Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1.CN(C=O)C.C(Cl)Cl>[CH3:36][NH:35][S:32]([C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH:24][C:14]([C:11]1[CH:12]=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9][CH:10]=1)=[O:16])(=[O:33])=[O:34]
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (545 mg, 2.5 mmol) and DCM (35 mL) is added oxalyl chloride (635 mg, 5 mmol) followed by the addition of DMF (20 μL). The reaction is stirred at room temperature for 3 hours. Anhydrous toluene (10 mL) is added and the reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc (30 mL). The resulting solution is added to a mixture of 3-aminomethyl-N-methyl-benzenesulfonamide hydrochloride (590 mg, 2.5 mmol), sodium carbonate (530 mg, 5 mmol) and water (10 mL) at 0° C. The resulting reaction mixture is warmed to room temperature and stirred overnight. Approximately 80% of EtOAc is removed in vacuo, and heptane is added to precipitate the product. The precipitate is collected by filteration, and recrystallized twice in EtOAc to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (400 mg). The mother liquors are concentrated and the residue is purified by flash chromatography to afford additional 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (130 mg) as a powder. MS: 401 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.41 (d, 3H), 4.64 (d, 2H), 7.42-7.50 (m, 2H), 7.57-7.70 (m, 4H), 7.78 (s, 1H), 8.16 (d, 1H), 8.31 (d, 1H), 9.33 (s, 2H), 9.53 (t, 1H). IC50=9.5 nM.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][C@H:4]([NH:21]C(=O)OC(C)(C)C)[CH:5]([C:7]1[N:8]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[N:10][CH:11]=1)[OH:6]>ClCCl.FC(F)(F)C(O)=O>[NH2:21][C@H:4]([CH:5]([C:7]1[N:8]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[N:10][CH:11]=1)[OH:6])[CH2:3][CH:2]([CH3:29])[CH3:1]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)c1cncn1COCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(O)c1cncn1COCc1ccccc1

Procedure:
A solution of the product from part (e) (0.11 g., 0.26 mmole) in dichloromethane (2 ml.) and trifluoroacetic acid (2 ml.) is stirred at 10° for 30 minutes and at room temperature for 10 minutes. The reaction mixture is evaporated in vacuo and then concentrated from acetonitrile (three times) to give α-[(S)-1-amino-3-methylbutyl]-3-[(phenylmethoxy)methyl]-3H-imidazole4-methanol which contains 2.5M of trifluoroacetic acid.
Reaction SMILES: [BH4-].[Na+].[OH-].[K+].Cl.[NH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:9]>CO>[NH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)[OH:9]
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: NCC(O)c1ccc(Br)cc1
Reaction time: 0.2 h

Procedure:
Sodium borohydride (227 mg, 6.00 mmol) was dissolved in methanol (10 mL) and 5% potassium hydroxide in methanol (4.49 mL, 4.00 mmol) was carefully added. To this solution was added 2-Amino-1-(4-bromo-phenyl)-ethanone hydrochloride (1.0 g, 4.00 mmol) dissolved in methanol (10 mL) and stirring continued for 0.2 hours at room temperature. The mixture was concentrated, and quenched with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane several times. The organics were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The title compound was isolated as a yellow solid (677 mg, 77%). 1H NMR (300 MHz, CDCl3): 7.51-7.47 (d. 2H), 7.27-7.23 (d, 2H), 4.63-4.59 (m, 1H), 3.03 (dd, 1H), 2.76 (dd, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH2:27][C:28]([N:30]2[CH2:35][C@H:34]([CH3:36])[N:33]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:32][C@H:31]2[CH3:45])=[O:29])=[C:6]([CH:25]=1)[CH2:7][NH:8][S:9]([CH2:12][CH2:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O)(=[O:11])=[O:10].NN>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH2:27][C:28]([N:30]2[CH2:35][C@H:34]([CH3:36])[N:33]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH2:32][C@H:31]2[CH3:45])=[O:29])=[C:6]([CH:25]=1)[CH2:7][NH:8][S:9]([CH2:12][CH2:13][NH2:14])(=[O:11])=[O:10]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CNS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CNS(=O)(=O)CCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of (2R,5S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid 5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamide (0.073 g, 0.111 mmol) in EtOH (1 mL) was added hydrazine (35% aq. 0.25 mL, 2.73 mmol) and the solution was stirred overnight at ambient temperature. The reaction was filtered through a glass frit and washed with EtOH. The filtrate was concentrated in vacuo to give the title compound (0.056 g, 96%)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:17][CH2:18][N:19]([CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:24][CH2:25]2)[C:13]1=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](NC(=O)OCc3ccccc3)C2=O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
Crude (S)-2-(benzyloxycarbonylamino)-5-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)pentanoic acid (84 g, 187 mmol) was dissolved in DMF (600 mL), and cooled to 0° C. N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (35.8 g, 187 mmol) and N-ethyl-N-isopropylpropan-2-amine (32.5 mL, 187 mmol) were added and the reaction stirred at ambient temperature overnight. The reaction was concentrated and dissolved in EtOAc (1000 mL), washed with 1N HCl, saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (50% EtOAc in hexanes) to afford (S)-tert-butyl 3-(benzyloxycarbonylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (49 g, 114 mmol, 60.8% yield) as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[NH2:27].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CC(C)=O.O.CN(C=O)C.C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:27][C:11](=[O:13])/[CH:10]=[CH:9]/[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:14]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(N)cc1OC
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(NC(=O)/C=C/c2ccc(C(C)(C)C)cc2)cc1OC

Procedure:
To a 20 mL round-bottomed flask equipped with reflux condenser and drying tube was added 4-tert-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) followed by CH2Cl2 (5 mL), oxalyl chloride (90 uL, 130 mg, 1.03 mmol, Aldrich) and DMF (1 uL). The reaction mixture was magnetically stirred and heated at reflux for 30 min. The reaction mixture was concentrated in vacuo and the residue dissolved in acetone (2 mL). The solution was added to a mixture of 3,4-dimethoxyaniline (180 mg, 1.17 mmol, Aldrich), potassium carbonate (200 mg), water (2 mL) and acetone (2 mL), magnetically stirred at 25° C. in a 10 mL glass vial. The reaction mixture was stirred at 25° C. for 16 h then diluted with EtOAc (60 mL) and washed successively with 1 N HCl (20 mL), 1 N NaOH (20 mL), water (20 mL) and satd NaCl (20 mL), dried over MgSO4, filtered and concentrated. Recrystallization from hexane and CH2Cl2 provided the title product as a yellow solid. MP 115-116° C. MS (ESI, pos. ion) m/z: 340 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:9])[N:6]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)(=[O:25])=[O:9])[N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ccc(S(=O)Cc2csc(N)n2)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)Cc2csc(N)n2)cc1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
To a solution of 2-amino-4-(4-aminophenylsulfinylmethyl)thiazole (2.8 g) in N,N-dimethylformamide (30 ml) was added portionwise the 3-chloroperbenzoic acid (2.6 g) at 5° C. with stirring. The mixture was stirred at room temperature for 2 hours and then the solution was poured into ice-water. The precipitates were collected by filtration, washed with aqueous sodium bicarbonate, washed with water and dried in vacuo to give 2-amino-4-(4-aminophenylsulfonylmethyl)thiazole (2.85 g, yield 95.6%). mp: 204°-208° C. (dec.)
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[N:10][C:11]([CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[N:10][C:11]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)CC1
Agent: Cl
Product: c1ccc(-c2cccc3nc(C4CCNCC4)nc(NCc4ccccn4)c23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Tert-butyl 4-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)piperidine-1-carboxylate (Example 211, 0.2 g 0.4 mmol) was dissolved in 10 mL HCl (2 M in ether). The reaction mixture stirred at RT for 16 h. After this time, the solvent was removed under reduced pressure. The resulting residue was neutralized with sat. NaHCO3 and the aqueous phase was extracted into DCM. The combined organic extracts were concentrated under reduced pressure and the resulting residue was purified by recrystallization with EtOAc to yield 5-phenyl-2-(piperidin-4-yl)-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.13 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.21 (d, 1H, J=4.0 Hz), 7.77-7.66 (m, 3H), 7.58-7.40 (m, 5H), 7.30-7.15 (m, 3H), 6.57 (br s, 1H), 4.56 (d, 2H, J=4.0 Hz), 3.05 (d, 2H, J=12.0 Hz), 2.80-2.70 (m, 1H), 2.60 (t, 2H, J=8.0 Hz), 1.95-1.80 (m, 2H), 1.80-1.65 (m, 2H). LCMS Method W: retention time 1.43 min, [M+1]=396.2; HPLC Method A1: purity 96.4%, retention time=9.00 min.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].CI.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([OH:31])=[O:30])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C.O>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([O:31][CH3:1])=[O:30])[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(=O)O)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
K2CO3 (383 mg, 2.8 mmol) and CH3I (236 mg, 1.66 mmol) were added, with vigorous stirring, to a solution of 4-(2-carboxy-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (371 mg, 1.1 mmol) in DMF (5 mL) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with cold water and the product extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 390 mg of 4-(2-methoxycarbonyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil. LC-MS purity: 92.15%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][C@H:15]([OH:18])[CH2:16][CH3:17].[H-].[Na+]>C1COCC1>[F:11][C:10]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:18][C@H:15]([CH2:16][CH3:17])[CH3:14])[C:6]#[N:7]
Reactant: CC[C@H](C)O
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](C)Oc1ccc(C#N)cc1C(F)(F)F
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A solution of 1.1 g (5.9 mmol) of 4-fluoro-3-trifluoromethylbenzonitrile and 485 mg (6.5 mmol) of (S)-(+)-2-butanol in 10 mL of THF at −10° C. was treated with 235 mg (5.9 mmol) of sodium hydride. The resulting mixture was stirred cold for 2 h, then quenched with 10 mL of H2O. The quenched solution was extracted with 30 mL of Et2O, dried over MgSO4 and concentrated. Chromatography on a Biotage 40M cartridge using 4:1 v/v hexanes/Ethyl acetate as the eluant afforded 550 mg of the title compound: 1H NMR (500 MHz) δ 0.99 (t, J=7.6, 3H), 1.35 (d, J=6.2, 3H), 1.58-1.83 (m, 2H), 4.51 (septet, 1H), 7.04 (d, J=8.7, 1H), 7.75 (d, J=8.7, 1H), 7.85 (s, 1H).
Reaction SMILES: CS[CH:3]1[C:12]2[N:11]=[CH:10][N:9]=[CH:8][C:7]=2[CH:6]=[C:5]2[N:13]=[N:14][N:15]=[C:4]12.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[ClH:24].BrC1C=C(C=CC=1)N>C(O)(C)C>[ClH:24].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][CH:3]1[C:12]2[N:11]=[CH:10][N:9]=[CH:8][C:7]=2[CH:6]=[C:5]2[N:13]=[N:14][N:15]=[C:4]12
Reactant: Nc1cccc(Br)c1
Reactant: CSC1C2=NN=NC2=Cc2cncnc21
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(NC2C3=NN=NC3=Cc3cncnc32)c1
Yield: 63.3 %

Procedure:
A mixture of 4-methylthiotriazolo[4,5-g]quinazoline (0.30 g, 1.38 mmol), 3-bromoaniline (2.1 mmol) and 3-bromoaniline hydrochloride (2.1 mmol) in isopropanol (400 mL) is heated under reflux for 6 h, and the solution is concentrated to give 4-(3-bromoanilino)-triazolo[4,5-g]quinazoline hydrochloride (0.33 g, 63 %). 1H NMR (DMSO) δ12.01 (1H, brs), 9.86 (1H, s), 9.02 (1H, s), 8.63 (1H, s), 8.39 (1H, s), 8.13 (1H, dd, J=1.9, 1.5 Hz), 7.85 (1H, ddd, J=7.7, 1.9, 1.5 Hz), 7.56 (1H, ddd, J=8.0, 1.7, 1.5 Hz), 7.41 (1H t, J=7.8 Hz).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:26]1[C:28]2([CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C.[Cl-].[Na+]>[OH:26][C:28]1([CH2:27][O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Reactant: C1CCC2(C1)CO2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC4(O)CCCC4)c23)CC1
Temperature: 80 °C
Yield: 74.1 %

Procedure:
A mixture of tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (100 mg, 0.287 mmol, EXAMPLE 17, step 2), 1-oxaspiro[2.4]heptane (59.7 mg, 0.609 mmol), and potassium carbonate (156 mg, 1.13 mmol) in ethanol (2 mL) was heated at 80° C. for 5 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (3 mL) and 5% aq. sodium chloride was added to the mixture. Organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a solid. The residual solid was purified by NH gel column chromatography (ethyl acetate/hexane 1:2) to give 95 mg (74%) of the title compound as a white solid.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16](O)=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[C:36](N1C=CN=C1)([N:38]1C=CN=[CH:39]1)=O.CNC.O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:32][CH2:33]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:17])[N:38]([CH3:39])[CH3:36])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred at room temperature for 2 hours. To the mixture was added dimethylamine in THF (0.8 ml, 1.6 mmol). The resulted mixture was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction mixture. The solvent was removed in vacuo. The resulted mixture was taken up in ethyl acetate (30 ml) and washed with water (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml), brine (20 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was stirred with ether overnight. The suspension was filtered to give a yellowish solid. The solid was purified by HPLC (CH3CN:Water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-dimethylcarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (200 mg, 50%): mp, 158–160° C.; 1H NMR (CDCl3): δ 0.86–0.92 (m, 2H, cyclopropyl ring CH2), 1.08–1.12 (m, 2H, cyclopropyl ring CH2), 1.66–1.70 (m, 1H, cyclopropyl ring CH), 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 15 Hz, 1H, CHHCO), 3.10 (s, 3H, NCH3), 3.64 (dd, J=8, 15 Hz, 1H, CHHCO), 4.13 (t, J=15 Hz, 2H, CHHN), 5.56–5.62 (m, 1H, CHN), 6.51 (t, JH-F=75 Hz, 1H, OCF2H), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 7.01 (d, J=8 Hz, 1H, Ar), 7.23–7.36 (m, 3H, Ar), 7.44 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 10.52 (s, 1H, NHCO); 13C NMR (CDCl3):8.22, 16.16, 35.58, 35.92, 37.27, 49.59, 53.83, 58.94, 111.0, 115.65, 117.64, 117.67, 119.90, 119.80, 121.66, 122.58, 125.64, 133.27, 138.05, 138.69, 141.49, 169.11, 169.81, 172.65; Anal. Calcd. for C25H25F4N3O5: C, 57.36; H, 4.81; N, 8.03. Found: C, 57.22; H, 4.76; N, 8.11.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[CH3:24])[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:26]1[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=3)[CH2:20][CH:19]2[CH3:24])[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCc1cnc(Cl)nc1
Reactant: CC1CNCCC1N(C(=O)c1ccc(-c2cnco2)cc1)C1CC1
Solvent: CN1CCCC1=O
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)C(C)C2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-N-(3-methyl-piperidin-4-yl)-4-oxazol-5-yl-benzamide and 2-chloro-5-ethyl-pyrimidine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 3): tR=1.83 min; Mass spectrum (ESI+): m/z=432 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[OH:18][CH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl.C(#N)C>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[CH:25]=[C:20]([CH2:19][OH:18])[CH:21]=[CH:22][CH:23]=4)=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cn3cc(-c4cccc(CO)c4)ccc3n2)cc1
Yield: 45.7 %

Procedure:
Under a stream of nitrogen, 200 mg of 6-bromo-2-p-tolylimidazo[1,2-a]pyridine, 160 mg of 3-(hydroxymethyl)phenylboronic acid and 24 mg of tetrakis(triphenylphosphine)palladium are placed in a microwave tube containing 2 ml of toluene degassed beforehand under a stream of nitrogen, 2 ml of acetonitrile and 2 ml of a 2M solution of sodium carbonate. The tube is placed in a microwave apparatus and irradiated at 150° C. for 15 min. The organic phase is separated and dried and the filtrate is concentrated under reduced pressure. The residue obtained is taken up with 6 ml of dichloromethane. The precipitate is recovered by filtration, washed with dichloromethane and dried in a desiccator under reduced pressure. 100 mg of compound are obtained. Mp=171-173° C. 1H NMR (DMSO-d6, δ in ppm): 2.32 (s, 3H); 4.57 (d, J=5.6 Hz, 2H); 5.23 (t, J=5.7 Hz, 1H); from 7.19 to 7.67 (m, 8H); 7.84 (d, J=8 Hz, 2H); 8.32 (s, 1H); 8.82 (m, 1H). M+H=315.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:5]=1)#[N:2].C(O)(C(F)(F)F)=O>>[C:1]([CH2:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1)#[N:2]
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(CC#N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(CC#N)c2cn1)c1ccccc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
(R)-1-(3-(cyanomethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (20 mg, 0.036 mmol) was dissolved in TFA (0.274 ml, 3.55 mmol) and stirred for 30 m at rt. The solvents were removed in vacuo and the residue purified by reverse-phase HPLC to provide pure (R)-1-(3-(cyanomethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (9 mg, 0.021 mmol, 58.3% yield). MS ESI Calc'd for C17H16N6O [M+H]+ 321, found 321.