Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12])=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1F
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1F
Yield: 62.5 %

Procedure:
N-(2-Hydroxy-4-nitophenyl)-N'-(2-fluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-fluoro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.59 g, 31%). EI-MS m/z 292(M+H)+
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.C([O-])(=[O:13])C.[Na+].C(OCC)(=O)C.Cl>CN(C)C=O.O>[F:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2](=[O:13])[NH:7][CH:6]=1
Reactant: N#Cc1nc(F)cnc1F
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)c[nH]c1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 45.6 %

Procedure:
In 10 mL of N,N-dimethylformamide was dissolved 1.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. At an ice-cooled temperature, 0.64 g of sodium acetate was added and stirred for 6 hours. The reaction mixture was added to a mixture of 20 mL of ethyl acetate and 20 mL of water, pH was adjusted to 1.5 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel chromatography [eluent: n-hexane:ethyl acetate-: 1:1] to obtain 0.45 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile as a yellow-colored solid product.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10](=[O:27])[C@H:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]2[CH2:15][CH2:14]2)=CC=1)([O-])=O.[OH-].[Na+].O>CO>[C:16]([N:12]([CH:13]1[CH2:15][CH2:14]1)[C@H:11]([C:10]([OH:27])=[O:9])[CH2:23][CH:24]([CH3:26])[CH3:25])([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccc([N+](=O)[O-])cc1)N(C(=O)OC(C)(C)C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of Boc-cyclopropyl leucine p-nitrobenzyl ester (8) (300 mg, 7.9 mmol) in MeOH (20 ml) was added 2N NaOH soln. (7 ml) under ice cooling and the mixture was stirred for 3 hr at room temperature, the starting material gradually dissolved and the mixture turned yellow. Water (10 ml) was added and the MeOH was evaporated in vacuo. The aqueous residue was washed with AcOEt, cooled in an ice bath and acidified by the addition of 10% citric acid to pH 3. The resulting white precipitate was extracted with AcOEt (3×20 ml) and the extract was washed with sat. NaCl soln, dried over Na2SO4, and evaporated in vacuo. The resulting of Boc-cyclopropyl-leucine (9) was recrystallized from AcOEt-n-hexane to give 140 mg, (72.5%) as colorless prisms; mp 196°-197° C. (dec.); IR: (KBr) 3230(NH), 1690(C=O), 1645(C=O). NMR (CDCl3 +DMSOd6) δ:5.78 (s, 1H, NH), 1.2-1.8 (m,4H,CH2, CHx2),1.4 (s,9H,Boc), 0.9-1.1 (m,6H,(CH3)2CH).
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[NH2:25][CH:26]([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])[CH3:29]
Reactant: CC(N)CO
Reactant: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC(C)CO)s1
Yield: 43 %

Procedure:
As described for example 127, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-thiazole-5-carboxylic acid ethyl ester (200 mg, 0.56 mmol) was converted, using rac-2-amino-1-propanol instead of isopropylamine, to the title compound (94 mg, 43%) which was obtained as a colourless gum after purification by chromatography (silica, 0 to 3% methanol in dichloromethane). MS: m/e=374.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:9]([C:11]([O:13]CC)=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:28][CH:27]=2)[CH:3]=1.C(=O)(O)[O-].[Na+].C(O)C>O>[OH:1][C:2]1[C:7]2[N:8]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:28][CH:27]=2)[CH:3]=1
Reactant: CCOC(=O)C1Oc2cc(OCc3ccc(OCc4ccc5ccccc5n4)cc3)cc(O)c2N1c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2c3c(O)cc(OCc4ccc(OCc5ccc6ccccc6n5)cc4)cc3OC2C(=O)O)cc1

Procedure:
0.11 g ethyl 4-hydroxy-3-(4-methoxyphenyl)-6-(4-(quinolin-2-ylmethyloxy)benzyloxy)-2,3-dihydrobenzoxazole-2-carboxylate and 0.78 g sodium bicarbonate are combined in 7 ml of water and 7 ml of ethanol and refluxed overnight. The mixture is extracted with ether and the aqueous neutralized to pH6. The resulting solid is collected, dried to give 4-hydroxy-3-(4-methoxyphenyl)-6-(4-(quinolin-2-ylmethyloxy)benzyloxy)-2,3-dihydrobenzoxazole-2-carboxylic acid.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH3:25][NH:26][O:27][CH3:28]>C(Cl)(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:1](=[O:8])[CH2:2][CH2:3][C:4](=[O:5])[CH3:6]
Reactant: CNOC
Reactant: CC(=O)CCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)CCC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of levulinic acid (30 g, 0.258 mol) in 850 mL CHCl3 at 0° C. was added triethylamine (43.2 mL, 0.310 mol), followed by isobutyl chloroformate (37 mL, 0.284 mol) over 15 minutes. After 30 minutes, triethylamine (57.6 mL, 0.413 mol) was added, followed by N,O-dimethylhydroxylamine hydrochloride (37.8 g, 0.387 mol) in 5 portions over 5 minutes. Vigorous bubbling ensued, and the mixture was allowed to warm to RT and stir for 1 h. The mixture was reduced to a moist solid by rotary evaporation under reduced pressure, slurried in 500 mL EtOAc, washed with 10% K2CO3, brine, and dried over Na2SO4. Evaporative removal of the solvent gave 4-1 as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCC(C)(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-acetate (Compound 88, 95.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 49.0 mg (53%) of the title compound as a colorless solid.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[O-]CC.[Na+].CN([CH:13]=[C:14]1[CH2:18][N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][C:15]1=O)C>C(O)C>[CH3:3][C:2]1[N:4]=[CH:13][C:14]2[CH2:18][NH:17][CH2:16][C:15]=2[N:5]=1
Reactant: CN(C)C=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc2c(n1)CNC2
Temperature: 85 °C

Procedure:
A solution of acetamidine hydrochloride (12.8 g, 135 mmol) and sodium ethoxide (59 mL, 157.5 mmol) in anhydrous ethanol (400 mL) was stirred under nitrogen for 15 min, and 4-[(dimethylamino)methylene]-1-tritylpyrrolidin-3-one from Step B (17.2 g, 45 mmol) was added. The resulting mixture was heated at 85° C. for 3.5 h, quenched with a solution of 5% aqueous citric acid (50 mL), and evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate solution. There was some insoluble solid material between the aqueous and the organic layers, which was filtered thorough a Celite pad and washed with ethyl acetate. The combined aqueous layers were extracted twice with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated. The residue obtained was purified by chromatography on a Biotage Horizon® system (silica gel, 0-75% ethyl acetate/dichloromethane gradient) to yield the N-trityl protected derivative of the desired product. A portion of this trityl protected product (1.9 g, 5.0 mmol) was dissolved in 4N methanolic hydrogen chloride (20 mL) and stirred at room temperature for 2.5 h. The solution was evaporated and the residue was purified by chromatography on a Biotage Horizon® system (silica, 4.5-14% gradient of 10% concentrated aqueous ammonium hydroxide in methanol/dichloromethane) to yield the desired product. LC-MS=136.0 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=1.CCCCCC>CN(C=O)C>[Br:19][C:20]1[CH:21]=[N:22][C:23]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:24][CH:25]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCN1c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl piperidine-2-carboxylate hydrochloride (0.5 g, 2.58 mmol) in DMF (15 mL) was added potassium carbonate (1.77 g, 12.89 mmol) at rt. The mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.5 g, 2.58 mmol). The reaction was heated up to 80° C. for 3 h. After reaction completion (by TLC), the mixture was poured onto 100 mL ice-cold water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 1.50% EtOAc: hexane to obtain the desired product as an off white solid (0.37 g, 46% yield). MS: 314.08 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:14]=2O)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[F:21][C:19]([F:22])([F:20])[C:18]1[O:23][C:14]2[C:15]3[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: CC(=O)NCCC1CCc2ccc(NC(=O)C(F)(F)F)c(O)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC(=O)NCCC1CCc2ccc3nc(C(F)(F)F)oc3c21
Yield: 65.4 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}-2,2,2-trifluoroacetamide (27.8 mg, 0.0842 mmol) and pyridinium p-toluenesulfonate (4.2 mg, 0.0168 mmol) were heated under reflux in xylene (1 mL) for 5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (17.2 mg, yield 65%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=[N:13]O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.CC(OC(C)=O)=O>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2cc(C=NO)ccc21
Solvent: CC(=O)OC(C)=O
Product: CN1CCCc2cc(C#N)ccc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
1-Methyl-1,2,3,4-tetrahydroquinoline-6-carbaldehyde oxime (8.0 g, ca. 42.0 mmol) and Ac2O (40 mL, 423.9 mmol, 10.1 eq) was mixed at room temperature then the mixture was heated to 110° C. and stirred for 4 h. The solvent was removed under reduced pressure then the residue was placed on ice (500 g). The resulting mixture was quenched with saturated aqueous NaHCO3 then extracted by CH2Cl2 (4×50 mL). The combined organic layers were dried over Na2SO4 then concentrated to give a crude product which was purified by flash column chromatography (0-25% EtOAc in hexanes) to afford the title compound (4.53 g, 26.3 mmol, 63% over two steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[C:6]([F:16])[C:7]=1[N:8]=NC1C=CC=CC=1>CO.[Pd]>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:17])=[CH:5][C:6]=1[F:16]
Reactant: Oc1cc(F)c(N=Nc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1c(F)cc(O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
20.4 g (0.09 mol) of 3,5-difluoro-4-(phenyldiazenyl)phenol from Example 1 and 0.5 g of Pd/C (10%) were initially charged in 120 ml of methanol. The solution was degassed and aerated with hydrogen. The mixture was stirred at room temperature under a 1 bar hydrogen atmosphere for 16 hours. On completion of hydrogen uptake, the catalyst was filtered off and the filtrate concentrated on a rotary evaporator. The residue was chromatographed on silica gel (n-hexane/ethyl acetate, 3:1). The resulting solid was stirred with n-hexane and dried. 7.6 g (60%) of 4-amino-3,5-difluorophenol were obtained as a yellow-brown solid.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.CN(C)C.[C:14](Cl)(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[C:14]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCC(=O)Cl
Reactant: Cc1cc(=O)c(O)co1
Agent: CN(C)C
Solvent: C1CCOC1
Product: CCCCCCCC(=O)Oc1coc(C)cc1=O
Reaction time: 0.08 h
Yield: 89.9 %

Procedure:
Allomaltol (600 mg; 4.76 mmol) was weighed out into a round bottom flask (100 ml) containing a stir-bar. The contents were diluted with anhydrous THF (˜20 ml) and stirred (˜5 min) to afford a solution. Next, trimethyl amine (833 μl; 6.33 mmol; 1.33 equiv.) was added drop-wise and the contents stirred (˜5 min). Octanoyl chloride (770 μl; 724 mg; 4.45 mmol) was then added drop-wise, capped and stirred at room temperature. The reaction was monitored via silica gel TLC. Once complete, the reaction mixture was concentrated under reduced pressure and the contents purified by silica gel chromatography to afford 1.01 g of light yellow crystalline product (4.00 mmol; 90% yield). This compound was found to have an EC50 of 532 μM. 1H NMR (DMSO-d6) δ 8.39 (s, 1H; 2-H); 6.35 (s, 1H; 5-H); 2.54-2.52 (t, 2H); 2.29 (s, 3H; 6-CH3); 1.60-1.58 (p, 2H); 1.34-1.31 (m, 2H), 1.31-1.24 (m, 6H); 0.87-0.85 (t, 3H; —CH3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.C[N:20]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21]1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[N:20][NH:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Cn1cc(B(O)O)cn1
Product: Cc1cc(Nc2cc3ccccc3c(-c3cn[nH]c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and N-methyl-pyrazole-4-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-isoquinolin-3-yl]-amine. LC-MS m/e 305(MH+).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.[Cl:9][C:10]1[C:11]([CH2:20][CH2:21][C:22](=O)[CH3:23])=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C([BH3-])#N.[Na+]>CO.CCCCCCC.C(OCC)(=O)C>[Cl:9][C:10]1[C:11]([CH2:20][CH2:21][CH:22]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH3:23])=[N:12][CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=1
Reactant: CC(=O)CCc1ncc(C(F)(F)F)cc1Cl
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(CCc1ncc(C(F)(F)F)cc1Cl)NC1CC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 51.2 %

Procedure:
To a cooled solution of 5.54 ml (80 mmol) of cyclopropylamine and 2.86 ml (50 mmol) of acetic acid, together with 5 g of 3 Å molecular sieves, in 100 ml of methanol, are added 5 g (20 mmol) of 4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]butan-2-one. The reaction mixture is stirred for 3.5 hrs at reflux. The reaction mixture is then cooled to 0° C. and 1.88 g (30 mmol) of sodium cyanoborohydride are slowly added and the reaction mixture is further stirred for 2 hrs at reflux. The cooled reaction mixture is then filtered over a cake of diatomaceous earth. The cake is washed twice by 80 ml of methanol and the combined methanolic extracts are concentrated under vacuum. 100 ml of water are then added to the residue and the pH is ajusted to 10 with a 1 N solution of sodium hydroxyde. The watery layer is extracted twice with ethyl acetate (2×50 ml). The combined organic layers are washed twice by brine and dried over magnesium sulfate to yield after concentration 5.02 g of a brown oil. Column chromatography (gradient heptane/ethyl acetate) yielded 3 g (51% yield) of N-{4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]butan-2-yl}cyclo-propanamine as a light-brown oil (M+H=293).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:40]=[CH:39][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([O:31]CC5C=CC=CC=5)=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:41])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[N:1]1([C:5]([C:7]2[CH:40]=[CH:39][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:41])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)OCc3ccccc3)[nH]2)c1
Agent: [Pd]
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)O)[nH]2)c1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
Benzyl 5-{3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylate (4.25 g, 7.61 mmol) synthesized in Example (66f) was dissolved in ethanol (150 mL), and a 10% palladium carbon catalyst (804 mg) was added, followed by stirring for 2 hours under hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to afford the desired compound (3.45 g, yield 97%) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C@@H:12]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C@@H:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:14].[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46](O)=[O:47])[CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:29][CH:28]([CH3:30])[CH2:27][C@H:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:46](=[O:47])[CH2:45][N:42]1[CH2:43][CH2:44][O:39][CH2:40][CH2:41]1)[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: O=C(O)CN1CCOCC1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CCc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Referring to FIG. 45. DIPEA (592 μL, 3.6 mmol, 2.6 eq) was added to a mixture of (S)-benzyl 2-((S)-2-amino-4-phenylbutanamido)-4-methylpentanoate hydrochloride (600 mg, 1.4 mmol), 2-morpholinoacetic acid (312 mg, 2.1 mmol, 1.5 eq) and HATU (816 mg, 2.1 mmol. 1.5 eq) in CH2Cl2 (25 mL) and the mixture was stirred overnight at RT. The reaction mixture was washed with water and the aqueous layer was extracted once with CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-100% EtOAc in heptanes, followed by 10% MeOH in EtOAc) to yield product (700 mg, 98%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:2]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([F:18])[CH:24]=3)=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)=[CH:12][CH:13]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Fc1ccc(-c2nn3ccccc3c2Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3ccccc3c2-c2ccnc(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
A solution of 3-bromo-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine (Example le. 1.30 g, 4.5 mmol), 2-fluoro-4-pyridinylboronic acid (Example 46a. 694 mg, 4.9 mmol) and dichlorobis(triphenylphosphine)palladium (316 mg, 0.45 mmol) in DMF (100 mL) was placed in a pre-heated oil bath at 110° C. To the reaction was added, in a dropwise manner, 2M aqueous sodium carbonate (4.5 mL, 9.0 mmol). The reaction was allowed to stir for 2 h and then cooled to room temperature and filtered through a pad of Celite. The Celite pad was washed with ethyl acetate and the filtrate was concentrated to dryness at 50° C. under vacuum. The residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated and purified by silica gel chromatography to yield the title compound (378 mg, 1.23 mmol, 27%). 1H NMR (CDCl3) δ 8.57 (d, 1H, J=6.9 Hz), 8.22(d, 1H, J=5.4 Hz), 7.7(d, 1H, J=9.0 Hz), 7.75(m, 2H), 7.33(m, 1H), 7.14(m, 3H), 6.95(m, 2H). MS (ES+ve) 308 (100, M+).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].O[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[CH3:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:11])[C:2]=1[O:1][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:6]=[O:7]
Reactant: OCCN1CCOCC1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C=O)cc(C)c1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (3.0 g, 20 mmol) in anhydrous THF (100 mL), triphenyl phosphene (10.49 g, 40 mmol), 4-(2-hydroxyethyl) morpholine (5.25 g, 40 mmol) and N,N-diisopropylethylamine (7.76 g, 60 mmol) were added. To this stirred solution was added diethylazodicarboxylate (6.97 g, 40 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen and diluted with ethyl acetate (200 mL). The organic layer was washed with water and brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by column chromatography (silica gel 230-400 mesh; 0-3% methanol in CH2Cl2 as eluent) to give 3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)benzaldehyde (1.66 g, 32%) as an oil.