Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[F-:27]>CC(C)=O.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:27])(=[O:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)CCCCCCCc1ccc(OCc2ccccc2)cc1
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=S(=O)(F)CCCCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a stirred solution of 12.1 (0.345 g, 0.9 mmol) in dry acetone (20 mL), was added anhydrous NH4F (0.066 g, 1.8 mmol) and the mixture refluxed for 2 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated, and the residue obtained was dissolved in diethyl ether (20 mL). The ethereal solution was successively washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (20% diethyl ether-hexane) afforded 13.1 (0.306 g, 93% yield) as a white solid (m p 35-38° C.).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([OH:27])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[O:25][CH3:26])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:40]([Si:44]([CH3:47])([CH3:46])Cl)([CH3:43])([CH3:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CO.C1COCC1.O.CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([O:27][Si:44]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:47])[CH3:46])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[O:25][CH3:26])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.5 g (3.17 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,4-dimethoxyphenyl)methyl]hexanoic acid, 1.76 g (25.36 mmol) of imidazole and 2.22 g (14.26 mmol) of tert-butyldimethylchlorosilane in 16 ml of abs. DMF is stirred at RT for 20 h under argon. After that, the reaction mixture is poured onto ice-water and the whole is extracted with ethyl acetate. The organic phase is washed with cold 10% citric acid solution and saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over Na2SO4, and the solvent is removed on a RE at about 30° C. An oil is obtained which is dissolved in 42.1 ml of methanol and 14.4 ml of THF, and this solution is then treated, at RT, with 2.5 g of potassium carbonate in 14.4 ml of water. After it has been stirred at RT for 2 h, the reaction mixture is concentrated down to half its volume at approximately 30° C. and the residue is diluted with ethyl acetate; the whole is then washed with 10% citric acid solution and with saline (both being cold). The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over Na2 SO4 and evaporated. Chromatography on silica gel (D) affords the pure title compound. TLC Rf (C)=0.34.-FAB-MS (M+H)+ =588.-HPLC tRet =20.24 min (gradient II).-IR(KBr)=inter alia 1712, 1654, 1614, 1588 und 1507 cm-1.-1H-NMR(CD3OD)=inter alia 7.30-7.10/m (5H); 6.98/d (1H); 6.50/d (1H); 6.40/d×d (1H); 3.80 and 3.76/each s (each 3H); 1.31/s (9H); 0.93/s (9H); 0.14 and 0.11/each s (each 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C[C:32]([N:34](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:32]#[N:34])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc4nc(C)oc4c3)cc2c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4nc(C)oc4c3)cc2c1O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 1-chloro-4-hydroxy-6-(2-methyl-benzooxazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester (199 mg, 0.47 mmol), tris(dibenzylideneacetone)dipalladium(0) (21 mg, 0.02 mmol), 1,1′-bis(diphenylphosphino)ferrocene (26 mg, 0.04 mmol), zinc cyanide (33 mg, 0.28 mmol), zinc (4 mg, 0.06 mmol) and dimethylacetamide (1.1 mL) was stirred at 120° C. for two hours before it was cooled to room temperature, partitioned between ethyl acetate and water, filtered. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (80 mg): MS: (+) m/z 418.38 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].[CH:25]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]I)[CH2:27][CH2:26]1>C(#N)C>[CH2:1]([N:3]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:25]1[CH2:27][CH2:26]1)[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: ICCCCCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCCC1CC1)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 1-cyclopropyl-5-iodopentane (Step II) to give N-[4-[4-[ethyl(5-cyclopropylpentyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide, a compound of Formula I'. A mixture of this compound and 0.5 equivalents of fumaric acid was crystallized from acetone to give the titled product, mp 127°-128° C. Anal. calc'd for C23H38N2O5S: C, 60.76; H, 8.42; N, 6.16; S, 7.05. Found: C, 60.66; H, 8.30; N, 6.17; S, 7.04.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18]([O-:20])=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18]([OH:20])=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)sc1C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccc(OCCCCl)cc2)sc1C(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate i105 (14.1 mmol, 1 eq, 4.6 g) and 2 M sodium hydroxide (28.2 mmol, 2 eq, 14.1 ml) in methanol (100 ml) is stirred at 70° C. overnight. The mixture is concentrated to dryness and taken up in a minimum of water. The aqueous phase is acidified by 1 N hydrogen chloride to reach pH 2 and poured into ice to afford precipitation of a white solid. The solid is filtered and dried under reduced pressure to give 3.9 g of 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid i106 as a white solid. This solid is used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1.Cl[C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(O)(=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:15]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ccc(C(F)(F)F)cc2C(=O)O)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (8.71 g, 50.0 mmol), 2-chloro-5-(trifluoromethyl)benzoic acid (12.4 g, 55.0 mmol), copper acetate (II) (1.00 g, 5.50 mmol) and potassium carbonate (7.60 g, 55.0 mmol) in N,N-dimethylformamide (50 mL) was heated under reflux for 1.5 hours under an argon atmosphere. The solution was cooled to room temperature, and poured into water. The solution was made acidic by the addition of acetic acid, and the resulting crude crystals were collected by filtration. The crystals were washed with water and air dried to give the title compound (17.7 g, 89% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCOCCCC(NC(=O)OC(C)(C)C)C(=O)N3C2)cc1
Yield: 35.7 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-methoxybenzoyl chloride (89 mg, 0.53 mmol). The final trituration (diethyl ether) and filtration gave 44 mg (36%) of 18-(4-methoxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.9% pure (HPLC), MS m/z 703 (M−H)−, HRMS: calcd. 705.2806 and found 705.2801 (M+H)+, mp 145-147° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]#N)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:31].[Na+].[K+]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH:18]=[O:31])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc([C@H]2CC[C@H](C#N)CC2)cc1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.0 g of trans-4-(p-pentylphenyl)cyclohexanecarbonitrile in 60 ml of methylene chloride was placed at -78° C. under argon gasification in a sulphonation flask equipped with a mechanical stirrer and treated within 3 minutes with 13.2 ml of a 1.5M solution of diisobutylaluminium hydride in toluene. The mixture was subsequently stirred for a further 2 hours with gradual warming to room temperature, then poured cautiously into 100 ml of 10% potassium sodium tartrate solution and extracted three times with 200 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over potassium carbonate and concentrated. There were obtained 1.98 g of trans-4-(p-pentylphenyl)cyclohexanecarboxaldehyde (purity 86.1%) as a viscous oil which was used without additional purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C(O)C>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(N)ccc1OCc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OCc2ccccc2)c(OC)c1)C(=O)OCC
Temperature: 120 °C
Yield: 100.1 %

Procedure:
A mixture of 4-(Benzyloxy)-3-methoxyaniline (9.3 g, 40 mmol) and diethyl ethoxymethylenemalonate (9.65 g, 45 mmol) were heated at 120° C. for 1–1.5 h, the ethanol produced was removed under reduced pressure, affording 16 g (100% yield) of the title compound.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:13][CH:14]=1
Reactant: OC(CCl)CCCl
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(OCC(O)CCCl)cc1

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-t-butylphenol to give white title compound, m.p. 45°-47° C. Petroleum ether (30°-60° C.) was the recrystallizing solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[O:18][CH3:19])[N:14]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:13](=[O:28])[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.Cl.O1CCOCC1.C(#N)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[O:18][CH3:19])[N:14]([CH2:20][C:21]([OH:23])=[O:22])[C:13](=[O:28])[CH2:12][CH2:11]3)=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1-c1ccc(Cl)cc1)CCC(=O)N2CC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1cc2c(cc1-c1ccc(Cl)cc1)CCC(=O)N2CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To the crude (tert-butyl 2-(6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate) form Example 4D was added 4N hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol). The reaction mixture was stirred at room temperature for 4 hours, and concentrated under reduced pressure. A second portion of 4N hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol) and anhydrous N,N-dimethylformamide (2 mL) were added, and the mixture stirred for another 13 hours. The solvent was removed under reduced pressure, and the crude reaction product subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 2-(6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (95 mg, 0.27 mmol, 72%). LCMS mz 346.0 (M+H), 368.0 (M+Na), anal HPLC >98% in purity. 1H NMR (400 MHz; CDCl3) δ 7.42 (d, J=8.6 Hz, 2H); 7.36 (d, J=8.6 Hz, 2H); 7.11 (s, 1H); 6.48 (s, 1H); 4.75 (s, 2H); 3.79 (s, 3H); 2.93 (m, 2H); 2.75 (m, 2H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26](I)=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(N(CC)CC)C>CN1C(=O)CCC1.C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([CH:29]=[CH2:30])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4cc(I)ccn34)nc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C=Cc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Temperature: 60 °C

Procedure:
To 8-(tert-butyldimethylsilyloxy)-2-(7-iodo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline (2.011 g, 4.003 mmol) in NMP/THF (10 mL/10 mL) was added tributyl(vinyl)stannane (1.523 g, 4.803 mmol), trifuran-2-ylphosphine (0.0929 g, 0.400 mmol), Pd2 dba3 (0.367 g, 0.4003 mmol) and triethylamine (0.405 g, 4.00 mmol). The reaction was degassed with N2 and heated to 60° C. for 1 hour. The crude mixture was diluted with ethyl acetate and the organic layer was washed with H2O. The combined organics fractions were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (eluting with a 5:1 mixture of Hexanes/ethyl acetate), affording the desired product.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:55][CH:56]3[CH2:58][CH2:57]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([Cl:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[C:68]([CH2:70][C:71](O)=[O:72])#[N:69]>C(Cl)Cl>[Cl:54][C:50]1[CH:49]=[C:48]([NH:47][C:45]([C:42]2[N:40]3[N:41]=[C:36]([NH:35][C@H:32]4[CH2:31][CH2:30][C@H:29]([NH:28][C:71](=[O:72])[CH2:70][C:68]#[N:69])[CH2:34][CH2:33]4)[CH:37]=[C:38]([NH:55][CH:56]4[CH2:57][CH2:58]4)[C:39]3=[N:44][CH:43]=2)=[O:46])[CH:53]=[CH:52][N:51]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Reactant: N#CCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CCC(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BOP (60.2 mg, 0.136 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (20.00 mg, 0.045 mmol), DIEA (0.032 mL, 0.181 mmol) and 2-cyanoacetic acid (7.72 mg, 0.091 mmol) in DCM (1 mL). The clear reaction mixture was stirred at room temperature for 30 min, concentrated and diluted with MeOH and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to isolate N-(2-chloropyridin-4-yl)-6-((trans)-4-(2-cyanoacetamido)cyclohexylamino)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (11 mg, 0.022 mmol, 47.7% yield) as white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.772 minutes. [M+H]=508.11. 1H NMR (400 MHz, MeOD) δ ppm 8.24-8.39 (1H, m), 7.95-8.03 (1H, m), 7.87-7.97 (1H, m), 7.51-7.67 (1H, m), 5.98-6.11 (1H, m), 3.60-3.83 (2H, m), 2.47-2.66 (1H, m), 2.19-2.37 (2H, m), 1.96-2.19 (2H, m), 1.28-1.55 (4H, m), 0.77-0.96 (2H, m), 0.52-0.75 (2H, m).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:24])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1cccnc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:5]([C:6]([O:8]C)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[O:16][CH3:17].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[O:16][CH3:17]
Reactant: COC(=O)c1c(Cl)cc(Cl)c(OC)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Yield: 94.1 %

Procedure:
To the methyl ester 2-2 (9.90 g, 35.3 mmol) in MeOH (150 mL) was added 2N NaOH (150 mL) and the reaction was heated to reflux for 2.5 h. Methanol was removed in vacuo and the mixture was extracted with EtOAc. The aqueous layer was acidified to pH 2 with a concentrated solution of HCl and then extracted into EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to provide the acid 2-1 as an orange solid (8.84 g, 94% yield). 1H NMR (400 MHz, d6-DMSO) δ 3.83 (s, 311), 3.95 (s, 3H), 8.23 (s, 1H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(O)=O>CCO>[CH2:21]([N:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(CN(Cc1ccccc1)Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 79.3 %

Procedure:
To a suspension of D-glucose (36.0 g, 200.0 mmol) and Bn2NH (39.5 g, 200.0 mmol) in absolute EtOH (200 mL) was added AcOH (12.0 g, 200.0 mmol). Upon refluxing for 3 h, the reaction mixture was cooled and filtered with suction. The resulting filter cake was washed with EtOH to colorless and dried in a desiccator over calcium chloride to give 1-dibenzylamino-1-deoxy-D-fructose as a white solid (57.0 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:19])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]2=O)=[CH:4][C:3]=1[S:20]([NH2:23])(=[O:22])=[O:21].O=C1C2C(=CC=CC=2)C(=O)N1.C(O)(=O)C.Cl>CN(C)C=O.[Zn].C(O)(=O)C.[Zn]>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:19])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8]2)=[CH:4][C:3]=1[S:20]([NH2:23])(=[O:22])=[O:21]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(Cc1ccccn1)C2=O
Agent: Cl
Agent: O=C1NC(=O)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc2c(cc1Cl)CN(Cc1ccccn1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Zinc-acetic acid reduction of 6-chloro-2,3-dihydro-1,3-dioxo-2-(2-pyridinylmethyl)-1H-isoindole-5-sulfonamide. Zinc dust (0.5 mole) is added in one portion to the 1,3-dioxoisoindole (0.1 mole) of part (a) in 800 ml. of acetic acid. The reaction mixture is stirred at room temperature for 1.0 hr. and then heated to reflux for a 6 hr. period during which time additional 9.0 g. portions of zinc are added at the end of 3, 4, and 5 hr., respectively. After stirring overnight, the reaction mixture is filtered and the filtrate concentrated to dryness under reduced pressure with additional water added to the residue and removed in vacuo to remove traces of acetic acid. Residual material is slurried in water, filtered, and the filtrate concentrated to dryness. Residual material is stirred with saturated sodium bicarbonate solution and an immiscible organic solvent such as hot ethyl acetate. The organic fraction is separated, dried over MgSO4 and concentrated to provide the product as the free base. The free base taken up in dimethylformamide and acidified with ethanolic hydrogen chloride affords 6-chloro-2,3-dihydro-3-oxo-2-(2-pyridinylmethyl)-1H-isoindole-5-sulfonamide hydrochloride.