Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1B(O)O)#[N:2].C([O-])([O-])=O.[K+].[K+].[CH3:20][O:21][C:22](=[O:50])[C@H:23]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](OS(C(F)(F)F)(=O)=O)=[CH:38][CH:37]=1)[NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][O:21][C:22](=[O:50])[C@H:23]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][C:5]=2[C:9]#[N:10])=[CH:40][CH:41]=1)[NH:24][C:25](=[O:34])[C:26]1[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: N#Cc1cccc(C#N)c1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2c(C#N)cccc2C#N)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 90 °C
Yield: 12.1 %

Procedure:
To a mixture of 2,6-dicyanobenzene boronic acid (0.516 g) and anhydrous K2CO3 (0.2 g) in toluene (10 mL) under N2 was added N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester (0.5 g). Pd(PPh3)4 (0.1 g) was added and the mixture was heated at 90° C. for 8 h. The mixture was cooled, diluted with EtOAc and washed successively with water and brine. The organic layer was dried (MgSO4) and evaporated, and the residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 1/1) to yield 58 mg of N-(2,6-dichlorobenzoyl)-4-(2,6-dicyanophenyl)-L-phenylalanine methyl ester.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(=O)=O.[CH2:15]([C:22]1([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:15]([C:22]1([OH:28])[CH2:27][CH2:26][N:25]([CH2:5][CH2:6][C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)CCC#Cc1ccccc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1(Cc2ccccc2)CCN(CCC#Cc2ccccc2)CC1
Yield: 30.4 %

Procedure:
A mixture of 1-mesyl-4-phenylbut-3-yne (300 mg, 1.34 mmol), 4-benzyl-4-hydroxypiperidine (307 mg, 1.61 mmol) and K2CO3 (555 mg, 4.02 mmol) in 15 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×20 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as an off-white solid (130 mg, 30%): mp 80-82° C.; 1H NMR (CDCl3) 1.50 (m, 3 H), 1.74 (m, 2 H), 2.41 (m, 2 H), 2.58 (m, 3 H), 2.75 (m, 5 H), 7.11-7.38 (m, 10 H).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1.O>CO>[NH:15]1[C:12]2[CH:13]=[CH:14][C:9]([C:1]3[CH:6]=[CH:5][C:4]4[N:7]=[C:22]([C:21]5[CH:25]=[CH:26][C:18]([NH2:17])=[CH:19][CH:20]=5)[NH:8][C:3]=4[CH:2]=3)=[CH:10][C:11]=2[N:16]=[C:9]1[C:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2nc3cc(-c4ccc5nc(-c6ccc(N)cc6)[nH]c5c4)ccc3[nH]2)cc1
Temperature: 200 °C
Yield: 97.5 %

Procedure:
A homogenous mixture of biphenyl-3,3′,4,4′-tetraamine (500 mg, 2.34 mmol) and 4-aminobenzoic acid (640 mg, 4.67 mmol) was added portionwise to stirred PPA (20 mL) at 200° C. The mixture was stirred at 200° C. for 2.5 h. The mixture was cooled (to <100° C.) and poured into water. The resulting mixture was stirred until a uniform green precipitate had formed. The solid was filtered off and washed with aqueous K2CO3 and water, then dried under suction. The crude product was purified by column chromatography (99:1 EtOAc-NEt3 to 89:10:1 EtOAc-MeOH-NEt3) to afford a yellow solid. This was dissolved in MeOH and 1M HCl, and then concentrated in vacuo. The material was then ground to a fine powder and stirred in aqueous NaHCO3. The solid was filtered, washed with water and dried (vacuum oven) to give the product as a yellow solid (475 mg, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>N1C=CC=CC=1>[F:35][C:23]([F:22])([F:34])[C:24]1[CH:25]=[C:26]([S:30]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:16]=[C:15]4[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]4)=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)(=[O:31])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1n[nH]c2cc(-c3cccc(N)c3)ccc12
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1n[nH]c2cc(-c3cccc(NS(=O)(=O)c4cccc(C(F)(F)F)c4)c3)ccc12
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl 6-(3-aminophenyl)-1H-indazole-3-carboxylate (10 mg) in pyridine (1 Ml), was added 3-trifluoromethylbenzenesulfonyl chloride (6.3 μl) at room temperature. After 3 h, pyridine was removed by evaporation. Ethyl acetate and water were added and the aqueous layer was extracted with ethyl acetate three times. The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated in ethyl acetate/hexane to give ethyl 6-(3-(3-(trifluoromethyl)phenylsulfonamido)phenyl)-1H-indazole-3-carboxylate (8.6 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([CH2:16][CH2:17][C:18](Cl)=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH2:16][CH2:17][C:18]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: O=C(CCC1CCCC1)Nc1ccc(C(=O)O)cc1

Procedure:
4-(3-Cyclopentylpropionylamino)-benzoic acid was prepared as described in Example 3 from 9.63 g (0.07 mol) of p-aminobenzoic acid and 12.4 g (0.077 mol) of 3-cyclopentylpropionyl chloride.
Reaction SMILES: [OH-].[Na+].O1CCOCC1.C([O:12][C:13]1[CH:40]=[CH:39][C:16]([C:17]([NH:19][C:20]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:29][C:21]=2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])=[C:15]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:14]=1)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[CH2:42]([O:41][C:15]1[CH:14]=[C:13]([OH:12])[CH:40]=[CH:39][C:16]=1[C:17]([NH:19][C:20]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(O)cc1OCc1ccccc1
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A 4 mol/L aqueous solution of sodium hydroxide (0.47 mL) was added to a dioxane (5.0 mL) solution of the obtained tert-butyl 2-(4-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.34 g), followed by stirring at 50 to 55° C. for 2 hours. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid (15 mL) and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.29 g of tert-butyl 2-(2-(benzyloxy)-4-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:20][CH2:21][C:22]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)=[CH:28][CH:27]=1)([CH3:25])[CH2:23][OH:24]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:22]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:20])=[CH:31][CH:30]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(CO)(CO)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (103 mg, 0.33 mmol, 1.0 eq) in DMF (5 mL) was added TEA (0.092 mL, 0.66 mmol, 2.0 eq) followed by phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)phenylcarbamate (100 mg, 0.33 mmol, 1.0 eq) at 0° C. and the mixture was stirred for 16 h at RT. The reaction mixture was concentrated under vacuum and the residue purified by neutral alumina column chromatography using MeOH/CHCl3 (0.5:9.5) as eluent to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,3-dihydroxy-2-methylpropan-2-yl)phenyl)urea (105 mg; 65%) as a white solid (TLC system: MeOH/CHCl3 (1:9), Rf: 0.3).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([OH:12])[C@@H:6]([CH2:10][OH:11])[O:7]2)[O:3]1.N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([OH:12])[C@@H:6]([CH2:10][O:11][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[O:7]2)[O:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)O[C@H]2O[C@H](CO)[C@H](O)[C@H]2O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@H](O)[C@H]2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of 1,2-O-isopropylidene-α-D-xylofuranose 1 (30 g, 0.15 mol) in 360 mL of CH2Cl2 was cooled to 0° C. and to it was added 20 mL (0.23 mol) of pyridine and a catalytic amount (1.0 g) of N, N-dimethylaminopyridine. The resulting mixture was stirred at 0° C. for 10 min, at which time 20 mL (0.17 mol) benzoyl chloride was added to it dropwise over a period of 30 min. The reaction mixture was stirred at 0° C. for an additional 30 min and then quenched by the addition of 200 mL a saturated solution of NH4Cl. The reaction was allowed to warm to room temperature, the layers were separated, and the aqueous layer was extracted with 3×50 mL of CH2Cl2. The combined organic extracts were washed with 3×50 mL of a 10% aqueous solution of CuSO4, 2×50 mL of water and brine. The organic solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product mixture was purified by chromatography on silica gel to afford 44.3 g (95% yield) of 2 as a colorless liquid: Rf 0.54 (60% EtOAc/hexane); 1H-NMR (CDCl3) δ 8.03 (m, 2H), 7.40-7.68 (m, 3H), 5.97 (d, 1H, J=3.6 Hz), 4.80 (m, 1H), 4.61 (d, 1H, J=3.4 Hz), 4.37 (m, 2H), 4.20 (s, broad, 1H), 3.35 (broad, 1H), 1.50 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: COCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 3-methoxypropan-1-ol (15.9 mL, 166 mmol) in CH2C12 (75 mL) and pyridine (50 mL) was added 4-(dimethylamino)pyridine (1.0 g, 8.3 mmol) followed by p-toluenesulfonyl chloride (31.7 g, 166 mmol). The mixture was allowed to stir at ambient temperature for 72 hours then was quenched with 5% aqueous HCl (20 mL), extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (31 g, 127 mmol, 76% yield). MS (DCI/NH3) m/z 262 (M+NH4)+.
Reaction SMILES: [NH2:1][C@H:2]([CH3:30])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)=[C:18]([Cl:29])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:31][C@@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34]>>[Cl:29][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][C@H:2]([NH:1][C:33](=[O:34])[C@H:32]([OH:31])[CH2:37][CH2:36][OH:35])[CH3:30])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: O=C1OCC[C@H]1O
Reactant: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12)NC(=O)[C@H](O)CCO
Yield: 73 %

Procedure:
The procedure described in Example 63 was repeated using 5-{[(2R)-2-aminopropyl]oxy}-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine and (R)-(+)-α-hydroxy-γ-butyrolactone to give the title compound in 73% yield; NMR spectrum (DMSO-d6) 1.22 (d, 3H), 1.46-1.61 (m, 1H), 1.72-1.87 (m, 1H), 3.40-3.54 (m, 2H), 3.84-3.97 (m, 1H), 4.19-4.41 (m, 3H), 4.42-4.58 (m, 1H), 5.35 (s, 2H), 5.40 (d, 1H), 7.14 (d, 1H), 7.25-7.38 (m, 2H), 7.53 (dd, 1H), 7.72 (t, 1H), 7.80 (d, 1H), 7.92-8.05 (m, 2H), 8.47 (s, 1H), 9.14 (d, 1H), 9.75 (s, 1H); Mass spectrum MH+ 543.9.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H].O.N>C(O)(=O)C.[Pd]>[CH2:2]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC(O)c1ccc(CC(=O)OCC)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCc1ccc(CC(=O)OCC)cc1
Temperature: 0 °C
Yield: 88.8 %

Procedure:
To the solution of ethyl 4-(1-hydroxyundecyl)-phenylacetate (9.7 g, 0.029 mol) in acetic acid (50 ml) was added 10%-palladium on carbon. The reaction mixture was stirred for 18 hours under 1 atmospheric pressure of hydrogen and then poured onto the mixture of concentrated ammonia water (100 ml) and ice (100 g). The resultant precipitate was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure to obtain ethyl 4-undecylphenylacetate (3-w, 8.2 g, 88%) as an oil.
Reaction SMILES: [CH:1]([CH:4]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[C:12]([CH:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)#[N:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH:1]([CH:4]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:5]([O:7][CH:14]([C:12]#[N:13])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CC(Br)c1cccc(Oc2ccccc2)c1
Reactant: C=C(C)CC(C(=O)O)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)CC(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-isopropyl-4-methylpent-4-enoic acid (1.0g), alpha-cyano-3-phenoxybenzyl bromide (1.9g) and potassium carbonate (1.0g) in anhydrous acetone (40ml) was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the product extracted with ether, the ethereal extracts washed with water (X2) and dried over magnesium sulphate. Evaporation of the solvent gave a crude product which was purified by chromatography on silica gel using 3% acetone in 60°-80° C. petroleum ether as eluent to give the desired ester. R.I. nD20 1.5343.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:19][NH:20][NH2:21].CC(O)=O>C(O)CCC>[Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:21][NH:20][CH3:19])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Reactant: CNN
Solvent: CC(=O)O
Solvent: CCCCO
Product: CNN=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Temperature: 135 °C
Yield: 61.5 %

Procedure:
A mixture of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone (0.383 g, 1.46 mmol; Example #23, Step B), methylhydrazine (0.24 mL, 4.56 mmol), and AcOH (0.084 mL, 1.47 mmol) in n-butanol (10 mL) was heated at about 135° C. for about 18 h. During this time, water was distilled from the reaction mixture via the use of a Dean-Stark trap. Additional methylhydrazine (0.24 mL, 4.6 mmol) and AcOH (0.084 mL, 1.5 mmol) were added and the reaction mixture was heated at reflux for about 2 days. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude product was diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-35% EtOAc in heptane gradient as the eluent to provide 5-chloro-4-(cyclohexyl(2-methylhydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine (0.261 g, 62%): LC/MS (Table 2, Method d) Rt=2.53 min; m/z: 291 and 293 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([C:20]5[CH:24]=[CH:23][NH:22][N:21]=5)=[CH:18][C:17]([C:25]([O:27]C)=[O:26])=[N:16][N:15]4[C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].O.Cl>CO>[NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([C:20]5[CH:24]=[CH:23][NH:22][N:21]=5)=[CH:18][C:17]([C:25]([OH:27])=[O:26])=[N:16][N:15]4[C:29]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(-c2cc[nH]n2)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC1(c2ccc(-c3nc4c(-c5cc[nH]n5)cc(C(=O)O)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 6 %

Procedure:
To a solution of methyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Example 56 (0.19 g, 0.41 mmol) in MeOH (5 mL) was added an aqueous NaOH solution (10% 0.65 mL, 1.64 mmol, 4.0 equiv). The resulting mixture was stirred at room temperature for 48 h. Water 10 mL) was added to the resulting mixture and the pH was adjusted to pH 4 using an aqueous 2N HCl solution. The resulting precipate was collected by filtration, and recrystallized from dimethyl sulfoxide to give 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylic acid (0.012 g, 6%).
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:43])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])[O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])=[O:23])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.O>[F:32][C:29]([F:30])([F:31])[C:28]1[O:27][C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])=[N:25][C:24]=1[C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][C:3]([OH:44])=[O:2])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)=[O:43])=[O:23]
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4C(F)(F)F)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4C(F)(F)F)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-{[5-trifluoromethyl-2-(2-trifluoromethylphenyl)oxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (455 mg, 0.727 mmol) was put into THF/water (50 mL, 3:1) solvent, and NaOH (145.47 mg, 3.637 mmol) was added thereto. The mixture was stirred at room temperature for 24 hours, THF was removed, and pH of the mixture was adjusted to be 2-3 with 1N hydrochloric acid. The reaction mixture was extracted with EtOAC (3×100 mL), washed with brine and dried with anhydrous sodium sulfate, and the solvent was removed. The obtained crude material was crystallized with acetonitrile to obtain the desired compound (435 mg, 98%) as a white solid.
Reaction SMILES: [CH2:1]([O:13][C:14](=[O:20])[C@H:15]([C@@H:17]([CH3:19])[OH:18])[NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:21](=[O:24])([O-])O.[Na+].Cl>O1CCOCC1.O>[CH2:1]([O:13][C:14](=[O:20])[C@H:15]([C@@H:17]([CH3:19])[OH:18])[NH:16][C:21](=[O:24])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCOC(=O)[C@@H](NC(=O)CCCCCCCCCCC)[C@@H](C)O
Temperature: 90 °C

Procedure:
The L-threonine dodecyl ester (8.8 g) was dissolved in 1,4-dioxane (60 ml) and water (50 ml), and sodium hydrogencarbonate (3 g, 35.7 mmol) and N-succinimidyl laurate (6.48 g, 21.8 mmol) were added. The cloudy mixture was refluxed at approximately 90° C. for 1 hour and then left to cool. At 50° C., the mixture was adjusted to pH 2-3 using 10% HCl and cooled to 15 to 20° C. in an ice bath. At approximately 40° C. the product begins to precipitate out. The crude product is filtered off, washed with water and recrystallized from methanol. Yield: 7.75 g (16.5 mmol, 78% over 2 steps) of colourless crystalline needles (HPLC>99%). m.p.: 97-98° C., 1H-NMR (CDCl3)δ=0.86 to 0.90 (6H, mn), 1.23 (3H, d, 6.4 Hz), 1.24 to 134 (34H, m), 1.60 to 1.70(4H, m), 2.00 (1H, d, 5.8 Hz), 2.43 (2H, dd, 2*7.4 Hz), 4.16 (2H, t, 6.8 Hz), 4.30 to 4.37 (1H, m), 4.61 (1H, dd, 8.8 Hz, 2.6 Hz), 6.15 ppm (1H, d, 8.8 Hz); 13C-NMR (CDCl3)δ=173.7 (s), 171.3 (s), 68.3 (d), 65.9 (t), 57.0 (d), 36.7 (t), 31.9 (2C, t), 29.7 (2C, t), 29.6 (5C, t), 29.5 (t), 29.4 (2C, t), 29.3 (t), 29.2 (t), 28.5 (t), 25.8(t), 25.7 (t), 22.7 (2C, t), 20.0 (q), 14.1 ppm (2C, q); elemental analysis: calc.: C 71.6%, H 11.8%, N 3.0%, O 13.6%; found: C 71.8%, H 11.2%, N 2.9%, O 13.5%.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](C3C=CC=C(C(F)(F)F)C=3)=[N:8][C:7]=2[CH:21]=1.B(Br)(Br)Br>C(Cl)Cl>[O:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:21][C:7]=2[N:8]=[CH:9]1
Reactant: COc1ccc2oc(-c3cccc(C(F)(F)F)c3)nc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: c1ccc2ocnc2c1
Reaction time: 48 h

Procedure:
To a solution of compound 10 (200 mg, 0.68 mmol) in CH2Cl2 (5 mL) was added BBr3 (1M in CH2Cl2, 1 mL, 1 mmol) dropwise. The resulting solution was allowed to stir for 48 h. The solvent was removed by evaporation (in vacuo) and the residue was dissolved in ethyl acetate and washed with saturated NaHCO3. The organic layer was dried over MgSO4 and evaporated (in vacuo). The residue was purified using column chromatography (30% ethyl acetate/hexanes) to yield compound 8 as a white solid.