Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=O.[Na+].[BrH:14]>O>[Br:14][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: Br
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](Br)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
D-Leucine (9.9 g, 75.2 mmol) was dissolved in 3M HBr in water (120 mL) and cooled to 0° C. A solution of sodium nitrite (8.3 g, 120 mmol) in water (20 mL, 100 mmol) was added. The mixture was stirred at 0° C. for 2.5 hours, extracted twice with EtOAc, washed twice with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to afford 12.6 g (86%) of Intermediate (9a) as a pale yellow oil. This was taken on to the next step without further purification.
Reaction SMILES: C(OC([N:8]([CH2:26][C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([O:44]C)=[O:43])=[CH:40][CH:39]=3)[CH:33]=2)[O:28]1)[CH2:9][C@@H:10]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[O:11][SiH2]C(C)(C)C(C)(C)C)=O)(C)(C)C.[Li+].[OH-].CO.P(=O)(O)(O)O>O1CCCC1>[OH:11][C@H:10]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][NH:8][CH2:26][C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=3)[CH:33]=2)[O:28]1
Reactant: COC(=O)c1ccc(Cc2ccc3c(c2)CC[C@H](CN(C[C@H](O[SiH2]C(C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)cc1
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 77.2 mg (0.11 mmol) methyl 4-[((2R)-2-{[(tert-butoxycarbonyl)((2R)-2-(3-pyridinyl)-2-{[([(1,1,2,2-tetramethylpropyl)silyl]oxy}ethyl)amino]-methyl}-3,4-dihydro-2H-chromen-6-yl)methyl]benzoate (Example 167) in 1 mL of tetrahydrofuran was added 0.54 mL of 1 M LiOH and 0.27 mL methanol. The mixture was stirred at room temperature for 3 hours after which point 0.5 mL of 1N phosphoric acid was added to the solution. The mixture was partitioned between ethyl acetate (3×5 mL) and water (5 mL). The organic layer was washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated. To the residue was added 0.4 mL of hydrochloric acid in dioxane. This solution was stirred at room temperature for 0.5 hour. The solution was then washed with water and concentrated in vacuo, followed by purification by preparative HPLC (gradient of 100:0 0.1% TFA/H2O:acetonitrile to 30:70 0.1% TFA/H2O:acetonitrile) to obtain 16.4 mg of product as the TFA salt. MH+ 419.3.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[C:14](N)[S:15][C:11]=2[CH:10]=1.[ClH:19]>CC#N.[Cu](Cl)Cl>[Cl:19][C:14]1[S:15][C:11]2[CH:10]=[C:9]([CH3:8])[CH:18]=[CH:17][C:12]=2[N:13]=1
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
t-Butyl nitrite (3.25 mL, 27.4 mmol) was added to a suspension of copper (II) chloride (2.95 g, 22.0 mmol) in CH3CN (31 mL). 6-Methyl-2-aminobenzothiazole (3.0 g, 18 mmol) was added portionwise over ˜30 min., and the reaction mixture was stirred at rt overnight. The reaction mixture was poured into 20% aqueous HCl (100 mL) and was extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 10% EtOAc in Hexanes gradient), yielding 2.50 g (74%) of the title compound as a yellowish oil that solidified on standing. LC-MS: RT=9.71 min., [M+H]+=184.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(CCCCBr)COC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
In a 500 ml three-neck flask fitted with a condenser and magnetic stirrer was placed under argon a mixture of 6-bromo-2,2-dimethyl-1-hydroxyhexane (25 g, 0.119 mol), dichloromethane (300 ml) and p-toluenesulfonic acid (0.15 g, 0.78 mmol). 3,4-Dihydro-2H-pyran (12.57 g, 0.1495 mol) was added slowly to the mixture at 0° C. The reaction mixture was stirred at room temperature for one hour, and then the mixture was filtered through aluminum oxide, which was further washed with dichloromethane (200 ml). The combined fractions were evaporated under vacuum to provide 33.73 g (97%) of the above-titled compound as a pale-yellow residue, ca. 90%: 1H NMR CDCl3, δ (ppm): 4.48-4.52 (m, 1H), 3.90-3.75 (m, 1H), 3.50-3.35 (m, 4H), 2.95 (d, J=12 Hz, 1H), 1.90-1.20 (m, 12H), 0.90 (s, 6H); 13C NMR CDCl3, δ (ppm): 99.0, 76.2, 61.8, 38.2, 34.0, 33.8, 33.6, 30.5, 25.5, 24.5, 24.4, 22.5, 19.3.
Reaction SMILES: Cl[CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[Cl:13]C(CCC)CC(OC(C)C)=O>CO>[Cl:13][CH2:12][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7]
Reactant: CCCC(Cl)CC(=O)OC(C)C
Reactant: CC(Cl)CCCC(=O)OC(C)C
Solvent: CO
Product: CC(C)OC(=O)CCCCCCl
Reaction time: 90 h

Procedure:
A solution of 10.5 gm (0.03 mol) of diamine 15, 6.2 gm (0.03 mol) of isopropyl 5-chlorohexanoate, and 10.0 gm of MeOH was charged to the flask and heated to reflux. After 90 hours, 1.0 gm (5 mmol) of isopropyl 3-chlorohexanoate was added to the mixture. At least 5% amine was present after refluxing 6 hours and the heating was stopped. The crude product was removed of volatiles by rotary evaporation and washed until all of the residue was removed leaving 15 gm (94%) of Quat 7.
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3]1.CC([O-])(C)C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:3]1
Reactant: OCCCN1CCC(F)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCCN2CCC(F)C2)cc1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 82 %

Procedure:
The crude 3-(3-Fluoro-pyrrolidin-1-yl)-propan-1-ol (assumed 3.06 mmol) was dissolved in THF (8 mL) and was cooled to 0° C. The 0° C. solution was treated consecutively with KOtBu (1.5 g, 13.5 mmol) then 4-fluoronitrobenzene (423.3 mg, 3 mmol). The resulting reaction mixture was allowed to warm to room temperature and stir for an additional 4.5 h. The reaction mixture was quenched with the addition of ice water (50 mL) followed by extraction with EtOAc (75 mL). The organics were subsequently washed with room temperature H2O (75 mL), then saturated NaHCO3(aq) (75 mL), and finally with brine (75 mL). The organics then were dried over anhydrous sodium sulfate, decanted and concentrated in vacuo to yield crude 3-Fluoro-1-[3-(4-nitro-phenoxy)-propyl]-pyrrolidine (660 mg) as a yellow oil. This material was carried on without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].O.O.O.O.O.O.O.O.O.[S-2:22].[Na+].[Na+]>C(O)C.O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[SH:22]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1S
Temperature: 100 °C

Procedure:
To a suspension of 2-chloro-5-nitroanisole (1.00 g; 5.33 mmol) in 10 mL of ethanol at rt was added a solution of sodium sulfide nonahydrate (1.30 g; 5.41 mmol) in 1.4 mL of water and 0.8 mL of ethanol in three portions over 3 minutes. The resulting suspension was heated at 100° C. for 10 min. The suspension was cooled and concentrated under reduced pressure to a dark solid which was used immediately in the next step. HPLC 2.23 min retention time; LCMS (ES): m/z 186 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:54])([O:4][C:5]([N:7](CC1C=CC(OC)=CC=1)[C@@H:8]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:9]1[CH:37]([OH:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:6])[CH3:3].C(#N)C.O.[Cl-].[Na+]>O.C(OCC)(=O)C>[CH3:54][C:2]([CH3:3])([O:4][C:5]([NH:7][C@@H:8]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:11]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:10]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:9]1[CH:37]([OH:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:6])[CH3:1]
Reactant: CCOC(=O)CC(O)[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1N(Cc1ccc(OC)cc1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)[C@H]1[C@H](NC(=O)OC(C)(C)C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
Dissolve [1R,2S,3R,4S,5R]-2-[[(1,1-dimethylethoxy)carbonyl][(4-methoxyphenyl)methyl]amino]-β-hydroxy-3,4,5-tris(phenylmethoxy)-cyclopentanepropanoic acid, ethyl ester (2.018 g, 2.73 mmol) in a 4:1 mixture of acetonitrile/water (75 mL) and cool to 0° C. with an ice bath. Add ceric ammonium nitrate (4.23 g, 7.72 mmol) and stir for 1 hour. Pour into a mixture of water/ethyl acetate containing sodium chloride, separate the organic phase, wash with dilute sodium hydrogen carbonate and aqueous sodium chloride. Dry (MgSO4), evaporate the solvent in vacuo and subject to Kugelrohr distillation to remove p-methoxybenzaldehyde (94° C. @ high vacuum) to give the title compound remaining as a white solid which is recrystallized from cyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[N:22])[C:16]3=[O:23])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[Cl-:26].[NH4+:27]>CO.C[O-].[Na+]>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21](=[NH:27])[NH2:22])[C:16]3=[O:23])[CH2:13][CH2:14]2)=[O:8])=[CH:24][CH:25]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COc1ccc(C(=O)C2CCN(C3CCN(CC#N)C3=O)CC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC(=N)N)C3=O)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetonitrile (690 mg, 2.0 mmol) in methanol (15 mL) was added sodium methoxide (0.046 mL, 0.20 mmol, 25%) and the mixture was stirred at ambient temperature for 2 h. Ammonium chloride (120 mg, 2.3 mmol) was added and the mixture was stirred at ambient temperature for 60 h. The reaction mixture was concentrated in vacuo, ethyl acetate in heptane (40%) was added, stirred at ambient temperature for 1 h then filtrated. the resulting solid was washed with ether to give a pale solid (800 mg, 100% yield). MS m/z 342.4 (M+1), retention time 0.79
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][C:17]([C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH2:29])[CH:28]=1)=[CH:16]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][C:17]([C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH:29][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:28]=1)=[CH:16]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
4-Nitrobenzaldehyde (0.3 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 6 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added, and the mixture was stirred for 2 hours. The mixture was shaken; the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a red solid. Recrystallization from methanol gave the product (450 mg), mp 181-182° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN1C(=O)CCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:7]2[CH:6]=[C:5]([Cl:9])[N:4]=[N:3][C:2]=2[Cl:1])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1cc(Cl)c(Cl)nn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nnc2Cl)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
3,4,6-Trichloropyridazin (10.5 g; 57.25 mmol) was dissolved in 10 ml of dry NMP. Afterwards were added DIPEA (28.4 ml; 171.73 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (12.04 g; 60.11 mmol) and all let stir at ambient temperature for 16 hours and 3 hours at 50° C. The reaction mixture was purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: C([O:4][C:5]12[CH:11]3[C:12]([CH3:18])([CH3:17])[CH:13]4[CH2:16][C:10]3([CH2:15][CH2:14]4)[C:9]([CH3:20])([CH3:19])[CH2:8][CH:7]1[O:6]2)(=O)C.[OH-].[Na+].Cl>O.C(O)C>[OH:4][CH:5]1[CH:11]2[C:12]([CH3:17])([CH3:18])[CH:13]3[CH2:16][C:10]2([CH2:15][CH2:14]3)[C:9]([CH3:20])([CH3:19])[CH2:8][C:7]1=[O:6]
Reactant: CC(=O)OC12OC1CC(C)(C)C13CCC(C1)C(C)(C)C23
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)C2CCC3(C2)C1C(O)C(=O)CC3(C)C
Reaction time: 8 h

Procedure:
2,2,8,8-Tetramethyl-5-oxatetracyclo[7.2.1.01.7.04.6]dodec-6-yl acetate (3, 14.5 g, 61% pure, 0.032 mol) was added at r. t. to a solution of sodium hydroxide (30 g, 0.75 mol) in water (0.75 l) and ethanol (0.75 l). After overnight stirring at r. t., the reaction mixture was neutralized to pH 7 with 2M aqueous HCl solution and extracted with MTBE (2×0.5 l). The combined organic phases were washed with water (2×0.2 l), dried (Na2SO4) and concentrated in vacuo to give crude 5-hydroxy-2,2,7,7-tetramethyltricyclo[6.2.1.01.6]undecan-4-one (4, 13 g, colourless oil, partly solidifying on standing) which was used without further purification in the next steps. Besides two isomeric hydroxyketones, the mixture contained tautomeric forms of the oxidised 4 (diketone).
Reaction SMILES: [C:1]([C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:11])=[CH:8][CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[F:37][C:22]([F:21])([F:36])[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:34]=[CH:33][C:32]([NH:35][CH:1]([C:6]3[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:11])=[CH:8][CH:7]=3)[CH2:2][CH2:3][CH3:4])=[CH:31][CH:30]=2)=[CH:27][CH:28]=1
Reactant: CCCC(=O)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCCC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(4-butyrylbenzamido)propanoate (128 mg, 0.46 mmol) and 6-(4-(trifluoromethyl)phenyl)pyridin-3-amine (100 mg, 0.42 mmol, prepared as in Example 2.7, Step B) in dry methanol (4.8 mL) was added decaborane (31 mg, 0.25 mmol). The resulting mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure and the residue was purified by preparative TLC to provide impure methyl 3-(4-(1-(6-(4-(trifluoromethyl)phenyl)pyridin-3-ylamino)butyl)benzamido)propanoate. This material was dissolved in THF (3 mL) and water (3 mL). Aqueous lithium hydroxide (1.00 mmol) was added. The resulting mixture was stirred at 20° C. for 1 h. The solvent was removed under reduced pressure. The residue dissolved in water and the solution brought to pH 3-4 by addition of 1N aqueous HCl. The mixture was extracted with dichloromethane (10 mL*2). The combined organic layers were concentrated. Purified by preparative HPLC (column: Phenomenex Gemini C18 250×21.2 mm×10 μm; modifier: 0.225% formic acid; gradient: 10 to 30% acetonitrile in water) to give 3-(4-(1-(6-(4-(trifluoromethyl)phenyl)pyridin-3-ylamino)butyl)benzamido)propanoic acid (20 mg) as a colorless solid. 1H NMR (400 MHz, CD3OD) δ 7.90-7.95 (m, 3H), 7.86-7.79 (m, 5H), 7.52 (d, J=8.0 Hz, 2H), 7.43-7.47 (m 1H), 4.57-4.60 (m, 1H), 3.60-3.64 (m, 2H), 2.62-2.65 (m, 2H), 1.94-1.96 (m, 1H), 1.82-1.86 (m, 1H), 1.57-1.43 (m, 2H), 1.01 (t, J=7.2 Hz, 3H). MS (M+1)=486.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)=[O:16])[CH3:2].I[C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[NH:40][N:41]=[C:42]([NH2:43])[C:35]=12>>[NH2:43][C:42]1[C:35]2[C:36](=[N:37][CH:38]=[CH:39][C:34]=2[C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15]([NH:14][C:5]3[CH:6]=[C:7]([C:10]([F:11])([F:13])[F:12])[CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[O:16])=[CH:19][CH:20]=2)[NH:40][N:41]=1
Reactant: Nc1n[nH]c2nccc(I)c12
Reactant: CCOc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(-c2ccnc3[nH]nc(N)c23)cc1

Procedure:
1-(2-Ethoxy-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea is coupled, by Suzuki reaction, with 4-iodo-1H-pyrazolo[3,4-b]pyrid-3-ylamine according to the preparation of Example 6. A yellow powder of 1-[4-(3-amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-ethoxy-5-trifluoromethylphenyl)urea is obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:22])[C:9]2[C:4](=[C:5]([O:23][CH3:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[ClH:1].[CH3:24][O:23][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:25])[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]1[CH3:22]
Reactant: COc1cccc2c(N3CCc4ccccc4C3C)nc(Cl)nc12
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3C)nc(N(C)c3ccccc3)nc12
Product: Cl
Yield: 22 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 8.00 g of the compound (8.82 mM) prepared in Example 5 and 15 ml of dimethyl-formamide, 2.00 ml of N-methyl aniline(18.45 mM) was added, 0.85 g of the title compound was prepared.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([OH:20])=[O:19])C(OC)=O.[OH-].[Na+]>CO.O>[C:3]([CH2:4][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([OH:20])=[O:19])([OH:21])=[O:2]
Reactant: COC(=O)C(C(=O)OC)c1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 102 %

Procedure:
To a solution of 2-(carboxy-5-nitrophenyl)malonic acid dimethyl ester, (25.0 g, 84 mmol) in methanol (200 mL), sodium hydroxide (5 g, 125 mmol) in water (200 mL) was added. After 3 hrs the reaction was complete, the methanol was removed under vacuum, the contents cooled to 0° C. and acidified with concentrated HCl (37 mL). The aqueous layer was extracted twice with ethyl acetate (200 mL then 100 mL), the combined organic layers were dried with magnesium sulfate, most of the solvent removed under vacuum, and methylene chloride (30 mL) was then added. The formed white solid was filtered off and dried to give 19.3 g of product as a white solid, mp 180-82°0 C. IR(KBr) 3080, 3055, 2983, 1707, 1611, 1585, 1516, 1491, 1424, 1358, 1298, 1237 cm-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].[CH2:20]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].CN(C)C=O>O>[CH2:39]([N:38]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 87.2 %

Procedure:
A mixture of 1-chloro-2,4-dinitrobenzene (Aldrich, 2.02 g, 10 mmol), sodium carbonate (1.27 g, 12 mmol), dioctadecylamine (Pfaltz & Bauer, 6.26 g, 12 mmol) and dry dimethylformamide (10 mL) was heated to 80°-90° C. under a nitrogen atmosphere for 1 h. The cooled mixture was diluted with water and extracted with ether. The extracts were washed with water and dried over magnesium sulfate. The solvent was removed and the solid recrystallized to give N,N-dioctadecyl-2,4-dinitrobenzenamine (6.0 g, 87%): mp 55.5°-57.5° C.
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].ClCC(OC(=O)CCl)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]>ClC(Cl)C>[C:4]([CH2:3][CH2:2][C:1]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[C:21]([O:26][CH3:27])[CH:22]=1)=[O:7])(=[O:5])[CH3:6]
Reactant: COc1ccccc1OC
Reactant: CC(=O)CCC(=O)O
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)CCC(C)=O)cc1OC
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 81.8 %

Procedure:
In 50 ml of dichloroethane were dissolved 5.8 g (0.05 mole) of levulinic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 8.98 g (0.065 mole) of 1,2-dimethoxybenzene and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 5.5 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 9.66 g of 4-(β-acetylpropionyl)-1,2-dimethoxybenzene.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CC(O)=O.C1C=CC=CC=1.C(OCC)(=O)C>[Br:18][CH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(O)c1ccc(CBr)nc1
Temperature: 120 °C

Procedure:
6-methylnicotinic acid (100 mg 0.14 mmol) was dissolved in 10% AcOH/benzene (1 mL) and treated with NBS (117 mg, 0.18 mmol) and benzoylperoxide (18 mg, 0.07 mmol). The reaction mixture was heated in a sealed microwave reactor at 120° C. for 1 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, dried (MgSO4), concentrated and purified by silica gel chromatography to yield 6-(bromomethyl)pyridine-3-carboxylic acid.