Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]([NH:22][C:23]3[N:27]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:26]=[C:25]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]=3)=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:48][O:49][CH2:50][C:51](Cl)=[O:52].N>C(Cl)Cl>[C:35]([C:25]1[CH:24]=[C:23]([NH:22][C:20](=[O:21])[NH:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([S:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:51](=[O:52])[CH2:50][O:49][CH3:48])[CH:7]=3)=[CH:10][CH:11]=2)[N:27]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:26]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Sc3ccnc(N)c3)c3ccccc23)cc1
Reactant: COCC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cc(Sc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-(2-aminopyridin-4-ylthio)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (44 mg, 0.084 mmol) and DIPEA (52 μL, 0.30 mmol) in DCM (2.0 mL) was added a solution of 2-methoxyacetyl chloride (19 μL, 0.21 mmol) in DCM (0.5 mL) over 5 min. The reaction mixture was kept at RT for 30 min and a solution of NH3 (1% in MeOH, 1.0 mL) was added. The mixture was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 12 g, EtOAc in isohexane, 30-80%, gradient elution) to afford the title compound, Example 21, as a white solid (36 mg, 70%). Rt 2.76 min (Method 2); m/z 595 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 2.39 (3H, s), 3.28 (3H, s), 3.95 (2H, s), 6.44 (1H, s), 6.56 (1H, dd), 7.37 (2H, d), 7.47 (2H, d), 7.65 (2H, m), 7.75 (1H, s), 7.93 (1H, d), 8.02 (1H, d), 8.17-8.23 (3H, overlapping m), 8.97 (1H, s), 9.37 (1H, s), 9.90 (1H, s).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][NH:5][CH:4]=1)#[N:2].[O:12]1CCC[CH2:13]1.C=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:12][CH2:13][N:5]1[CH:6]=[C:7]([C:8]([F:11])([F:9])[F:10])[C:3]([C:1]#[N:2])=[CH:4]1
Reactant: C1CCOC1
Reactant: N#Cc1c[nH]cc1C(F)(F)F
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: N#Cc1cn(CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
585 mg of 3-cyano-4-trifluoromethyl-1H-pyrole, 10 ml of tetrahydrofuran and 10 ml of formaldehyde 36% in water were mixed. 0.1 ml of tetrabutylammonium hydroxide 10% in water was added to the mixture at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 1-hydroxymethyl-3-cyano-4-trifluoromethyl-1H-pyrole.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1>[Pt].O1CCCC1>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)c2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 78.6 %

Procedure:
A mixture of 32.25 gm (124 mMol) N-(4-fluorobenzoyl)-4-nitroaniline and 3.2 gm platinum on carbon in 500 mL tetrahydrofuran was hydrogenated at room temperature for 18 hours with an initial pressure of 60 p.s.i. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure to give 22.45 gm (79%) of N-(4-fluorobenzoyl)-4-aminoaniline.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.CS[C:28]1[NH:29][CH2:30][CH2:31][N:32]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[NH:32]1[CH2:31][CH2:30][N:29]=[C:28]1[N:22]1[CH2:23][CH2:24][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:20][CH2:21]1
Reactant: CSC1=NCCN1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(N3CCNCC3)cccc21
Agent: I
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)n1ccc2c(N3CCN(C4=NCCN4)CC3)cccc21
Temperature: 50 °C

Procedure:
A solution of 1-(phenylsulfonyl)-4-piperzin-1-yl-1H-indole (71 mg, 0.18 mmol) in dioxane is treated with 2-methylthio-2-imidazoline hydroiodide (52.7 mg, 0.22 mmol) and N,N-diisopropylethylamine (62 μl, 0.36 mmol), heated at 50° C. for 16 hr., cooled and concentrated in vacuo to give a residue. The residue is purified by HPLC to give the title product, 15 mg, identified by HPLC and mass spectral analyses (2.57 min; 410 M+H) using the LCMS conditions described in Table I.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.[OH-].[Na+]>C1COCC1>[C:29]([NH:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[C:20](=[O:32])[N:19]([CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1)[CH2:4][C:3]([OH:33])=[O:2])[CH2:27]2)(=[O:31])[CH3:30]
Reactant: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To the THF solution of 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (2.5 g, 5.4 mmol) was added dropwise 10N NaOH (1 ml, 10 mmol) and was stirred at room temperature overnight. The resulted suspension was filtered and the solid was dissolved in water (20 ml). The aqueous solution was acidified to pH=4 to obtain a milky suspension. The suspension was extracted with EtOAc (50 ml×3). The organic layer was washed with water (50 ml×2), brine (30 ml), dried over Na2SO4 and concentrated to give white solid (2.3 g, 96% yield): mp 105-107° C.; 1HNMR (CDCl3): δ 1.42 (J=7.5 Hz, 3H, OCH2CH3), 2.22 (s, 3H), 3.11 (dd, J=5, 12 Hz, 1H, CH2), 3.25 (dd, J=10, 15 Hz, 1H, CH2), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.12 (d, J=17.5 Hz, 1H, CH2N), 4.38 (d, J=17.5 Hz, 1H, CH2N), 5.81 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 6.96 (m, 3H, Ar), 7.13 (d, J=7.5 Hz, 1H, Ar), 7.45 (m, 1H, Ar), 8.43 (d, J=7.5 Hz, 1H, Ar), 10.25 (s, 1H, NHCO). 13CNMR (CDCl3): δ14.6, 24.8, 36.7, 46.8, 51.7, 64.9, 111.8, 111.3, 115.9, 117.1, 117.3, 118.0, 118.9, 120.1, 122.8, 133.5, 136.7, 137.8, 140.1, 141.2, 150.9, 169.47, 169.49, 173.5: Anal. Calcd. for C22H22F2N2O6+0.22H2O: C, 58.41; H, 5.00; N, 6.19. Found: C, 58.06, H, 4.92, N, 5.90.
Reaction SMILES: [CH:1]1([C:8]2[S:12][C:11]([N:13]3[CH:18]([OH:19])[CH2:17][CH2:16][N:15]([CH3:20])[C:14]3=[O:21])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[CH:1]1([C:8]2[S:12][C:11]([N:13]3[CH:18]([O:19][C:22](=[O:24])[CH3:23])[CH2:17][CH2:16][N:15]([CH3:20])[C:14]3=[O:21])=[N:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CN1CCC(O)N(c2nnc(C3CCCCCC3)s2)C1=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CCCCCC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydro-1-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.1 mole), acetic anhydride (0.11 mole), toluenesulfonic acid (0.05 gram) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is heated on a steam bath with stirring for a period of about 2 hours. After this time the reaction mixture is cooled to room temperature and is stripped of solvent under reduced pressure leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acetyloxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]OS(C)(=O)=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:4][CH2:3][O:2][CH3:1])=[CH:13][C:12]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1
Reactant: COCCOS(C)(=O)=O
Reactant: CC1(C)OB(c2cc(O)ccc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCCOc1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
Methanesulfonic acid 2-methoxyethyl ester (70.5 mg, 0.50 mmol) and 2-[2-chloro-5-hydroxyphenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (Preparation 66,100 mg, 0.42 mmol) were stirred together in N,N-dimethylacetamide (4 ml). Potassium carbonate (58 mg, 0.42 mmol) was added and the resultant solution was heated to 100° C. for 10 hours. The reaction mixture was cooled then quenched with water (10 ml) and extracted with ethylacetate (10 ml). The organic layer was dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to give crude title compound. Material taken on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6](=[O:15])[CH2:7]C(OC(C)(C)C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:5][C:6](=[O:15])[CH3:7]
Reactant: COC(=O)[C@H](CC(=O)CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](CC(C)=O)NC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 80 %

Procedure:
In a flask under argon was placed (S)-2-benzyloxycarbonylamino-4-oxo-hexanedioic acid 6-t-butyl ester 1-methyl ester (3.04 g, 8.01 mmol), toluene (80 mL) and para-toluene sulfonic acid hydrate (115 mg, 0.61 mmol) and refluxed for 6.5 h and then overnight for 16 h at room temperature. The mixture was concentrated in vacuo and purified by flash column chromatography (silica gel 60, 230-400 mesh; 50% ethyl acetate/hexanes) which afforded (S)-2-benzyloxycarbonylamino-4-oxo-pentanoic acid methyl ester (1.79 g, 80%) as a pale yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([O:9][CH2:10][CH3:11])[N:3]=1.C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>CCOCC>[Cl:1][C:2]1[C:7]([NH:8][C:21](=[O:22])[CH2:20][Cl:19])=[CH:6][CH:5]=[C:4]([O:9][CH2:10][CH3:11])[N:3]=1
Reactant: O=C(Cl)CCl
Reactant: CCOc1ccc(N)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOc1ccc(NC(=O)CCl)c(Cl)n1

Procedure:
A solution of 2-chloro-3-amino-6-ethoxypyridine (17 grams) in ether (200 ml), and triethylamine (10 grams) are placed in a glass reaction flask equipped with stirrer, thermometer and addition funnel. The mixture is cooled to about 0° to 10° C and a solution of chloroacetyl chloride (11.3 grams) in ether (40 ml) is slowly added thereto over a period of about 30 minutes resulting in the formation of a precipitate. The precipitate is recovered by filtration and is washed first with aqueous sodium bicarbonate and then with water. The washed product is then dried to yield the desired product N-(2-chloro-6-ethoxy-3-pyridyl)-α-chloroacetamide.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])(=[O:13])[CH3:12].Cl>O1CCCC1.C(OCC)(=O)C>[C:17]([C:16]1[CH:15]=[C:14]([C:11](=[O:13])[CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccc(C#N)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a suspension of sodium hydride (1.2 g of 60% suspension in mineral oil, hexane-washed, 30.3 mmol) in 40 mL of tetrahydrofuran was added diethyl carbonate (3.7 mL, 30.3 mmol) and 3-acetyl benzonitrile (2.2 g, 15.2 mmol). The resulting suspension was stirred at 65° C. for 1 h and then was cooled to room temperature. There was added 40 mL of 10% aqueous HCl and the reaction mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to afford 3.2 g (96%) of the title compound, which was sufficiently pure to be used without purification. MS(NH3—CI) 218.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Cl:12]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][C:4]([Cl:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1csc(N)n1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(N)sc1Cl
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Ethyl 2-aminothiazole-4-carboxylate (4.72 g, 27.4 mmol) was combined with N-chlorosuccinimide (4.0 g, 30 mmol) and dissolved in acetonitrile (50 mL). The mixture was heated at mild reflux (>81.5° C.) for 5 hours. Subsequently, the flask was cooled to rt and decolorizing carbon was added to the mixture which was further diluted with EtOAc. The resulting slurry was filtered through a pad of silica and concentrated under reduced pressure to provide 5.57 g (98%) of the desired product ethyl 2-amino-5-chlorothiazole-4-carboxylate (1H). The analytical data on this compound corresponded to that previously reported (see, South, M. S. J. Heterocyclic Chem. 1991, 28, 1003.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH2:14][CH:15]([CH2:17][NH2:18])[O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:15]1[CH2:14][C:13]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:9][CH:10]=[CH:11][C:12]=2[O:16]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccccc1-c1cccc2c1CC(CN)O2
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cccc2c1CC(CNC(=O)OCc1ccccc1)O2
Yield: 82 %

Procedure:
Treatment of (±)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.533 g, 1.94 mmol) with diisopropylethylamine (0.375 g, 2.90 mmol) and benzyl chloroformate (0.363 g, 2.13 mmol) generally according to the procedure described for Intermediate 12 provided 0.594 g (82%) of (±)-benzyl[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as colorless oil. Rf=0.42 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C24H23NO3: C, 77.19H, 6.21; N, 3.75. Found: C, 76.0H, 6.01; N, 3.55. Chiral HPLC separation of (±)-benzyl[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, methanol) provided two fractions. Fraction 1 (Rt=5.952 min Chiralcel OD, methanol); Fraction 2 (Rt=7.345 min, Chiralcel OD, methanol).
Reaction SMILES: [C:1](Cl)(=O)C.[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([Cl:15])[CH:7]=1>CO>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:1])=[O:11])=[C:8]([Cl:15])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Solvent: CO
Product: COC(=O)c1ccc(N)cc1Cl

Procedure:
Acetyl chloride (35.2 mmol, 2.5 mL) was added dropwise to a stirring solution of 4-amino-2-chloro-benzoic acid 70l (12.9 mmol, 2.22 g) in methanol (50 mL). The mixture was heated at reflux for 18 h, cooled, and concentrated under vacuum. The residue was taken up in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried, and concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 30% EtOAc/hexanes) to give compound 70m.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.Cl[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>C1COCC1>[CH2:11]([O:10][C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:20](=[O:21])[O:22][CH3:23])[CH2:3]1)=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cl
Reactant: N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl N-[(1S,3R)-3-aminocyclohexyl]carbamate, 18e, (0.99 g, 3.99 mmol) was dissolved in THF (20 mL) and treated with methyl chloroformate (0.62 mL, 7.97 mmol), followed by triethylamine (1.67 mL, 11.96 mmol). After stirring for 1 hour at room temperature, the solvent was evaporated under reduced pressure and the residue was diluted into 1:3 mixture of CH2Cl2:EtOAc (130 mL) and washed with 1N HCl (50 mL) and 2N Na2CO3 (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the desired product, 19a, as a white solid (1.09 g, 89% yield).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]2[N:10]=[C:3]3[C:2]([C:23]4[CH:24]=[N:20][NH:21][CH:22]=4)=[CH:7][CH:6]=[CH:5][N:4]3[N:8]=2)=[CH:13][CH:14]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1ccc(Nc2nc3c(-c4cn[nH]c4)cccn3n2)cc1

Procedure:
(4-Methoxy-phenyl)-[8-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (200.0 mg, 0.6266 mmol) and 1H-pyrazole-4-boronic acid (75.0 mg, 0.670 mmol) with Pd(dppf)Cl2 (50.0 mg) as the catalyst in a manner analogous to Step 2c and was isolated as a brown solid (0.065 g, 34%). MP=224-226° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 13.03 (br s, 1H), 9.38 (s, 1H), 8.59 (d, J=6.5 Hz, 1H), 8.49 (s, 2H), 7.85 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.11 (t, J=7.2 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 3.73 (s, 3H). MS=307 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.[Br-].[CH3:15][CH2:16][CH:17]([Zn+])[CH2:18][CH3:19].O>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:17]([CH2:18][CH3:19])[CH2:16][CH3:15])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Reactant: CCC([Zn+])CC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1cc(C(=O)OC)cc(OC)n1
Temperature: 85 °C

Procedure:
Under argon, Pd(dppf) (3.04 g, 4 mmol) is added to a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (50 g, 0.248 mol) in THF (100 mL). A 0.5 M solution of 3-pentylzincbromide in THF (550 mL) is added via dropping funnel. Upon complete addition, the mixture is heated to 85° C. for 18 h before it is cooled to rt. Water (5 mL) is added and the mixture is concentrated. The crude product is purified by filtration over silica gel (350 g) using heptane:EA 7:3 to give 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid methyl ester (53 g) as a pale yellow oil; 1H NMR (CDCl3): δ0.79 (t, J=7.5 Hz, 6H), 1.63-1.81 (m, 4H), 2.47-2.56 (m, 1H), 3.94 (s, 3H), 3.96 (s, 3H), 7.12 (d, J=1.0 Hz, 1H), 7.23 (d, J=1.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21]OS(C)(=O)=O)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21][N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Reactant: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)cc1F
Yield: 80.9 %

Procedure:
Following the procedure of Example 1(10), 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 80.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CC(C)([O-])C.[K+].Cl.Cl[CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH3:35]>CC(N(C)C)=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH3:35])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CN1CCCC1CCCl
Reactant: COc1cc(CCc2ccccc2O)cc(OC)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(CCc2ccccc2OCCC2CCCN2C)cc(OC)c1
Yield: 80.4 %

Procedure:
Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(3,5-dimethoxyphenyl)ethyl]phenol (prepared as described in Preparation 27), 1.30 g of potassium t-butoxide and 1.06 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.15 g (yield 80%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[FH:16].[F-].[K+]>>[F:16][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CO1
Reactant: F
Agent: [F-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1C[C@@H](O)CF

Procedure:
A sample of 2-[(2R)-Oxiranylmethyl]-1H-isoindole-1,3-dione (G. Alexander et al. Tetrahedron Asymmetry, 7, 1641-8, 1996) is treated with potassium hydrogen difluoride to give 2-[(2R)-3-fluoro-2-hydroxypropyl]-1H-isoindole-1,3-dione in the presence of catalyst nBu4NH2F3. The procedures and methods used in this synthesis are identical to those of Example 3, except that in step Example-3B 2-[(2R)-3-fluoro-2-hydroxypropyl]-1H-isoindole-1, 3-dione is used instead of (S)-1-[(benzyloxycarbonyl)amino]-2-propanol to produce the title product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15]C(=O)[C@@H]3C(C)C)=[CH:8][C:6]=2[N:7]=1.[CH2:28]1[C@@H:33]2[CH2:34]NCCN2[CH2:31][CH2:30][O:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[C@H:33]([CH2:28][O:29][CH2:30][CH2:31]4)[CH2:34]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)[C@H]1C(=O)NCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CN2CCOC[C@@H]2CN1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCOC[C@@H]4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of (S)-4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3-isopropyl-piperazin-2-one using (5)-octahydro-pyrazino[2,1-c][1,4]oxazine in place of (S)-3-isopropyl-piperazin-2-one. The title compound was obtained as a pale yellow solid (210 mg, 90%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[CH:4]=1)=[N+:13]=[N-:14]
Reactant: ClCc1ccn2ncnc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccn2ncnc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of 7-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (4-3) (400 mg, 2.4 mmol) in dried DMF (5 mL) was added NaN3 (250 mg, 3.6 mmol) under N2. The reaction mixture was stirred at 80° C. for 2 h, then quenched with aqueous Na2S2O3. The resulting mixture was extracted with EtOAc, dried on Na2SO4, and concentrated to afford the title compound (340 mg), which was used in next step without further purification. MS (m/z): 175 (M+1)+.