol) in dichloromethane (1 mL) was treated with N′″-tert-butyl-N,N, N′, N′, N″, N″-hexamethylphosphorimidic triamide (0.016 g, 0.068 mmol), allyl bromide (0.011 g, 0.09 mmol) and stirred for 3 hours at 20 C. The product mixture was diluted with 10% aqueous HCl, extracted twice with dichloromethane (20 mL), and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.011 g of a clear oil. MS calculated for C18H21BrF3NO2+H: 420, observed: 420.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])=[C:4]([CH3:15])[CH:3]=1.[ClH:16]>CC(O)=O>[ClH:16].[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[C:4]([CH3:15])[CH:3]=1
Reactant: CCOC(=O)/C=C/c1cnc(N)cc1C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(N)ncc1/C=C/C(=O)O
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To ethyl (E)-3-(6-amino-4-methylpyridin-3-yl)acrylate (1.50 g, 7.3 mmole) was added HOAc (15 mL) and conc. HCl (15 mL). The solution was stirred at 100° C. for 10 hr, cooled to RT, and concentrated to dryness. Trituration with Et2O, filtration and drying under vacuum gave the title compound (1.65 g, quantitative) as a white solid: LCMS (ES) m/e 179.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1 H), 8.28 (br s, 3 H), 7.51 (d, J=16.0 Hz, 1 H), 6.86 (s, 1 H), 6.46 (d, J=16.0 Hz, 1 H), 2.41 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[CH2:19][C:20]#[CH:21]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]#[C:20][CH2:19][N:18]([CH3:22])[CH3:17])=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)c(Cl)c1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester (10.0 g) in triethylamine (120 ml) is added 1-dimethylamino-2-propyne (2.82 g), bis(triphenyl-phosphine)palladium(II) chloride (0.4 g), and cuprous iodide (0.054 g). The mixture is stirred at room temperature under an atmosphere of argon for approximately 6 hours and is then heated briefly (ca. 10 minutes) to 60° C. The reaction mixture is then cooled, filtered through diatomaceous earth, and the solvent is removed by evaporation under reduced pressure. The residue is dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the purified product as an amber oil that solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]=[O:20])=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH2:19][OH:20])=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)COc1cc(/C=C/C=O)ccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cc(/C=C/CO)ccc1Cl
Reaction time: 3 h

Procedure:
A solution of the compound (631 mg, 2.00 mmol) of Example 20-3 in tetrahydrofuran (4.0 ml) and methanol (2.0 ml) was stirred at ice cooling. Thereto was dropped an aqueous solution (0.20 ml) of sodium borohydride (38.0 mg, 1.00 mmol) under ice cooling and the mixture was stirred for 3 hour at the same temperature. Thereto was added 10% aqueous citric acid solution and the solution was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogencarbonate, solution and an aqueous saturated sodium chloride solution in the order, and dried over sodium sulfate. The solvent was removed to give the subject compound as a colorless oil (651 mg, quantitatively).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:11](=[O:12])[O:13][CH2:14][CH3:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(Cl)nnc1N
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nnc(Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A 100 mL flask was charged with 6-chloro-4-methylpyridazin-3-amine (700 mg, 4.88 mmol) and pyridine (20 mL) then ethyl chloroformate (0.421 mL, 4.39 mmol) was added portionwise. The reaction mixture was stirred for 1 h at 0° C. The reaction mixture was then concentrated and partitioned between ammonium chloride and DCM. The aqueous layer was extracted with DCM (2×). The organic layers were combined and washed with brine (1×), eluted through a phase separator and concentrated to afford ethyl (6-chloro-4-methylpyridazin-3-yl)carbamate (549 mg, 49.6% yield).
Reaction SMILES: C(C1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:5][CH:4]=1)#N.Cl.[C:24]([OH:27])(=[O:26])[CH3:25]>O>[C:24]([C:25]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:5][CH:4]=1)([OH:27])=[O:26]
Reactant: Cc1cc(CCCCCCCOc2ccc(C#N)cc2)on1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: Cc1cc(CCCCCCCOc2ccc(C(=O)O)cc2)on1

Procedure:
A mixture of 3.0 g (0.01 mole) of 5-[7-(4-cyanophenoxy)heptyl]-3-methylisoxazole (Example 5), 20 ml of 20% aqueous hydrochloric acid and 20 ml of glacial acetic acid was heated at reflux for 19 hours. The reaction mixture was cooled, 20 ml of water added, and the solid product collected by filtration to give 3.0 g of 5-[7-(4-carboxyphenoxy)heptyl]-3-methylisoxazole as a colorless solid, m.p. 129°-130° C.; MIC vs. rhinovirus Type 2 in vitro=10 μg/ml.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12]([C:18]([O:20][CH3:21])=[O:19])#[C:13][C:14]([O:16][CH3:17])=[O:15]>CO>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6]/[C:13](=[CH:12]/[C:18]([O:20][CH3:21])=[O:19])/[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CO
Product: COC(=O)/C=C(/Nc1cccc(C(F)(F)F)c1)C(=O)OC

Procedure:
3-(Trifluoromethyl)aniline (10.0 g, 62.0 mmol) and dimethyl acetylenedicarboxylate (8.4 mL, 68.4 mmol) were dissolved in methanol (100 mL) and the mixture was refluxed for 2 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with 0-30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 3.71 (s, 3H), 3.73 (s, 3H), 5.49 (s, 1H), 7.16 (m, 2H), 7.36 (d, J=7.80 Hz, 1H), 7.48 (t, J=7.80 Hz, 1H). MS (ESI) m/z 303.97 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cn1cc(N)cn1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Yield: 73 %

Procedure:
As described for example 254, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine instead of 2-amino-2-methyl-1-propanol, to the title compound (90 mg, 73%) which was obtained as a white solid. MS: m/e=424.2 [M+H]+.
Reaction SMILES: C1([C@H](OC(=O)[NH:11][C@@H:12]2[C@@H:21]([O:22][CH3:23])[CH2:20][C:19]3[C:14](=[CH:15][C:16]([OH:24])=[CH:17][CH:18]=3)[C:13]2([CH2:27][CH3:28])[CH2:25][CH3:26])C)C=CC=CC=1.Cl.O1CCOCC1>>[NH2:11][C@H:12]1[C:13]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:14]2[CH:15]=[C:16]([OH:24])[CH:17]=[CH:18][C:19]=2[CH2:20][C@@H:21]1[O:22][CH3:23]
Reactant: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1NC(=O)O[C@H](C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 115.8 %

Procedure:
((2S,3S)-1,1-Diethyl-7-hydroxy-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid (R)-1-phenyl-ethyl ester (635 mg, 1.60 mmol) was treated with 4.0 N HCl in dioxane (6.0 mL, 24 mmol) and stirred at RT. After 3 days, the solvent was removed at reduced pressure and the residual solid was triturated with 50% dichloromethane in heptane (4 mL). The solid was collected on a Buchner funnel and dried under vacuum to give the hydrochloride salt of the title compound (462 mg). (m/z): [M+H]+ calcd for C15H23NO2 250.36. Found 250.2. 1H NMR (d6-DMSO, 400 mHz) δ (ppm) 9.23 (s, 1H), 8.02 (br s, 3H), 6.92 (d, J=8.2 Hz, 1H), 6.61 (m, 2H), 3.77 (m, 1H), 3.41 (s, 3H), 3.30 (m, 1H), 3.17 (m, 1H), 2.44 (dd, J=15.9 Hz, 9.8 Hz, 1H), 1.85 (m, 2H), 1.62-1.52 (m, 2H), 0.66 (t, J=7.2 Hz, 3H), 0.55 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][CH2:16][S:17][C:18]4[S:22][CH:21]=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:23]O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][CH2:16][S:17](=[O:23])[C:18]4[S:22][CH:21]=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CC2CCSc3sccc3C2=NN1c1ccc(Cl)cc1
Reactant: OO
Solvent: CC(=O)O
Product: O=C1CC2CCS(=O)c3sccc3C2=NN1c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a solution of 5.4 g of 2-(4-chlorophenyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in 60 ml of acetic acid is added 3.5 ml of 30% aqueous hydrogen peroxide solution under ice-cooling and stirred at the same temperature for 3 hours. Furthermore, to the solution is added 2 ml of 30% aqueous hydrogen peroxide solution and stirred for 2 hours. To the solution is additionally added 2 ml of aqueous 30% hydrogen peroxide solution, stirred for 2 hours and the mixture is poured into ice-cold water. The mixture is extracted with chloroform three times, the extract is washed with water and saline solution and dried over magnesium sulfate. The chloroform is distilled off to give 7 g of 2-(4-chlorophenyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one 7-oxide as pale brawn oil.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].NN>CO>[NH2:3][CH:12]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC(c1cccc2ccccc12)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(N)c1cccc2ccccc12
Reaction time: 12 h
Yield: 55.5 %

Procedure:
To a solution of 1,1-dimethylethyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-(1-naphthalenyl)ethyl]carbamate (1.29 g, 3.1 mmol) in MeOH (30 mL) was added anhydrous hydrazine (0.5 mL, 15.5 mmol) at 25° C. After 12 h, the solution was partitioned between DCM/H2O. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly yielding the title compound as a white solid (491 mg, 1.72 mmole, 55%): LCMS (ES) m/z 287 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:22]
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOC)ccc21
Yield: 39.3 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (68.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methoxy-ethylamine (45.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 431; and 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (1H, br. s), 8.08 (1H, br. s), 7.92 (1H, br. s), 7.76-7.65 (2H, m), 7.51 (1H, m), 7.40-7.38 (1H, m), 4.22 (2H, br. s), 3.50-3.43 (4H, m), 3.29 (3H, s), 1.33-1.30 (3H, t), —NH proton signal was not observed.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1I)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]1([CH3:34])[C:31]([CH3:33])([CH3:32])[O:30][BH:29][O:28]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[B:29]1[O:30][C:31]([CH3:33])([CH3:32])[C:27]([CH3:34])([CH3:26])[O:28]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(COCC(=O)OC(C)(C)C)c1I
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cccc(COCC(=O)OC(C)(C)C)c1B1OC(C)(C)C(C)(C)O1

Procedure:
The procedure used in Example 3: step b was followed using (2-iodo-3-methyl-benzyloxy)-acetic acid tert-butyl ester ((Example 299: step a) 571 mg, 1.6 mmol), PdCl2(PPh3)2 (55 mg, 0.08 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL) at a reaction temperature of 80° C. Analogous aqueous workup and purification by SiO2 flash column chromatography yielded the title compound contaminated with the product resulting from halide reduction (542 mg, 95%). The material was used without further purification. 1H-NMR (CDCl3): δ 7.20 (t, 1H, 7.4 Hz), 7.11 (d, 1H, J=7.4 Hz), 7.07 (d, 1H, J=7.4 Hz), 4.72 (s, 2H), 3.86 (s, 2H), 2.43 (s, 3H), 1.46 (s, 9H), 1.39 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Yield: 90.9 %

Procedure:
The product of step 2 (4.5 g, 13 mmol) and K2CO3 (18 g, 130 mmol) was heated at reflux for 5 h in 50% aqueous ethanol. The mixture was cooled and concentrated, and the residue partitioned between water (50 ml) and dichloromethane (100 ml). The organic extract was dried (MgSO4) and solvent removed. The residual solid was recrystallized from hexane/ethyl acetate to afford 3.2 g (91%) of the title compound. m.p.: 128-130° C. 1H-NMR (CDC13) δ: 7.85-7.76 (2H, m), 7.64 (1H, br s), 7.59-7.49 (4H, m), 7.22 (1H, d, J=1.8 Hz), 7.02 (1H, dd, J=1.8, 8.4 Hz), 5.60 (2H, br s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:19]=[N:20][C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=3)[CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1.[NH4+].[Cl-]>CO.[Zn]>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:9])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: CN1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(N)nc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of 4-methyl-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (0.400 g, 1.116 mmol) in MeOH (20 mL) was treated with NH4Cl (2.00 g, 37.4 mmol) and zinc powder (1.00 g, 15.29 mmol) and stirred at RT overnight. The solids were removed via filtration, washed with DCM and the filtrate concentrated to dryness. The residue was treated with DCM and a few drops of MeOH, the solids again removed via filtration and the filtrate concentrated to dryness to afford N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-4-methylpiperazine-1-carboxamide (346 mg, 94%). MS (ESI) m/z: 329.2 (M+H+).