Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])=O.[Na+].S([O-])([O-])(=O)=O.O[NH3+:21].O[NH3+]>C(O)=O>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:21]
Reactant: O=Cc1ccc(O)cc1O
Reactant: [NH3+]O
Agent: O=C[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1ccc(O)cc1O
Temperature: 33 °C
Reaction time: 0.17 h
Yield: 117.7 %

Procedure:
In a double walled reactor 50.0 g (0.362 mol, 1.0 meq) 2,4-dihydroxybenzaldehyde were added to 180 mL formic acid, which resulted in a brown suspension at room temperature. Then 45.8 g (0.673 mol, 1.8 meq) sodium formate were added over 2 min, and the temperature increased to 33° C. After the temperature decreased to 30° C., 35.6 g (0.217 mol, 1.2 meq) hydroxyl ammonium sulfate were added during 3 min to give a thick brown suspension which became a brown solution after stirring 10 min at 30-32° C. While heating the mixture to 100° C., crystallization occurred at 38° C. and stirring was interrupted. At 70° C. the reaction mixture became a thin suspension, which was easy to stir. This reaction mixture was stirred for 2 hours at 100° C. The color turned dark brown. TLC (silica gel 60 F254, acetone:n-hexane:water 20:20:1) showed an almost complete reaction. Formic acid (170 mL) was evaporated under reduced pressure (60° C., 10 mbar). The solid dark brown residue was stirred with 400 mL MTBE at 40° C. for 1 hour (incomplete dissolution). The insoluble residue (62.5 g) was filtered and washed two times each with 50 mL MTBE. To the mother liquor 10 g activated carbon (Norit CA 5) were added and this mixture was refluxed for 1 hour and filtered at 40° C. by Celite Super Hyflow (washing with 2×50 mL portions of MTBE). The MTBE-mother liquor was washed three times each with 100 mL water. After removing the water from this MTBE solution with azeotropic distillation (water separator) it was concentrated under reduced pressure to 20% of the starting volume and 500 mL toluene were added. Then the MTBE was distilled off under reduced pressure. During this process a brown residue began to precipitate, which was filtered. The toluene mother liquor was concentrated to 150 mL and 2,4-dihydroxybenzonitrile precipitated, which was filtered and washed two times each with 30 mL toluene. The pale tan product was dried under reduced pressure (45° C., 20 mbar). The reaction yielded 34.5 g of 2,4-dihydroxybenzonitrile (70.5%, purity 97% (HPLC)).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[OH-].[K+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH3:22])([S:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][CH:7]=1)[CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: FC(F)(F)c1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Sc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a stirred solution of 10 g (56 mmol) of 4-trifluoromethylbenzene-1-thiol in ethanol (100 mL) were added 3.14 g (56 mmol) KOH pellets, followed by 10.95 g (56 mmol) ethyl α-bromoisobutyrate. The reaction mixture was heated to reflux for 18 h. The reaction was cooled to room temperature. The solid (KBr) was separated by filtration and rinsed with ethanol (20 mL). The filtrate was concentrated under reduced pressure and the residue dissolved in DCM (60 mL). The organic layer was washed with water (2×30 mL). The aqueous washes were back-extracted with DCM (15 mL). The combined organics were washed with brine and dried over Na2SO4. Filtration and concentration under reduced pressure afforded 16.3 g of 2-methyl-2-(4-trifluoromethyl-phenylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13]Br>C(OCC)C>[CH2:11]([O:10][C:8]([C:3]1[CH2:4][CH2:5][CH2:6][CH:7]([Br:13])[C:2]=1[OH:1])=[O:9])[CH3:12]
Reactant: BrBr
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: CCOCC
Product: CCOC(=O)C1=C(O)C(Br)CCC1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
Ethyl 2-oxocyclohexanecarboxylate (30 g, 176 mmol, 28 mL) was dissolved in diethyl ether (30 mL) and cooled to 0° C. under nitrogen. Bromine (28 g, 176 mmol, 9.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to RT over 90 min. The mixture was slowly poured into ice-cold saturated aqueous potassium carbonate (250 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo and dried on the vacuum line for 18 h to afford 41.4 g (94%) of 3-Bromo-2-hydroxy-1-enecarboxylic acid ethyl ester (4) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 14.1, 17.7, 21.8, 32.0, 60.0, 60.8, 99.7, 166.3, and 172.8.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]([CH3:14])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[CH2:28](OCC)C>C(OCC)(=O)C>[C:17]1([CH3:27])[CH:18]=[CH:19][C:20]([S:23]([OH:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1.[CH3:15][N:2]([CH3:1])[CH:3]([CH3:14])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:28])[C:10]([Cl:13])=[N:11][CH:12]=1
Reactant: CCOCC
Reactant: CC(CCOc1ccc(Cl)nc1)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(OCCC(C)N(C)C)cnc1Cl
Reaction time: 0.08 h

Procedure:
A solution of the product 45A (63 mg, 0.26 mmol) in ethyl acetate (1 mL) was treated with p-toluenesulfonic acid monohydrate (49 mg, 0.27 mmol) and stirred for 5 minutes. Then ethyl ether (30 ml) was added and stirred for an additional 5 minutes. The ether was decanted and the procedure was repeated. The residue was then dried under vacuum to provide 48 as a white solid. MS (CI/NH3) m/e 243(M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.39 (d, J=7 Hz, 3H), 2.09 (m, 1H), 2.33 (m, 1H), 2.37 (s, 3H), 2.38 (s, 3H), 2.87 (s, 6H), 3.70 (m, 1H), 4.15-4.27 (m, 2H), 7.35 (d, J=8 Hz, 2H), 7.37 (d, J=4 Hz, 1H) 7.68 (d, J=8 Hz, 2H), 7.87 (d, J=3 Hz, 1H). Analysis calculated for C12H19N2ClO.1.3C7H8O3S.H2O: C, 52.30; H, 6.53; N, 5.78; Found: C, 52.00; H, 6.33; N, 6.10
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[N:3]=1.CC(O)=O>CO.[Pd]>[NH2:15][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])nc1C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc(N)nc1C
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-(2-methyl-6-nitropyridin-3-yl)propanoate (1.6 g, 6.7 mmol), 10% Pd/C (0.1 g) and AcOH (3 mL) in MeOH (50 mL) was stirred over night under 1 atm of H2 at room temperature. The mixture was filtered and concentrated to give the crude product ethyl 2-(6-amino-2-methylpyridin-3-yl)propanoate.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:23].O>ClCCl>[CH3:14][C:13]([C:7]1[CH:8]=[C:9]([S:11]([CH3:12])=[O:23])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:17])([CH3:16])[CH3:15]
Reactant: CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2,6-bis(1,1-dimethylethyl)-4-(methylthio)phenol (2.0 g, 3.9 mmole) and meta-chloroperoxybenzoic acid (0.86 g, 4.1 mmole) in dichloromethane (25 ml) was stirred at room temperature for 20 hours. Water was added and the phases were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel gave the title compound, m.p. 171°-173°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:49][C:48]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([CH3:19])[C:11]=2[OH:18])[O:17][C:45](=[O:46])[C:44]=1[S:43][CH2:42][CH2:41][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1O
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(OCc2ccccc2)ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)c1O

Procedure:
The title compound was prepared by Method A using 4'-benzyloxy-2'-hydroxy-3'-methylacetophenone (1.29 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (2.11 g, 12.6 mmol), chlorotrimethylsilane (1.60 mL, 12.6 mmol), THF (127 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 147°-148° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.14 (s, 3 H), 2.77 (t, 2 H), 2.98 (t, 2 H), 5.17 (s, 2 H), 5.29 (s, 1 H), 6.79 (d, 1 H), 7.30 (m, 13H), 9.36 (s, 1 H), 11.85 (bs, 1 H).
Reaction SMILES: O=[C:2]1[NH:7][CH2:6][C:5]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:4][CH2:3]1.B.C1COCC1.CSC.B>C1COCC1>[O:4]1[C:5]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:7][CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)CO2
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of tert-butyl 3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step a) (8.2 g) in THF (100 mL) was treated dropwise with borane THF complex (1M in THF, 91 mL) and the resultant mixture heated at 55° C. for 2 hours. Borane dimethylsulfide complex (2M in THF, 15.17 mL) was added and the resultant mixture heated at 55° C. for 2 hours. The mixture was cooled to room temperature and quenched with methanol, then the solvents were evaporated under reduced pressure. The residue was dissolved in methanol (250 mL) and the solution treated with N1,N2-dimethylethane-1,2-diamine (10 g) and the resultant mixture was heated at reflux for 6 hours. Further N1,N2-dimethylethane-1,2-diamine (3 g) was added and heated at reflux continued for 6 hours. The mixture was cooled to room temperature and the solvents evaporated under reduced pressure, the residue was purified by flash silica chromatography eluting with 1% triethylamine and 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 7.40 g.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)=[N+:2]=[N-:3].[Cl:23][C:24]1[CH:36]=[CH:35][C:27]([CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1.CCN(CC)CC>CC#N>[N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:32]1[CH2:33][CH2:34][CH:29]([CH2:28][C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:36][CH:35]=2)[CH2:30][CH2:31]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCCC[C@H]1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc(CC2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: [N-]=[N+]=N[C@H]1CCCC[C@H]1N1CCC(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 8.6 %

Procedure:
A murky solution of (±)-trans-4-nitro-benzenesulfonic acid 2-azido-cyclohexyl ester (1.77 g, 5.41 mmol), 4-(4-chlorobenzyl)-piperidine (1.14 g, 5.43 mmol), and Et3N (0.75 mL, 5.4 mmol) in CH3CN (11.2 mL) was stirred at room temperature for 17 hours, 65° C. for 31 hours, and 80° C. for 5 d, allowed to cool to room temperature, and concentrated. The residue was partitioned between CH2Cl2 and 1 N NaOH, the aqueous phase was extracted with CH2Cl2 and the extracts were dried and concentrated. Chromatography of the residue with 98:1.9:0.1–95:4.75:0.25 CH2Cl2:MeOH:NH4OH to 100% MeOH and subsequent chromatography with 10:1 hexanes:EtOAc to 100% EtOAc followed by 95:5 EtOAc:MeOH gave, in order of elution, starting (±)-trans-4-nitro-benzenesulfonic acid 2-azidocyclohexyl ester (1.2 g, 68%), desired product (155 mg, 9%), and starting 4-(4-chlorobenzyl)-piperidine (810 mg, 71%). Product: 1H NMR δ 1.19–1.81 (m, 12H), 1.92–2.08 (m, 3H), 2.22 (m, 1H), 2.48 (d, J=7.0 Hz, 2H), 3.02 (m, 2H), 4.05 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 333.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:18][C:19](=[O:21])[CH3:20])[NH:11][C:10]=2[CH3:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>O>[C:19]([NH:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]([S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[C:10]([CH3:22])[N:11]2[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1cccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-4-yl]acetamide (1.0 g, 3.0 mmol), anhydrous potassium carbonate (0.63 g, 4.6 mmol), acetone (10 mL) and ethyl bromoacetate (0.50 mL, 4.5 mmol) was heated under reflux for 1.5 h then cooled to r.t. and left stirring at this temperature overnight. After heating under reflux for an additional 1 h, the mixture was cooled to r.t. Water (2×10 mL) was added, the solid product was collected by filtration, washed with water (10 mL), then dried in a vacuum oven at 40° C. to afford the title compound as an off-white solid; 1.16 g (92%); purity 95.4 area % by HPLC; m/z: 417/419 (MH+); 1H-NMR: 9.52 (1H, s), 7.45 (1H, d, J=7.9 Hz), 7.33 (1H, d, J=8.2 Hz), 7.29 (2H, d, J=8.6 Hz), 7.11 (1H, t, J=8.0 Hz), 6.97 (1H, d, J=8.6 Hz), 5.24 (2H, s), 4.18 (2H, q, J=7.1 Hz), 2.39 (3H, s), 1.86 (3H, s), 1.22 (3H, t, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[I:9]N1C(=O)CCC1=O.O.C([O-])(O)=O.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[I:9]
Reactant: Nc1cncc(Cl)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cnc(I)c(Cl)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 6-chloropyrazin-2-amine (10.0 g, 77 mmol) in DMSO (100 ml) was treated with 1-iodopyrrolidine-2,5-dione (20.84 g, 93 mmol). The reaction mixture was stirred at RT for 2 days and then added to water (800 ml). The pH was adjusted to pH 8-9 using a sat. NaHCO3 solution and the resulting suspension was filtered, washing with water (×3) and dried under vacuum to afford the titled compound as an orange solid;
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][CH:2]2[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCC(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC2CCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a mixture of 3.0 g (0.03 mole) of 3-hydroxy-1-methylpyrrolidine, 3.1 g (0.03 mole) of triethylamine, and 25 mL of methylene chloride was added 5.6 g (0.03 mole) of 4-methylphenylsulfonyl chloride, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to a residue. The residue was dissolved in ether, the solution filtered, and the filtrate concentrated to give 5.75 g of product as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:7]([CH:8]=[N:12][OH:13])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1c(Cl)ccnc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1c(Cl)ccnc1Cl
Temperature: 65 °C
Yield: 79.8 %

Procedure:
A solution of 2,4-dichloro-3-pyridinecarbaldehyde (2.15 g, 12.4 mmol) in ethanol (18 mL) was added to a solution of hydroxylamine hydrochloride (1.01 g, 14.5 mmol) and sodium hydroxide (0.58 g, 14.5 mL) in water (9 mL). The resulting solution was heated in a 65° C. oil bath for 3 hours. The mixture was filtered to yield a white solid which was dried in a vacuum oven at 45° C. with P2O5 to yield 2,4-dichloro-3-pyridinecarbaldehyde oxime (1.89 g, 80%). 1H NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 8.35 (d, J=5 Hz, 1H), 8.19 (s, 1H), 7.68 (d, J=5 Hz, 1H).
Reaction SMILES: OC(CN1CCOCC1)CN1CCCC2NC(C=O)=C(C)C=2C1=O.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])/[C:29]/2=[CH:36]\[C:37]1[NH:46][C:45]2[CH2:44][CH2:43][CH2:42][N:41]([CH2:47][C@H:48]([OH:56])[CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[C:40](=[O:57])[C:39]=2[C:38]=1[CH3:58].[F:59][C:60]1[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=1C1C(F)=CC=C2C=1CC(=O)N2.N1CCCCC1>C(O)C>[F:59][C:60]1[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=1[C:27]1[C:26]([F:25])=[CH:34][CH:33]=[C:32]2[C:28]=1/[C:29](=[CH:36]/[C:37]1[NH:46][C:45]3[CH2:44][CH2:43][CH2:42][N:41]([CH2:47][C@H:48]([OH:56])[CH2:49][N:50]4[CH2:51][CH2:52][O:53][CH2:54][CH2:55]4)[C:40](=[O:57])[C:39]=3[C:38]=1[CH3:58])/[C:30](=[O:35])[NH:31]2
Reactant: O=C1Cc2c(ccc(F)c2-c2cccc(F)c2F)N1
Reactant: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CCC2
Agent: Cc1c(C=O)[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)c(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 74.9 %

Procedure:
5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 53f (84 mg, 0.25 mmol) and 4-(2,3-difluoro-phenyl)-5-fluoro-1,3-dihydro-indol-2-one 74 g (60 mg, 0.23 mmol) were dissolved in 2 ml of ethanol, and added with 35 μl of piperidine to the solution at room temperature. Upon completion of the addition, the mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound 2-((Z)-(4-(2,3-difluorophenyl)-5-fluoro-2-oxoindolin-3-ylidene)methyl)-5-((R)-2-hydroxy-3-morpholinopropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 75 (100 mg, yield 78%) as an orange solid.
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([O:11][CH:12]([F:14])[F:13])=[N:6]2.C(=O)([O-])[O-].[Na+].[Na+].[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:13][CH:12]([F:14])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:5]([N:4]=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:2]=2[C:35]2[CH:36]=[CH:37][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=2)[N:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Fc1cccc(-c2nn3nc(OC(F)F)ccc3c2Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3nc(OC(F)F)ccc23)cc1
Yield: 38.1 %

Procedure:
To a stirred solution of 3-bromo-6-difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine (286 mg) in DMF(20 ml) was added 2N aq sodium carbonate (10 ml). To this mixture was added 4-methanesulfonyl-phenylboronic acid (180 mg) and tetrakis triphenylphosphine palladium(0) (34 mg). The resulting mixture was stirred and heated to reflux for 18 hours. The cooled reaction mixture was diluted with ethyl acetate (300 ml) and the organic solution washed with water (10×30 ml) and brine (30 ml), dried (Na2SO4) and evaporated to give a gum which was purified by flash column chromatography with chloroform:ethyl acetate (50:1 to 5:1) as eluant. Combination of appropriate fractions and concentration gave the title compound as an off-white solid (132 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:6]([CH3:13])[CH2:5][C:4](=[O:14])[CH:3]=1.[H][H]>[OH-].[K+].[Pd]>[CH3:1][CH:2]1[CH:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:6]([CH3:13])[CH2:5][C:4](=[O:14])[CH2:3]1
Reactant: CC(C)=CCC1C(C)=CC(=O)CC1C
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Product: CC(C)=CCC1C(C)CC(=O)CC1C
Yield: 87.4 %

Procedure:
A solution of 3,5-dimethyl-4-(3-methyl-2-butenyl)-2-cyclohexen-1-one (8.2 g, 0.043 mol) in 0.3 M ethanolic KOH (16 mL) was hydrogenated at room temperature and 1 atmosphere over 5% palladium on carbon (0.8 g). After uptake of 1 equivalent of hydrogen, the solution was filtered through Celite and concentrated. The residue was partitioned between hexane and water; then the hexane layer was dried (Na2SO4) and the solvent removed on a rotary evaporator. Kugelrohr distillation gave 7.3 g of 3,5-dimethyl-4-(3-methyl-2-butenyl) cyclohexanone, bp 115° C./0.5 mm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:31])=[C:4]2[N:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([NH2:30])(=[O:29])=[O:28])=[CH:17][CH:16]=3)[C:5]2=[N:6][CH:7]=1.[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35].CO>N1C=CC=CC=1>[CH2:32]([S:36]([NH:1][C:2]1[C:3]([CH3:31])=[C:4]2[N:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([NH2:30])(=[O:29])=[O:28])=[CH:19][CH:20]=3)[C:5]2=[N:6][CH:7]=1)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CCCc1nc2c(C)c(N)cnc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Solvent: CO
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a mixture of 6-amino-7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine (80 mg, 0.15 mmol) in pyridine (0.5 mL) at 0° C. was added butylsulfonyl chloride (0.02 mL, 0.15 mmol). The mixture was stirred for 1 h, then 1 mL of MeOH was added and the mixture was concentrated. Purification (SiO2, 5% MeOH-EtOAc) gave 50 mg of 6-[(Butylsulfonyl)amino]-7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[CH:17]=[N:16][C:15](=[O:20])[NH:14][C:13]=2[N:12]=1.S(=O)(=O)(O)[OH:22]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:10])=[O:22])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[CH:17]=[N:16][C:15](=[O:20])[NH:14][C:13]=2[N:12]=1
Reactant: O=S(=O)(O)O
Reactant: COc1cc(C#N)ccc1-c1nc2[nH]c(=O)ncc2[nH]1
Product: COc1cc(C(N)=O)ccc1-c1nc2[nH]c(=O)ncc2[nH]1

Procedure:
Prepared by partial saponification of 8-(2-methoxy-4-cyanophenyl)-3H-purin-2-one with concentrated sulfuric acid at ambient temperature.