Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C:19]1([C@@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CCC>[C:19]1([C@@H:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Solvent: CCCCO
Product: C[C@H](Nc1nnc(Cc2ccncc2)c2ccccc12)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 1.273 ml (10 mmol) (S)-1phenylethylamine and 5 ml 1-butanol is stirred for 24 h at 110° C. The reaction mixture is evaporated under vacuum and the residue distributed between dichloromethane and 20% aqueous potassium carbonate solution. The organic phase dried over anhydrous sodium sulfate is evaporated in the RE and then under HV and the residue purified on silica gel by flash chromatography using dichioromethane/methanol (50:1). The product-containing fractions are dissolved in 5 ml methanol, acidified with 0.75 ml 3N methanolic HCl and evaporated under vacuum. After recrystallization of the residue from methanol/acetonitrile, drying of the crystallizate under HV (8 h, 100° C.) and equilibration for 15 h at 20° C. and in room atmosphere, title compound is obtained with a water content of 10.66%; m.p. 190° C. (decomp.); ESI-MS: (M+H)+=341; [a]D20=+42.1±0.8° (c=1.272%, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].[C:14]12(O)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.S(=O)(=O)(O)O>ClCCl>[C:14]12([C:11]3[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=3[OH:13])[C:6]([O:8][CH3:9])=[O:7])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(O)c(C23CC4CC(CC(C4)C2)C3)c1

Procedure:
12.37 g (68 mM) of methyl 3-methoxy-4-hydroxybenzoate in 150 ml of dichloromethane are treated with 10.33 g (68 mM) of adamantanol and 3.72 ml of concentrated sulphuric acid under the conditions described in Example 9(a). After the same treatment, there are isolated 20.3 g (94.5%) of the expected derivative, of melting point 179° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH2:22]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1)[CH2:23][CH2:24][CH3:25]>ClCCl>[CH2:22]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH:32][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH:27]=1)[CH2:23][CH2:24][CH3:25]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCCCc1cc(CN)no1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1cc(CNc2c([N+](=O)[O-])cnc3ccccc23)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.9 %

Procedure:
4-Chloro-3-nitroquinoline (1.35 g, 6.48 mmol) and triethylamine (1.36 mL, 9.73 mmol) were sequentially added to a solution of (5-butylisoxazol-3-yl)methylamine (1.00 g, 6.48 mmol) in dichloromethane, and the solution was stirred for 48 hours at room temperature. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 3% methanol in dichloromethane) to provide 1.33 g of N-[(5-butylisoxazol-3-yl)methyl]-3-nitroquinolin-4-amine as a yellow, crystalline solid.
Reaction SMILES: O.C([O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:25][O:26][CH3:27])=[N:15][N:16]2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:12][CH:11]=1)C1C=CC=CC=1>[Pd].C1COCC1>[CH3:27][O:26][CH2:25][C:14]1[C:13]2[C:17](=[CH:18][C:10]([OH:9])=[CH:11][CH:12]=2)[N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:15]=1
Reactant: COCc1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: COCc1nn(C2CCCCO2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
5% Palladium on carbon-STD-type-50% wet with water (199 mg; manufactured by N.E. Chemcat Corp.) and 6-(benzyloxy)-3-(methoxymethyl)-1-(tetrahydro-2H-pyran-2-yl)indazole (450 mg) that can be produced by the method described in Reference Example 54 or the like, were dissolved in THF (12.7 mL; manufactured by Kanto Chemical Co., Inc.). The reaction system was purged with hydrogen, and under a hydrogen atmosphere, the reaction solution was stirred overnight at room temperature. The reaction solution was purged with nitrogen, and then was filtered. The filtrate was concentrated under reduced pressure, and thus the title compound (337.4 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:32][CH2:33][OH:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[CH3:35][S:36]([O:34][CH2:33][CH2:32][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]([CH3:29])[C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=2)=[N:9]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(-c2nn(CCO)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Solvent: c1ccncc1
Product: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a 0° C. mixture of N2-{4-[4-amino-1-(2-hydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.343 g, 0.750 mmol) and pyridine (7.5 mL) was added methanesulfonyl chloride (0.14 mL, 1.8 mmol) dropwise over 30 sec. The reaction mixture was stirred at 0° C. for 2 h then ice water (10 mL) was added. The precipitate was collected by filtration and dried in vacuo to afford 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate as a beige solid (0.268 g, 0.500 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.44 (1H, s), 8.30 (1H, s), 8.13 (1H, d, J=8.0 Hz), 7.70 (1H, d, J=8.0 Hz), 7.59 (1H, d, J=8.4 Hz), 7.31-7.38 (4H, m), 7.15 (1H, t, J=7.6 Hz), 4.70 (3H, s), 4.04 (3H, s), 3.96 (3H, s), 3.37 (2H, obscured by water peak), and 3.12 (2H, s); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 11.22 min. MS: M+ 536.2.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]([C:16]2[S:20][C:19]([C:21]3[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=3[CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[O:15])[N:12]=[C:11]([C:36]2[CH:41]=[N:40][CH:39]=[CH:38][N:37]=2)[CH2:10]1>CO>[NH2:24][CH2:23][C:22]1[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=1[C:19]1[S:20][C:16]([C:14]([N:13]2[CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])[CH2:10][C:11]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)=[N:12]2)=[O:15])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(C(=O)N2N=C(c3cnccn3)CC2c2ccccc2O)s1
Agent: Cl
Solvent: CO
Product: NCc1ccccc1-c1ccc(C(=O)N2N=C(c3cnccn3)CC2c2ccccc2O)s1

Procedure:
HCl (0.16 mL, 5.4 mmol) was added to a solution of tert-butyl [2-(5-{[5-(2-hydroxyphenyl)-3-pyrazin-2-yl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}-2-thienyl)benzyl]carbamate (0.030 g, 0.054 mmol) in MeOH (1 mL) over the course of 3 h at rt. A white precipitate formed and was filtered and dried under vacuum to give 2-[1-({5-[2-(aminomethyl)phenyl]-2-thienyl}carbonyl)-3-pyrazin-2-yl-4,5-dihydro-1H-pyrazol-5-yl]phenol (I-205), (25 mg). LCMS: (FA) ES+ 456.1.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[CH2:13]([S:20][C:21]1[NH:22][C:23]([CH3:28])([CH3:27])[C:24](=[S:26])[N:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([S:20][C:21]1[N:25]=[C:24]([S:26][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]([CH3:12])[CH3:2])[C:23]([CH3:28])([CH3:27])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)NC(SCc2ccccc2)=NC1=S
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccccc1CSC1=NC(SCc2ccccc2)=NC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Initially, 0.65 g of 2-dimethylaminobenzylchloride hydrochloride was added to a solution of 0.7 g of 2-benzylthio-5,5-dimethylimidazolin-4-thione in 20 mL of ethanol (EtOH). The reaction mixture was stirred at the room temperature for one hour, and concentrated in vacuo. The residue was treated following the procedure used in Example 62, and purified by column chromatography (CHCl3). Recrystallization from diethyl ether-n-hexane gave 2-benzylthio-4-(2-dimethylaminobenzylthio)-5,5-dimethyl-5H-imidazole in the form of a needle-like crystal. The yield of this compound was 0.75 g with a yield ratio of 72.2%, and the melting point was 91°-92° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Br)[CH3:18]>CN(C)C=O>[CH2:17]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[Cl:1])[CH3:18]
Reactant: CCOC(=O)CCCBr
Reactant: Clc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
25 g (0.162 mol) of 6-chloropurine was dissolved in 500 ml of dimethylformamide and 89.4 g (0.647 mol) of potassium carbonate was added to this solution. 23.4 ml (0.162 mol) of 4-bromobutyric acid ethyl ester was added dropwise over a period of 4 hours. The solution was stirred for 16 h at room temperature. The solvent was removed in vacuo, the residue was dissolved in EE and the solution was washed three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/EE (1/1). Yield: 28.7 g.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[O:3]1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>S(Cl)(Cl)=O>[O:1]=[C:2]1[C:7]([C:8]([O:10][C:16]2[C:17]3[C:18](=[CH:14][CH:4]=[CH:5][CH:6]=3)[CH:19]=[CH:20][N:15]=2)=[O:9])=[CH:6][C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Oc1nccc2ccccc12)c1cc2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.0 g of the commercially available 2-oxo-2H-1-benzopyran-3-carboxylic acid and 10 ml of thionyl chloride were refluxed for 3 h. The resulting solution was evaporated under reduced pressure. The residue was suspended in 10 ml anhydrous toluene. The solvent was eliminated by distillation under reduced pressure. The two last steps were repeated twice. The residue was dispersed in 10 ml dioxane. To this suspension were added 1-hydroxyquinoleine (1.1 éq.) and anhydrous pyridine (1.1 eq.). After 90 min stirring at room temperature, the solvent was removed by distillation under reduced pressure. The residue was solubilized in chloroform and the organic phase was washed three times with HCl 0.1N, then dried over MgSO4. The solvent was evaporated under reduced pressure and the residue obtained was recrystallized in ethyl acetate.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([O:36]CC)=[O:35])[CH2:29][CH2:28]2)[C:9]=1[Br:39].C1COCC1.[Li+].[OH-]>O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:28][CH2:29][CH:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][CH2:32]2)[C:9]=1[Br:39]
Reactant: CCOC(=O)CC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Br)c(C2CCC(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 20 mL scintillation vial was charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)-methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (100 mg, 130 μmol) and 2:1 THF:H2O (10 mL). To this solution was added 1N LiOH(aq) (200 μL). The resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in TFA and stirred at room temperature for 1 hour. This solution was concentrated in vacuo and the residue was dissolved in 3:1 DMSO:MeCN. The crude product was purified via reverse-phase preparatory HPLC to yield 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetic acid (m+H=480.1, retention time=3.95 min (isomer 1) and 4.03 min (isomer 2))
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]1C(=O)C2=CC=CC=C2C1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>ClCCl>[C:1]([O:5][C:6]([CH2:8][O:9][NH2:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CON
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
In 1.35 l of dichloromethane is dissolved 37.4 g (0.135 mole) of N-(tert-butoxycarbonylmethoxy) phthalimide, and 9.21 ml (0.189 mole) of hydrazine hydrate is added dropwise to the solution over the period of 10 minutes, followed by stirring at room temperature for 2 hours. 3.95 ml (0.081 mole) of hydrazine hydrate is furthermore added, followed by stirring for further 1.5 hours. The reaction solution is filtered, and the filtrate is washed with 300 ml of 2N ammonium water and aqueous sodium chloride solution successively, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to give 18.95 g (95.4%) of O-(tert-butoxycarbonylmethyl)hydroxylamine as a yellow oily product.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccccc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethylaniline (12.1 g, 0.1 mol) in conc. H2SO4 (50 mL) at 0° C. was added fuming HNO3 (9.3 g) drop wise. After stirring at ambient temperature for 30 min, the mixture was poured into ice-water, and 2 N NaOH was added to neutralize the excess acid. The resulting reddish-brown solid was collected by filtration and washed with petroleum ether to give 2-ethyl-5-nitroaniline as crude product (9 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([NH:14][CH:15]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH2:16][NH:17]C(=O)OC(C)(C)C)=[O:13])[CH:8]=2)=[CH:5][CH:4]=[N:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:17][CH2:16][CH:15]([NH:14][C:12]([C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:11][CH:10]=1)=[O:13])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)c2cccc3ccccc23)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)NC(CN)c2cccc3ccccc23)cs1
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A solution of 1,1-dimethylethyl [2-({[5-(1-methyl-1H-pyrazol-5-yl)-3-thienyl]carbonyl}amino)-2-(1-naphthalenyl)ethyl]carbamate (76 mg, 0.16 mmol) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated with a toluene azeotrope and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH4OH)) affording the free base of the title compound (14 mg, 23%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:8][CH2:7]1)=[O:5].[N:30]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C@H:31]1[C:40](O)=[O:41].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>>[C:46]([O:45][C:43]([N:30]1[C@H:31]([C:40]([NH:2][C@H:3]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:11]2)=[O:5])=[O:41])[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:39]1)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: COC(=O)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared according to the procedure described in Preparation V by using methyl 2-{4-[(2R)-2-amino-3-(4-chlorophenyl)propanoyl]piperazinyl}-benzoate hydrochloride (2.6 g, 5.9 mmol), Boc-L-Tic-OH (Bachem) (1.8 g, 6.5 mmol), HOAT (Aldrich) (810 mg, 5.9 mmol), and EDC (Aldrich) (2.3 g, 12 mmol) and DIEA (Aldrich) (1.0 mL, 5.9 mmol). The title compound was isolated and purified by column chromatography (CH2Cl2 with 1.5% NH3 2M in MeOH) (2.8 g). MS (ESI, pos. ion) m/z: 661 (M+H). Calc'd for C36H41ClN4O6: 660.27.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.O.[NH2:19][NH2:20]>O>[F:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:20][N:19]=[C:4]2[CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1
Reactant: CN1CCC(C(=O)c2cc(F)ccc2F)CC1
Reactant: NN
Solvent: O
Product: CN1CCC(c2n[nH]c3ccc(F)cc23)CC1
Yield: 22 %

Procedure:
A mixture of 4-(2,5-difluorobenzoyl)-1-methylpiperidine of Example 111 (38.5 g, 0.16 moles) and hydrazine monohydrate (79.5 g, 1.59 moles) was heated in an autoclave at 150° for 22 hours. The autoclave was cooled in an ice bath and then opened. The reaction mixture was poured into H2O, causing the product to crystallize. The product was collected and then recrystallized twice from toluene to yield 8.2 g (22%) of 5-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole, m.p. 202°-204°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](O)=[O:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:23][C:15]1[CH:14]=[C:13]([NH:12][C:10](=[O:11])[NH:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[O:40])[CH2:3]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: Cc1cc(NC(=O)NCCN2CCC(N)C2)c2ccccc2n1
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)NCCN2CCC(NC(=O)c3ccccn3)C2)c2ccccc2n1
Reaction time: 0.75 h

Procedure:
To a solution of 1-[2-(3-amino-pyrrolidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea (0.03 mmol) in DMF (0.3 mL) is added DIPEA (3 eq). The resulting solution is treated with a solution of pyridine-2-carboxylic acid (1.1 eq) in DMF (0.25 mL). A solution of TBTU (1.1 eq) in DMF (0.25 mL) is added. The reaction is stirred at 20 C for 45 min. The reaction mixture is evaporated to dryness. The residue is taken up in CH3CN/H2O/TFA (6:10:1; 1 mL) and is purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[N:6]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][N:39]([CH:50]1[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]1)[C:40]1[O:41][C:42]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][C:43]=2[N:44]=1.CC(C)=O>CN(C=O)C>[CH3:38][N:39]([CH:50]1[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]1)[C:40]1[O:41][C:42]2[CH:48]=[CH:47][C:46]([NH:49][C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)=[CH:15][CH:14]=3)=[CH:45][C:43]=2[N:44]=1
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)cs1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(=O)Nc3ccc4oc(N(C)C5CCN(C)CC5)nc4c3)cc2)cs1
Yield: 106.5 %

Procedure:
Combine 4-(2-methyl-1,3-thiazol-4-yl)benzoic acid (55 mg, 0.251 mmol), TBTU (74 mg, 0.232 mmol), and N2-Methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (46 mg, 0.177 mmol) in DMF (1.0 mL) and shake at room temperature. Add acetone (2.0 mL) a put the mixture on an SCX cartridge (previously conditioned with MeoH). Wash with acetone (3×3.0 mL) non basic impurities and then with MeOH (3×3.0 mL). Eluting with a 2N solution of NH3 in MeOH (4.0 ml) and concentrate to afford the title compound (87 mg, 100%). LC/MS, RT=4.45 min., mass spectrum (m/z) found (M+H)+: 462.2. The material is dissolved in MeOH and treated with 2M HCl in ether (2.0 mL). Organic solvent is removed in vacuo and the resulting precipitate is collected to give 96 mg of the hydrochloride salt.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1.[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH2:13][CH2:12]1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CN1CCN(c2ccccn2)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCN(c2ccccn2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 33.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(pyridin-2-yl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 126, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(pyridin-2-yl)piperazin-1-yl)acetamido)propanamide (15.7 g, 33.6%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (s, 1H), 8.11-8.12 (m, 1H), 8.05 (d, 1H), 7.60 (d, 2H), 7.51-7.55 (m, 1H), 7.28-7.33 (m, 5H), 7.19-7.25 (m, 2H), 6.98-7.04 (m, 4H), 6.81 (d, 1H), 6.63-6.66 (m, 1H), 4.71 (m, 1H), 4.52 (s, 2H), 3.72-3.78 (m, 2H), 3.47-3.49 (m, 4H), 3.06 (s, 2H), 2.55-2.59 (m, 4H). MS (EI) for C33H34FN5O4. found 584.6 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:4]=1[O:5][CH2:6][C:7]#[N:8])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:14][N:13]([CH3:15])[C:10]1[CH:11]=[CH:12][C:3]2[CH:1]=[C:6]([C:7]#[N:8])[O:5][C:4]=2[CH:9]=1
Reactant: CN(C)c1ccc(C=O)c(OCC#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc2cc(C#N)oc2c1

Procedure:
15.3 parts of the nitrile is dissolved in 100 parts by volume of dimethylformamide and stirred with 10 parts of potassium carbonate for 15 hours at 70°C. The whole is then diluted with 1,000 parts of water, filtered by suction and the filter residue is dried. For further purification it is sublimed at 80°C and 1 mm and the sublimate is recrystallized from methylcyclohexane. The 6-dimethylaminobenzofuran-2-carbonitrile is obtained in the form of colorless crystals having a melting point of 70° to 71°C which dissolve in benzene with an intense blue-violet fluorescence.