Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH2:18][C:12]=2[CH:11]=[CH:10][CH:9]=1>C(#N)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH2:18][C:12]=2[CH:11]=[CH:10][C:9]=1[N+:1]([O-:4])=[O:2]
Reactant: COc1cccc2c1CCCC(=O)C2
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34.6 %

Procedure:
To potassium nitrate in acetonitrile (50 mL) and trifluoroacetic anhydride (100 mL) at 0° C. was added dropwise 1-methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one (25 g, 0.131 mol) in 50 mL acetonitrile. The reaction was stirred for 2.5 hours while warming to RT. The reaction was concentrated without heat on a rotary evaporator. MeOH was added and stirred briefly. Reconcentrated and worked-up by partitioning between dichloromethane and sat. sq. sodium bicarbonate solution. The organic layer was separated and dried (Mg2SO4), concentrated and purified by chromatography ISCO (330 g silica cartridge: gradient elution−10 to 50% EA:HEX over 60 minutes) affording two isomers. The title compound was the later eluting (10.7 grams, 34.6% yield). 1H-NMR (400 MHz, CDCl3) 7.70 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 2H), 3.13-3.09 (m, 2H), 2.60 (t, J=7.0 Hz, 2H), 2.10-2.03 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[C:22]([N:30]2[CH:34]=[CH:33][CH:32]=[CH:31]2)[CH:21]=1)([O-:19])=[O:18].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][N:13]([CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:14]([CH3:16])[CH3:15])=[C:22]([N:30]2[CH:34]=[CH:33][CH:32]=[CH:31]2)[CH:21]=1)([O-:19])=[O:18]
Reactant: COc1ccc(CCNC(C)C)cc1OC
Reactant: O=[N+]([O-])c1ccc(OCCBr)c(-n2cccc2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(CCOc2ccc([N+](=O)[O-])cc2-n2cccc2)C(C)C)cc1OC
Temperature: 85 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
2-(3,4-Dimethoxyphenyl)-N-isopropylethylamine (2.4 g, 11 mmol) and 1-[4-nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-bromoethane (3.04 g, 10 mmol) were dissolved in DMF and, thereafter, potassium iodide (1.61 g, 11 mmol) and anhydrous potassium carbonate (1.5 g, 10 mmol) were added and the mixture was stirred at 80-90° C. for 1 h; thereafter, ice water was added and extraction was conducted with ethyl acetate. The extracted organic layer was dried with magnesium sulfate and the solvent was evaporated; the resulting residue was purified by being subjected to column chromatography on silica gel using a 7:3:1 solvent system of cyclohexane, ethyl acetate and methanol as an eluent. The fractions containing the product were collected and the solvent was evaporated to yield the end compound 1-[4-nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-isopropylamino]ethane (0.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]#[N:10])[N:3]=1.[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([C:9]#[N:10])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C#N)nc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(Cl)n1
Reaction time: 1 h
Yield: 40 %

Procedure:
2-Chloro-6-cyano-3-methylpyridine (92.0 mg, 0.603 mmol) obtained in Step 2 was dissolved in carbon tetrachloride (4 mL), and the mixture was stirred for 1 hour under reflux after adding N-bromosuccinimide (118 mg, 0.663 mmol) and α,α-azobisisobutyronitrile (9.90 mg, 0.0603 mmol). The mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC to give 3-bromomethyl-2-chloro-6-cyanopyridine (55.8 mg, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.5 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole) in anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 21/2 hours. The nitrogen flow was stopped and a solution of monomethylene (1M in tetrahydrofuran) (33 ml) was added. The solution was stoppered and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake (5.5 g, 96%) was recrystallized from tetrahydrofuran-ethanol to give 3.0 g of a white flocculent solid, mp 258°-259° C. after forming a polymorph from 250°-255° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][N:9]=2)[N:4]=1.Br>C(O)(=O)C>[CH3:14][O:13][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[CH:12][C:3](=[O:2])[NH:4]2)=[N:9][CH:8]=1
Reactant: COc1cnc2ccc(OC)nc2c1
Agent: Br
Solvent: CC(=O)O
Product: COc1cnc2ccc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
2,7-bis(methoxy)-1,5-naphthyridine (7.45 g, 39.210 mmol) stirred in glacial acetic acid (100 ml) at rt under argon, was treated with 33% HBr in acetic acid (100 ml). After stirring at rt for 18 h, the solvents were evaporated under reduced pressure (copious fumes of HBr were produced). The orange solid residue was stirred with water (ca. 250 ml) and the pH of the suspension was adjusted to ca. pH 6 by addition of solid sodium hydrogen carbonate. The mixture was then filtered and dried in a vacuum desiccator over P2O5 overnight to give 7-(methoxy)-1,5-naphthyridin-2(1H)-one as an off-white solid (5.958 g, 86%).
Reaction SMILES: [OH2:1].[OH-].[Li+].[CH3:4][C@H:5]([O:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16](CC([O-])=O)=[C:15]([N:26]([CH3:28])[CH3:27])[CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl>C1COCC1.O>[CH3:4][C@H:5]([O:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([OH:1])=[C:15]([N:26]([CH3:28])[CH3:27])[CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC[C@H](C)Oc1cc(N(C)C)c(CC(=O)[O-])cc1[N+](=O)[O-]
Reactant: O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCC[C@H](C)Oc1cc(N(C)C)c(O)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 92 %

Procedure:
Lithium hydroxide monohydrate (226 mg, 5.38 mmol) was added to a stirred solution of compound 59 in 15 ml THF and 5 ml water. The reaction mixture was stirred for 15 minutes and was then acidified with concentrated HCl. Extracted with ether, the organic layer was washed with brine and dried over MgSO4. The crude product was purified via flash chromatography over silica gel (80/20, v/v, Hex/EtOAc). Evaporation of solvent yielded 308 mg (92%) of a viscous orange oil. This product rapidly decomposes in chloroform and should be carried on immediately to the next step.
Reaction SMILES: [I-].Cl[C:3]1[CH:8]=CC=C[N+:4]=1C.C(N(CC)CC)C.C(N)C.[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[C:27]1[C:37]([OH:39])=O)(=[O:22])[CH3:21]>ClCCl>[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[C:27]1[C:37]([NH:4][CH2:3][CH3:8])=[O:39])(=[O:22])[CH3:21]
Reactant: COc1ccc2cc(C(=O)O)n(CCNC(C)=O)c2c1
Reactant: C[n+]1ccccc1Cl
Agent: CCN
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O

Procedure:
Under nitrogen, add 0.18 g of 2-chloro-1-methylpyridinium iodide, 0.25 ml of triethylamine and 0.04 ml of ethylamine in dichloromethane to a solution of 0.20 g of the compound obtained in Step C of Example 1 in 20 ml of dichloromethane and then heat at reflux for 14 hours. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous sodium chloride solution. Extract and dry the organic phase over sodium sulfate and then filter and evaporate. Purify the compound by column chromatography on silica gel using as eluant a 19/1 dichloromethane/ethanol mixture. After triturating in diisopropyl ether, the title compound is obtained in the form of a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:22]12[CH2:29][NH:28][CH2:27][C:26]=1[CH2:25][NH:24][CH2:23]2.C(N(C(C)C)CC)(C)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][C:26]5[CH2:27][NH:28][CH2:29][C:22]=5[CH2:23]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1NCC2=C1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Yield: 76.5 %

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.4 g) and 3,7-diazabicyclo[3.3.0] oct-1(5)-ene dihydrobromide (4.2 g) were added to diisopropyl ethylamine (11.6 ml) in acetonitrile (120 ml) and refluxed for 7 hours. The produced precipitate was filtered, washed with acetonitrile (100 ml), water (50 ml), ethanol (50 ml) and them ethyl ether (50 ml) to give the title compound (4.2 g, yield 77%).
Reaction SMILES: [C:1]([S:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Ba+2].[OH-]>CC(O)C.O.CO>[C:1]([S:5]([NH:7][CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)N1CCC(NS(=O)C(C)(C)C)CC1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C)S(=O)NC1CCNCC1

Procedure:
In a mixture of 5 ml of 2-propanol and 5 ml of water, 378 mg of 4-t-butylsulfinylamino-1-ethoxycarbonyl piperidine was suspended and 1.77 g of barium hydroxide was added. The mixture was refluxed with stirring and heating for 4 hours. The mixture was diluted with methanol and the insoluble material was filtered off. The solvent was removed under reduced pressure to give 4-t-butylsulfinylaminopiperidine. Without purification, the obtained material was dissolved in 5 ml of THF, and 984 mg of N-phenoxycarbonyl-4-butyl aniline and 236 mg of diisopropyl ethylamine were added, followed by stirring at room temperature overnight. An aqueous solution of potassium hydrogen sulfate was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 291 mg of 4-t-butylsulfinylaminopiperidine-1-carboxylic acid (4-t-butylphenyl)amide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]=[N+:16]=[N-:17])[C@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:29])CCOC.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]=[N+:16]=[N-:17])[C@H:10]([F:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN=[N+]=[N-])[C@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](CN=[N+]=[N-])[C@H](F)C1

Procedure:
To a stirred solution of (±)-trans-4-azidomethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.35 mmol, 350 mg) in dichloromethane (6 mL) was added bis-(2-methoxyethy) aminosulfur trifluoride (1.62 mmol, 358 mg) at −40° C. After stirring the reaction at −40° C. for 3 h, saturated sodium bicarbonate solution (6 mL) was added, and the product was extracted with dichloromethane (6 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified using hexane:ethyl acetate to provide (±)-cis-4-azidomethyl-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: ClC[C:3]([N:5]([CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])[CH2:6][CH2:7][N:8]1[C:16](=O)C2C(=CC=CC=2)C1=O)=[O:4].O.NN>CCO>[O:4]=[C:3]1[CH2:16][NH:8][CH2:7][CH2:6][N:5]1[CH2:19][CH2:20][N:21]1[C:22](=[O:31])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]1=[O:30]
Reactant: O=C(CCl)N(CCN1C(=O)c2ccccc2C1=O)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: O=C1CNCCN1CCN1C(=O)c2ccccc2C1=O
Reaction time: 12 h
Yield: 34.4 %

Procedure:
To a solution of 2-chloro-N,N-bis[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]acetamide (2 g, 4.55 mmol) in EtOH (230 mL) was added hydrazine hydrate (213 μL, 6.83 mmol). After 12 h at 85° C., the solution was concentrated and the residue purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound (428 mg, 34%) as a yellow foam: LCMS (ES) m/e 274 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]([CH3:29])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3=CC=CC=C3C2=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6](=[O:30])[C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][NH2:18])[N:14]=1)([CH3:29])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN2C(=O)c3ccccc3C2=O)cs1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN)cs1
Yield: 91.2 %

Procedure:
2-Methyl-2-{[4-(3-phthalimidopropyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (31.1 g) obtained in Example 32 was dissolved in ethanol (400 mL), hydrazine monohydrate (10 mL) was added, and the mixture was refluxed for 2 hr. The precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Water and dichloromethane were added to the residue, and the organic layer was washed with water, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give the title compound (20.1 g). The obtained compound was used in the next reaction without purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([CH3:13])[CH:3]=1.Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[OH-].[Na+]>O1CCOCC1>[CH3:13][C:4]1[CH:3]=[C:2]([O:1][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:7]([CH3:8])=[CH:6][C:5]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: ClCCN1CCOCC1
Reactant: CC(=O)Nc1cc(C)c(O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(C)c(OCCN2CCOCC2)cc1C
Yield: 89 %

Procedure:
To a suspension of N-(4-hydroxy-2,5-dimethyl-phenyl)-acetamide (8.0 g, 44.6 mmol) and 4-(2-chloro-ethyl)-morpholine hydochloride (9.97 g, 53.6 mmol) in 50 mL of dioxane was added a solution of NaOH (4.29 g in 50 mL of water). The mixture was refluxed for 2 h and evaporated to dryness under reduced pressure. The residue was dissolved in CH2Cl2 and washed with 0.5 N NaOH. The organic phase was dried (Na2SO4), evaporated, and crystallized from CH2Cl2-hexane to give N-[2,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide as gray solid (11.6 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]3[CH2:14][CH2:13][CH2:12][CH:7]3[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([NH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]3[CH2:14][CH2:13][CH2:12][CH:7]3[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)S(=O)(=O)NC1CCCN21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC1CCCN21
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A stirred solution of 7-amino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide (150 mg; 0.5 mmol) and triethylamine (70 μl; 0.5 mmol) in THF (1 ml) was added a solution of CH3SO2Cl (40 μl; 0.5 mmol) in THF (1 ml) and stirred at rt. over night. The reaction mixture was evaporated to dryness, suspended in H2O and extracted by EtOAc. The combined organic fractions were evaporated to dryness. Column chromatography gave 40 mg product. M.p. 177–180° C.
Reaction SMILES: BrC1[C:3]([C@@H:10]([NH:20][C:21](=O)[CH2:22][N:23]2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=[N:24]2)CC2C=C(F)C=C(F)C=2)=[N:4]C(NC)=NC=1.[Br:40][C:41]1[C:42]([C@@H:51]([NH:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:52][C:53]2[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=2)=[N:43][C:44](S(C)(=O)=O)=[N:45][CH:46]=1.N1(CCN)C=CN=N1>>[N:20]1([CH2:10][CH2:3][NH:4][C:44]2[N:43]=[C:42]([C@@H:51]([NH:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:52][C:53]3[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=3)[C:41]([Br:40])=[CH:46][N:45]=2)[CH:21]=[CH:22][N:23]=[N:24]1
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Agent: NCCn1ccnn1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCCn2ccnn2)ncc1Br

Procedure:
The title compound (23C) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 23B and 2-(1H-1,2,3-triazol-1-yl)ethanamine. MS (m/z) 545.97 [M+Na]+.
Reaction SMILES: Cl.[CH:2]12[CH:7]([C:8]([NH2:10])=[O:9])[CH:6]1[CH2:5][NH:4][CH2:3]2.C(N(CC)CC)C.[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][N:4]1[CH2:5][CH:6]2[CH:2]([CH:7]2[C:8]([NH2:10])=[O:9])[CH2:3]1
Reactant: NC(=O)C1C2CNCC21
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)CCN1CC2C(C1)C2C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
The 3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (169 mg, 1.04 mmol) prepared in Example 5 and a molecular sieve were dried in vacuum and dissolved in 5 mL of methylene chloride. Then, triethylamine (151 μL, 1.08 mmol) was added dropwise at 0° C. After adding 3,3-dimethylbutyraldehyde (135 μL, 1.08 mmol), the mixture was stirred at room temperature for 1 hour. After adding sodium triacetoxyborohydride (687 mg, 3.24 mmol) and then adding 10 mL of methylene chloride, the mixture was stirred for 2 hours and 30 minutes. The completion of the reaction was confirmed by TLC (CH2Cl2:MeOH=10:1). After the reaction was completed, the reaction mixture was diluted with methylene chloride and extracted several times with saturated sodium bicarbonate. The organic layer was dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (CH2Cl2:MeOH=10:1) to obtain 173 mg (79.2%) of the target compound.
Reaction SMILES: [Na].[O:2]=[C:3]1[N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]2[C:5](=[O:19])[CH2:4]1.Br[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][C:4]1([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3](=[O:2])[N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[N:6]2[C:5]1=[O:19])=[O:24])[CH3:27]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)CC(=O)N12
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCC1(CCC(=O)OCC)C(=O)N2CCCC(C(=O)OC(C)(C)C)N2C1=O
Yield: 18.2 %

Procedure:
(b) 0.43 g of sodium was dissolved in 20 ml of ethanol. A solution of 2.27 g of tert.butyl hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in 20 ml of ethanol was added and the mixture was heated under reflux for 2 hours. 5 g of ethyl 3-bromopropionate were added and the mixture was heated under reflux for an additional 2 hours. The solvent was removed and the residue was partitioned between dichloromethane and 2N hydrochloric acid. The organic layer was separated and evaporated. The residue was chromatographed on silica gel to give 0.37 g (9%) of tert.butyl 2,2-bis(2-ethoxycarbonylethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of an oil.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][N:7]=[CH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][CH3:28].C(O)(=O)C.[OH-].[Na+]>C(O)C>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][CH3:28])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][O:6][CH3:5])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCC=NOC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCNOC
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Sodium cyanoborohydride (5.40 g, 86 mmol) was added to a mixture of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde O-methyloxime (5.60 g, 17.2 mmol), acetic acid (30 mL), and ethanol (75 mL) and stirred for 1 hour. The reaction mixture was cooled to 0° C. and the pH was adjusted to 8 with 25% sodium hydroxide solution. The reaction mixture was then concentrated under reduced pressure and diluted with dichloromethane (200 mL) and saturated aqueous sodium bicarbonate solution (75 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×75 mL). The combined organics were washed with water (2×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to afford 5.2 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-O-methyl-hydroxylamine as a light brown solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[N:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][N:21]=1.C(Cl)CCl.[Br:31][C:32]1[C:33]([CH2:49][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:36]([CH:40]=1)[C:37](O)=[O:38]>CN(C)C=O>[Br:31][C:32]1[C:33]([CH2:49][N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[C:36]([CH:40]=1)[C:37]([NH:26][C:23]1[CH:24]=[CH:25][N:20]=[N:21][CH:22]=1)=[O:38]
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Reactant: Nc1ccnnc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Reaction time: 8 h

Procedure:
Diisopropylethylamine (0.08 ml, 0.47 mmol), HOBT (43.0 mg, 0.28 mmol), 4-pyridazinamine (33.4 mg, 0.35 mmol) and EDC (90 mg, 0.47 mmol) were added to a solution of 5-bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 7; 95 mg, 0.23 mmol) in N,N-dimethylformamide (5 ml). The mixture was stirred overnight, the solvent removed in vacuo and the solid recrystallised with 1:1 methanol/DMSO to give the title compound as a white solid. 56.1 mg.