Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:15]=[C:16]([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH3:15][C:16]([O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:12]=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: C=C(C)C
Reactant: O=C(O)CCCOc1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.3 g of 4-(3-bromophenoxy)butanoic acid, 8 ml of liquid isobutene and 2 drops of sulfuric acid are placed in a pressure-resistant reactor. The reactor is closed and stirred at room temperature for 16 hours. The residual pressure is released gently and the product is taken up with ethyl acetate and sodium bicarbonate solution. The organic phase is washed with water and then dried and concentrated under reduced pressure to give the expected ester in the form of a colorless liquid (yield=94%).
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].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].N1C=CC=CC=1>C(O)C>[C:20]([C:19]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=1)=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)#[N:21]
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCO
Product: N#CC(=Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A 1.5 g sample of p-nitrobenzaldehyde and 1.7 g of p-nitrobenzylcyanide were dissolved in 5 ml of hot ethanol, and 0.05 ml of pyridine was added. The mixture was heated for 10 minutes. After cooling overnight, the precipitated crystals were filtered and recrystallized from a mixture of acetone and ethanol to obtain 1-cyano-1,2-bis(p-nitrophenyl)ethylene having a melting point of 216.5°-217.5° C.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:26])[C:23](=[NH:25])[NH2:24])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[S:27](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O>C(Cl)Cl.C(N(CC)CC)C>[NH2:25][C:23]1[C:22]([NH:21][CH2:20][CH2:19][CH2:18][O:17][C:13]2[CH:12]=[C:11]([CH2:10][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:16]=[CH:15][N:14]=2)=[N:26][S:27][N:24]=1
Reactant: N=C(N)C(=N)NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nsnc1NCCCOc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the product prepared in Step C in 50 ml of CH2Cl2 and 5.7 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (5.44 g; 13.7 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 40 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product. The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) using ethyl acetate-methanol (96:4) as the eluent to give 3.44 g of the title compound as a viscous oil. Treatment of the product with one equivalent of cyclohexyl sulfamic acid in acetone gave the cyclohexyl sulfamate of the title compound, mp 124.5°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([Cl:15])=[O:12]
Reactant: O=C(O)CCc1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CCc1ccccc1Cl

Procedure:
A mixture of 3-(2-chlorophenyl)propanoic acid (5.0 g, 27.1 mmole), thionyl chloride (10.9 ml, 149 mmole) and toluene (75 ml) was refluxed for two hours. Concentration in vacuo gave 3-(2-chlorophenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH:23]4[CH2:25][CH2:24]4)=[CH:21][C:20]([CH:26]4[CH2:28][CH2:27]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34]>>[CH:23]1([C:22]2[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:33][CH2:32][CH2:31][C:30]5=[O:34])=[N:7][C:6]=4[CH3:8])=[O:10])[CH2:12][CH2:13]3)=[N:18][CH:19]=[C:20]([CH:26]3[CH2:28][CH2:27]3)[CH:21]=2)[CH2:25][CH2:24]1
Reactant: Cc1nc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1CCCN1
Product: Cc1nc(N2CCCC2=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 103 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 251 and pyrrolidin-2-one (29 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (104 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[C:24]2[C:19](=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[CH:18]=[CH:17][NH:16]3)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3[nH]ccc23)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) in toluene (8.06 mL) was added 1H-indol-4-ylboronic acid (0.973 g, 6.05 mmol), potassium carbonate (1.671 g, 12.1 mmol) and palladium tetrakistriphenylphosphine (0.466 g, 0.403 mmol). The reaction was stirred at 100° C. and stirring continued for 19 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude product was placed in DCM and filtered to give the desired product. The filtrate was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-2-(1H-indol-4-yl)-3-methylquinoline as a yellow solid. Mass Spectrum (ESI) m/e=329.0 (M+1).
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[N:20][C:19]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.[Cl:35][CH2:36][C:37]1[CH:46]=[CH:45][C:40]([C:41](Cl)=[N:42][OH:43])=[CH:39][CH:38]=1.CCN(CC)CC>>[NH2:8][C:16]1[N:17]=[CH:18][C:19]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])[CH:25]=2)=[N:20][C:21]=1[C:22]1[O:43][N:42]=[C:41]([C:40]2[CH:45]=[CH:46][C:37]([CH2:36][Cl:35])=[CH:38][CH:39]=2)[CH:23]=1
Reactant: C#Cc1nc(-c2ccnc(C(C)(C)C#N)c2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: ON=C(Cl)c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1cc(-c2cnc(N)c(-c3cc(-c4ccc(CCl)cc4)no3)n2)ccn1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of tert-butyl N-tert-butoxycarbonyl-N-[5-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]-3-ethynyl-pyrazin-2-yl]carbamate (300 mg, 0.6472 mmol), 4-(chloromethyl)-N-hydroxybenzimidoyl chloride (158.5 mg, 0.7766 mmol) and Et3N (98.24 mg, 135.3 μL, 0.9708 mmol) were stirred at ambient temperature for 60 hours. A further aliquot of 4-(chloromethyl)-N-hydroxybenzimidoyl chloride (50.0 mg, 0.2450 mmol) and Et3N (36.30 mg, 50.0 μL, 0.3587 mmol) were added and the reaction mixture stirred at ambient temperature for a further 24 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 and the layers separated. The aquoeus layer was extracted with DCM (×3) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DCM (10 mL) and TFA (2 mL) was added. The reaction mixture was stirred at ambient temperature for 1 hour then concentrated in vacuo. The residue was partitioned between DCM and saturated aqueous NaHCO3 and the layers separated. The aquoeus layer was extracted with DCM (×3) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo yielding 2-(4-(5-amino-6-(3-(4-(chloromethyl)phenyl)isoxazol-5-yl)pyrazin-2-yl)pyridin-2-yl)-2-methylpropanenitrile as a yellow solid that was used without further purification
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[CH2:20][CH2:19][C:18]([O:24][CH3:25])([C:21]([OH:23])=O)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:27][C:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][O:24][C:18]1([C:21](=[O:23])[NH:32][C:28]2([CH3:27])[CH2:31][CH2:30][CH2:29]2)[CH2:17][CH2:16][N:15]([CH:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH2:20][CH2:19]1
Reactant: COC1(C(=O)O)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: CC1(N)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC1(C(=O)NC2(C)CCC2)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
1-[1-(tert-butoxycarbonyl)azepan-4-yl]-4-methoxypiperidine-4-carboxylic acid (0.163 g, 0.44 mmol) was dissolved in DMF (5 mL) and (1-methyl)cyclobutylamine hydrochloride (0.08 g, 0.66 mmol), HATU (0.25 g, 0.66 mmol) and DIPEA (0.284 g, 0.38 mL, 2.20 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min, gradient 1% to 6% MeOH in DCM]) to give tert-butyl 4-{4-methoxy-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}azepane-1-carboxylate (0.025 g, 13.4%) as a pale yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+].O>CS(C)=O>[CH3:25][O:24][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:26][CH3:27])[N:14]=[C:13]([N:7]1[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[CH:12][C:3]=3[CH2:2][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:8]1)[NH:22][C:21]2=[O:23]
Reactant: C1COCCN1
Reactant: COc1cc2nc(N3CCc4c(CBr)cccc4C3)[nH]c(=O)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nc(N3CCc4c(CN5CCOCC5)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(5-bromomethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 23a (54 mg, 0.12 mmol), morpholine (12 mg, 0.13 mmol) and sodium bicarbonate (16 mg, 0.18 mmol) in dimethyl sulfoxide (0.5 mL) was heated to 80° C. with stirring for 18 h. After cooling to room temperature, water (2 mL) was added and the precipitated product was separated by filtration, rinsed with water and dried. 6,7-Dimethoxy-2-(5-morpholin-4-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-3H-quinazolin-4-one 701 was purified by flash chromatography eluting with 2% methanol in dichloromethane containing 0.2% of ammonium hydroxide. The product was converted to the hydrochloric acid salt. Yield 15 mg, mp. 227.9-229.6° C., [M+H]+=437.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=O)[CH:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH:30]1[C:40]2[C:41]3[CH:32]([CH2:33][C:34](=[O:42])[NH:35][C:36]=3[CH:37]=[CH:38][CH:39]=2)[CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]([N:30]5[C:40]6[C:41]7[CH:32]([CH2:33][C:34](=[O:42])[NH:35][C:36]=7[CH:37]=[CH:38][CH:39]=6)[CH2:31]5)=[O:26])[CH:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3ccnc(C(=O)O)c3)CC1)C(=O)N2
Reactant: O=C1CC2CNc3cccc(c32)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ccnc(C(=O)N4CC5CC(=O)Nc6cccc4c65)c3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
67 mg (0.17 mmol) 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylic acid and 30 mg (0.17 mmol) 1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one in 56 μL (0.40 mmol) TEA and 1.8 mL DMF were combined with 58 mg (0.18 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@@H:7]([CH3:28])[NH:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH2:11].FC(F)(F)C(O)=O.COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](CC1C=CC(OCC2C=CC=CC=2)=CC=1)N.[C:76]([O:80][C:81]([NH:83][C@H:84]([C:94](O)=[O:95])[CH2:85][O:86][CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)=[O:82])([CH3:79])([CH3:78])[CH3:77].C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@@H:7]([CH3:28])[NH:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH:11][C:94](=[O:95])[C@H:84]([CH2:85][O:86][CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)[NH:83][C:81]([O:80][C:76]([CH3:79])([CH3:77])[CH3:78])=[O:82]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Nα -t-Butoxycarbonyl-O-benzyl-L-seryl-O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester is prepared from 10 mmoles of O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester is prepared from 10 mmoles of O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester trifluoroacetic acid salt by neutralizing to litmus with triethylamine in the cold and then adding 1.4 ml. (10 mmol) of additional triethylamine (pH 8.5). The cold solution is treated with 2.95 g. (10 mmol) of Nα -t-butoxycarbonyl-O-benzyl-L-serine, 1.35 g. of 1-hydroxybentriazole and 2.2 g. of dicyclohexylcarbodiimide. The mixture is stirred for two and one-half hours at -5° C. and overnight at room temperature. The mixture is filtered, the solid rinsed with dimethylformamide and the filtrate evaporated at 40° C. under reduced pressure. The residue is dissolved in 50 ml. of ethyl acetate and 200 ml. of ether and washed three times with 5% sodium bicarbonate solution and with saturated salt solution, dried over magnesium sulfate and evaporated. The residue is crystallized from a minimum of methanol by adding ether; 6.6 g. The product is recrystallized from methanol-ether; 6 g.; m.p. 67°-71° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[C:8]([C:10]1([C:13](OCC)=[O:14])[CH2:12][CH2:11]1)#[N:9]>COC1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:8]#[N:9])[C:13]2=[O:14])=[N:3]1
Reactant: CCOC(=O)C1(C#N)CC1
Reactant: Cn1ccc(N)n1
Solvent: CCOC(C)=O
Solvent: COC1CCCC1
Product: Cn1ccc(N2CCC(C#N)C2=O)n1
Temperature: 120 °C
Reaction time: 30 h

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-amine (223 mg) in cyclopentyl methyl ether (5.0 mL) was added ethyl 1-cyanocyclopropanecarboxylate (0.90 ml). The reaction mixture was stirred at 120° C. for 30 hr, and diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (237 mg).
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.C(C1C(C2C=C(N)C=CC=2)=C2C=CC=CN2N=1)(C)C>>[CH:11]([C:3]1[C:2]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1nn2ccccc2c1I
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)c1nn2ccccc2c1-c1cccc(N)c1
Product: CC(C)c1nn2ccccc2c1-c1cnn(C)c1

Procedure:
2-Isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine was prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and 1-Methylpyrazole-4-boronic acid pinacol ester following the method used in Step 3 of the synthesis of 3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine (Example 59) (138 mg, 13%). 1H-NMR (250 MHz, DMSO-d6) δ 8.59 (d, J=6.8 Hz, 1H), 7.93 (s, 1H), 7.64 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 6.80 (t, J=6.8 Hz, 1H), 3.91 (s, 3H), 3.29 (sept, J=7.0 Hz, 1H), 1.29 (d, J=6.8 Hz, 6H); LC/MS 241.1 m/z (M+H+). Compound 1112.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1.[Br:28]C(F)(F)C(Br)(F)F>C1COCC1>[Br:28][C:15]1[CH:16]=[C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)[CH:18]=[N:19][C:14]=1[F:13]
Reactant: Fc1ccc(C23CCCN2CCC3)cn1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1ncc(C23CCCN2CCC3)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.4 %

Procedure:
n-BuLi (2.5M in hexanes, 0.252 mL, 0.63 mmol) was added to di-isopropylamine (0.082 mL, 0.63 mmol) in THF and stirred at room temperature for 10 minutes, then cooled to -78° C. 7a-(6-Fluoro-3-pyridinyl)-hexahydro-1H-pyrrolizine (123 mg, 0.60 mmol, from Example 12d) and 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.215 mL, 1.80 mmol) were added. The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with 2N HCl, and the mixture was washed with Et2O. The aqueous layer was basified with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried, (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (64 mg, 37%). 1H NMR (CDCl3, 300 MHz) δ1.59-1.71 (m, 2H), 1.79-2.06 (m, 6H), 2.64-2.72 (m, 2H), 3.12-3.19 (m, 2H), 8.14 (dd, J=8.8, 2.2 Hz, 1H), 8.19 (dd, J=2.2, 1.2 Hz, 1H); MS (CI/NH3) m/z: 285/287 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=N/NC2C3C(=CC=CC=3)C=NN=2)=[CH:5][CH:4]=1.[NH2:22][C@H:23]([C:31]([OH:33])=[O:32])CC1C=CC=CC=1.CS(C)=O.C(S)[C@@H](O)[C@H](O)CS>C1N(CCO)CCN(CCS(O)(=O)=O)C1>[NH2:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: COc1ccc(/C=N/Nc2nncc3ccccc23)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CS(C)=O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 0.02 h

Procedure:
PAH activity was measured at 25° C. for 1 min essentially as described (BjØrgo E, et al., Eur. J. Biochem. 1988; 257(1):1-10). Tetrameric hPAH (1-2 μg) was incubated in 20 mM Hepes 0.2 M NaCl pH 7.0, containing catalase (0.04 mg/ml), 0.1-1 mM L-Phe, DMSO 2.5% and 0-100 μM of each compound. After 4 min incubation at 25° C., ferrous ammonium sulphate (100 μM) was added, and the reaction was triggered after 1 min by adding BH4 (10-200 μM) in the presence of 5 mM DTT. In some experiments, the preincubation step with L-Phe was omitted and L-Phe was added together with BH4 to analyze the L-Phe induced activation of the enzyme. To determine the kinetic parameters for BH4 and L-Phe, BH4 was used at 0-200 μM (at fixed 1 mM L-Phe) and L-Phe at 0-1 mM (BH4 was fixed at 75 μM). L-Tyr formed was quantified by HPLC and fluorimetric detection (DØskeland A P, et al., J. Biol. Chem. 1984; 259:11242-11248). The saturation curves were fitted to hyperbolic (for BH4) or sigmoidal (for L-Phe) kinetic models by using Sigma Plot v.9.0 (SPSS Inc).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1>C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:12]=2)[C:8]([NH:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (73 mg, 0.2 mmol) and triphenylphosphine (79 mg, 0.3 mmol) in methylene chloride (5.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (60.5 mg, 0.34 mmol). After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The reaction mixture was then treated with 2-aminopyridine (28.2 mg, 0.3 mmol) and pyridine (1 drop). The resulting reaction mixture was stirred at 25° C. for 48 h. The reaction mixture was then diluted with methylene chloride (50 mL). The organic layer was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (2×25 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 50/50 heptane/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2-yl propionamide (54.2 mg, 61.5%) as a white solid: mp 86-89° C.; EI-HRMS m/e calcd for C21H23F3N2O3S (M+) 440.1383, found 440.1381.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1.[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1Cl)[CH3:23]>C(Cl)Cl.[Cu]>[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:3]1)[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C[C@@H]1Cc1ccccc1
Reactant: CCOCCn1c(Cl)nc2ccccc21
Agent: [Cu]
Solvent: ClCCl
Product: CCOCCn1c(N[C@@H]2CCN(C(=O)OC(C)(C)C)[C@@H](Cc3ccccc3)C2)nc2ccccc21
Yield: 72.8 %

Procedure:
(±)-1,1-dimethylethyl trans-4-amino-2-(phenylmethyl)-1-piperidinecarboxylate (5 g), 1-(2-ethoxyethyl)-2-chloro-1H-benzimidazole (4.5 g) and copper (1.28 g) were stirred at 150° C. for 4 hours. The mixture was taken up in CH2Cl2 and filtered. The filtrate was washed with water/NH3. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 98/2). The pure fractions were collected and the solvent evaporated, yielding 6 g (73.7%) of (±)-1,1-dimethylethyl trans-4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]amino]-2-(phenylmethyl)-1-piperidine-carboxylate (interm. 6).