Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:19]1([PH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:5]=[C:4]1[CH2:3][CH:2]([CH2:1][P:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:6]1
Reactant: C=C1CC(=O)O1
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=C1CC(CP(c2ccccc2)c2ccccc2)O1
Temperature: 85 °C

Procedure:
A mixture of 2.1 parts of diketene and 0.4 parts of azobisisobutyronitrile were added dropwise over 15 minutes to 18.6 parts of diphenylphosphine which was stirred and heated at 85° C. in a nitrogen atmosphere. After the addition, the reaction mixture was heated for a further 5 minutes at 85° C., then cooled to room temperature. The excess diphenylphosphine and volatile impurities were removed by distillation on a wiped wall still at a wall temperature of 85° C. and a pressure of 0.04 mb, then the residue was distilled in the wiped wall still at 120° C. and a pressure of 0.013 mb. The product, (2-oxo-4-oxetanylmethyl)-diphenylphosphine, was obtained as a colourless oil and had an absorption at 1825 cm-1 in the infra-red spectrum, characteristic of a β-lactone.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.[Br:9]Br>CC(O)=O>[NH2:1][C:2]1[S:3][C:4]([Br:9])=[C:5]([C:7]#[N:8])[N:6]=1
Reactant: BrBr
Reactant: N#Cc1csc(N)n1
Solvent: CC(=O)O
Product: N#Cc1nc(N)sc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
2-Aminothiazole-4-carbonitrile (1.40 g, 11.18 mmol) was dissolved in 20 mL AcOH in a 150 mL round bottom flask. Br2 (1.78 g, 11.18 mmol) was added to the reaction in a dropwise manner. After stirring at room temperature for 10 minutes, AcOH was removed under vacuum. Saturated sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and dried over sodium sulfate. 2-amino-5-bromothiazole-4-carbonitrile (1.20 g, yield: 53%) was obtained. LCMS (API-ES) m/z (%): 205.9 (100%, M++2H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[O:12]=[C:13]1[NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[CH2:22][N:23]1[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1
Reactant: CCOC(=O)N1CCC(NCc2ccncc2NC(=O)OC(C)(C)C)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(N2Cc3ccncc3NC2=O)CC1
Reaction time: 8 h
Yield: 39.7 %

Procedure:
Trifluoroacetic acid (1.43 g) was added to a solution of the material from Step A (0.47 g, 1.24 mmol) in dichloromethane (10 mL). After stirring overnight, the reaction was concentrated. This material was dissolved in acetonitrile (5 mL) and carbonyldiimidazole (0.62 g, 3.73 mmol) was added at room temperature. After 2 d, the acetonitrile was evaporated in vacuo, the residue partitioned between 1N NaOH and dichloromethane, and the organic phase dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 1 to 20% methanol in methylene chloride gradient elution), which gave the title compound (0.15 g). MS 305.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([NH2:33])[S:28][C:29]=2[CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=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>C(Cl)Cl>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]=[C:27]([NH:33][C:15]([C@@H:11]3[CH2:12][CH2:13][CH2:14][N:10]3[C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:17])[S:28][C:29]=2[CH2:30][CH2:31][CH3:32])=[CH:23][CH:24]=1
Reactant: CCCc1sc(N)nc1-c1ccc(F)cc1
Reactant: O=C(O)[C@@H]1CCCN1c1nc2ccccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1sc(NC(=O)[C@@H]2CCCN2c2nc3ccccc3o2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 70 mg of (S)-1-benzooxazol-2-yl-pyrrolidine-2-carboxylic acid (intermediate 2), 71 mg of 4-(4-fluoro-phenyl)-5-propyl-thiazol-2-ylamine (intermediate 1), 128 mg of HATU and 0.16 mL of DIEA in CH2Cl2 was stirred at room temperature overnight. Solvent was evaporated and crude material was purified by chromatography (C-18, CH3CN/H2O) to provide the title compound. 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.98 (t, J=7.33 Hz, 3H) 1.62-1.81 (m, 2H) 2.03-2.37 (m, 4H) 2.52-2.68 (m, 1H) 2.82 (t, 2H) 3.76 (q, J=8.84 Hz, 1H) 3.92 (br. s., 1H) 4.88 (br. s., 1H) 7.02-7.14 (m, 3H) 7.22 (t, J=7.71 Hz, 1H) 7.32 (d, J=7.96 Hz, 1H) 7.41-7.58 (m, 3H). MS m/z 451.0 (M+H), 449.1 (M−H). HRMS calcd for C24H23FN4O2S=450.15257, found=450.15235. HPLC (0-95% ACN in 20 min using 0.1% TFA on 150 mm Atlantis C18 column) Rt=15.36.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:10])[CH:8]=[O:9].[CH:11]1(C(=O)C(C)(C2C=CC=CC=2)CC=O)CCCCC1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH2:10][CH3:11])[CH:8]=[O:9]
Reactant: CC(C=O)c1ccccn1
Reactant: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Product: CCC(C=O)c1ccccn1

Procedure:
Scheme VI, steps A-D: 4-Cyclohexyl-3-methyl-4-oxo-3-(2-pyridylbutyraldehyde is prepared from 2-(2-pyridyl)-propanaldehyde in a manner analogous to the procedure described in example 7 for the preparation of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde.
Reaction SMILES: [CH:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[CH:8][CH:7]=1)[C:4]#[N:5])=O.O.Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25]>CO>[NH2:5][C:4]1[N:23]([C:24](=[O:25])[NH2:26])[N:22]=[CH:1][C:3]=1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[CH:8][CH:7]=1
Reactant: Cc1cccc(Cc2ccc(C(C#N)C=O)cc2)c1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Reaction time: 13 h

Procedure:
To a solution obtained by dissolving α-formyl-4-(3-methylphenylmethyl)phenylacetonitrile thus obtained in methanol (50 ml) and water (10 ml) was added semicarbazide hydrochloride (3.2 g) under stirring on ice-cooling. Ice bath was removed, and after 13 hours, the mixture was adjusted to alkaline (pH 10 to 11) with 5N-sodium hydroxide aqueous solution, and stirred for 1 hour. Next, the reaction mixture was neutralized (pH 8 to 9) with 10% hydrochloric acid aqueous solution, and the precipitate was separated by filtration. By washing and drying, 3-amino-2-carbamoyl-4- {4-(3-methylphenylmethyl)phenyl}pyrazole (6.3 g) was obtained. The product was used in subsequent procedure without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].CI.[C:16](OCC)(=O)C>CN(C=O)C>[CH3:16][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cc(C=O)ccc21
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of indole-5-carbaldehyde (1.0 g, 6.9 mmol) in DMF (15 mL) was added sodium hydride (303 mg of 60% dispersion in oil, 7.59 mmol) in 3 portions. The mixture was stirred for 30 mins. Methyl iodide (1.96 g, 13.8 mmol) was then added and the mixture was stirred overnight. Ethyl acetate (200 mL) was added and solution was washed with H2O (3×20 mL) and brine (25 mL) dried over MgSO4 and concentrated to afford N-methylindole-5-carboxaldehyde as an orange oil (1.0 g, 91%). 1H NMR (200 MHz, CDCl3) δ 10.05 (s, 1H), 8.09 (s, 1H), 7.90-7.80 (m, 1H), 7.35-7.15 (m, 2H), 6.85-6.80 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([N:9]([CH2:23][CH2:24][CH3:25])[CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20](=O)[CH3:21])[O:12][CH2:11]1)[CH2:7][CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:6]([N:9]([CH2:23][CH2:24][CH3:25])[CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20]([CH3:2])=[CH2:21])[O:12][CH2:11]1)[CH2:7][CH3:8]
Reactant: [Li]CCCC
Reactant: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C(C)c1cccc2c1CC(N(CCC)CCC)CO2
Reaction time: 4 h

Procedure:
Methyltriphenylphosphoniumbromide (0.62 g, 1.74 mmol) was dissolved in dry ethyl ether (20 ml) under nitrogen at ambient temperature and n-BuLi (0.7 ml, 2.5 M, 1.74 mmol) was added and the solution was stirred for 4 hours. 3-Dipropylamino-5-acetylchroman (Example 7; 0.40 g, 1.45 mmol) was dissolved in dry diethyl ether (2.0 ml) and this solution was added to the previously formed Wittig-reagent.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[O:8][C:7](C3C=CC=CC=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22]C1CC2N(C)C(CCC2)C1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:8]1[C:4]2=[CH:3][CH:2]=[CH:16][C:15]([C:17]([NH2:22])=[O:19])=[C:5]2[N:6]=[CH:7]1
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(F)cc2oc(-c3ccccc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2ocnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 215.9 %

Procedure:
A mixture of 6-fluoro-2-phenylbenzo[d]oxazole-4-carboxylic acid (30 mg, 0.12 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (32 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (0.10 mL, 0.72 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight, and then was quenched with a saturated solution of sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-phenyl)benzoxazole-4-carboxamide (42 mg, 91%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.96 (d, J=7.5 Hz, 1H), 8.23-8.22 (m, 2H), 7.96 (d, J=10.5 Hz, 1H), 7.63-7.55 (m, 3H), 7.42 (d, J=7.0 Hz, 1H), 4.62-4.53 (m, 1H), 3.13-3.11 (m, 2H), 2.67-2.60 (m, 2H), 2.54 (s, 3H), 2.15-1.98 (m, 3H), 1.62-1.46 (m, 3H), 1.18-1.13 (m, 2H); 19F NMR (282 MHz, CDCl3) δ −113.93; MS (ESI+) m/z 394 (M+H); HPLC>99% (AUC), tR=12.78 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21]([N:23]=[C:24]=[O:25])[CH:20]=[CH:19][C:18]=1[CH3:26]>ClCCl>[NH:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:24]([NH:23][C:21]2[CH:20]=[CH:19][C:18]([CH3:26])=[C:17]([Cl:16])[CH:22]=2)=[O:25])[CH2:2]1
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: c1ccc2[nH]c(C3CCCNC3)nc2c1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N2CCCC(c3nc4ccccc4[nH]3)C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
2-(piperidin-3-yl)-1H-benzo[d]imidazole (100.0 mg, 0.497 mmol) was dissolved in dichloromethane (3.0 mL). To the stirred suspension was added 2-chloro-4-isocyanato-1-methylbenzene (84.1 mg, 0.502 mmol). The reaction was stirred at ambient temperature for one hour. The crude mixture was then concentrated in vacuo and the residue was dissolved in minimal amounts of dimethylformamide and purified via preparative HPLC (10%-50% acetonitrile in water). The pure fractions were combines and lyophilized to yield the title compound 1 as a fluffy white solid (147.5 mg, 63.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.65 (m, 1H), 1.83 (d, J=13.73 Hz, 1H), 1.97 (q, 0.1=18.28 Hz, 1H), 2.25 (s, 3H), 2.30 (s, 1H), 2.99 (t, J=11.44 Hz, 1H), 3.23 (t, J=13.34 Hz, 1H), 3.34-3.38 (m, 1H), 4.11 (d, J=13.35 Hz, 1H), 4.48 (d, J=13.35 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.51-7.34 (m, 1H), 7.63 (s, 1H), 7.78-7.80 (m, 1H), 8.76 (s, 1H), ESI-MS: m/z 369.2 (M+H)+.
Reaction SMILES: Cl[Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[OH:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].N1C=CN=C1>CN(C)C=O.O>[CH:3]([Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[O:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])([CH3:5])[CH3:4]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=Cc1cccc(CCO)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCc1cccc(C=O)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
Chlorotriisopropylsilane (0.640 g, 0.71 mL, 3.3 mmol) was added dropwise to a 0° C. cooled solution of 13 (0.450 g, 3.0 mmol) and 1H-imidazole (0.410 g, 6.0 mmol) in anhydrous N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 0° C. for 3 h and then diluted with water. The resulting mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using ethyl acetate-hexanes 1:9 as eluent to furnish the desired compound as colorless oil. Yield: 96%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Product: N#Cc1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 74 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (150 mg, 0.51 mmol), using 6-chloro-3-pyridinecarbonitrile instead of 4-fluoroacetophenone, was converted to the title compound (149.5 mg, 74%) which was obtained as a white solid. MS: m/e=398.3 [M−H]−.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.[CH3:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[CH3:12][N:13]([CH2:2][C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CNS(C)(=O)=O
Reactant: OB(O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN(Cc1cccc(B(O)O)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
175 a) A suspension of [3-(bromomethyl)phenyl]boronic acid (1.0 g, 4.6 mmol), N-methyl-methanesulfonamide (0.56 g, 5.1 mmol) and potassium carbonate (1.9 g, 14 mmol) in acetone (10 mL) was stirred for 6 hours at room temperature. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. Crude (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid was isolated as a yellow viscous oil (1.08 g, 88%). MS=266 (M+Na)+. 175 b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid (650.0 mg, 2.674 mmol) in a manner analogous to Example 2c. Product isolated as a pale yellow foam (0.331 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.8 Hz, 1H), 7.99-7.95 (m, 2H), 7.74 (d, J=7.4 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.1 Hz, 1H), 4.42 (s, 2H), 2.92 (s, 3H), 2.84 (s, 3H). MS=351 (MH)+. 175 c) N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.007 g, 6%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.7 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.55-7.46 (m, 3H), 7.42 (d, J=7.4 Hz, 1H), 7.00-6.91 (m, 3H), 6.65 (s, 3H), 4.42 (s, 2H), 3.19-3.14 (m, 4H), 2.87 (s, 3H), 2.83 (s, 3H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS=506 (MH)+.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[CH2:24][CH2:23]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[NH:32]1[CH2:33][CH2:34][CH:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[CH2:27][CH2:26]2)[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C1CC(CN2CCN(CC3CCNCC3)CC2)CCN1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A 4N hydrogen chloride in ethyl acetate (4 ml; 16 mmol) was added to a solution in methylene chloride (2 ml) of 1,4-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]-piperazine (195 mg; 0.40 mmol) synthesized by the above process under ice cooling, and the mixture was stirred for 30 minutes. The ice bath was removed, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resultant crude crystals were recrystallized from methylene chloride-methanol-diethyl ether, thereby obtaining 154 mg (yield: 84%) of the title compound as a colorless crystalline powder (melting point: 280° C. or higher).
Reaction SMILES: [Cl-:1].[CH2:2]1[C:10]2[N+:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1.N1CCCC1>C(O)(C)C>[Cl-:1].[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=[C:2]2[C:10]3[N+:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[CH:13]1
Reactant: c1cc[n+]2c(c1)CCC2
Reactant: Cn1cc(C=O)c2ccccc21
Agent: [Cl-]
Solvent: C1CCNC1
Solvent: CC(C)O
Product: Cn1cc(C=C2CC[n+]3ccccc32)c2ccccc21
Temperature: 80 °C

Procedure:
1.55 g of 2,3-dihydro-1H-indolizinium chloride and 1.59 g of 1-methylindole-3-carboxaldehyde were suspended in 15 ml of isopropanol, in a 50 ml three-necked flask. The reaction mixture was heated at 80° C. and then 820 μl of pyrrolidine were introduced. The reaction mixture was immediately cooled to ambient temperature. The precipitate was filtered off, and washed with 2 times 30 ml of isopropanol before being dried under a strong vacuum in the presence of P2O5, until a constant weight was obtained. 2.59 g of orange powder were recovered. The analyses (NMR) (d6-DMSO) and mass spectrometry ESI+M/Z=261) were in conformity with the expected structure.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1>>[CH2:1]([NH:9][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: O=C1CCCO1
Product: CCCCCCCCNC(=O)CCCO

Procedure:
1 mol of octylamine was heated to 100° C. with stirring. 1 mol of gamma-butyrolactone was added dropwise over a period of 30 minutes. The mixture was heated for three hours to 120° C. At the end of the reaction, a vacuum of 50 mbar was applied. The product was obtained after cooling in the form of a pale yellow solid.
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19](O)=[O:20].C1CCN2C(=NCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:24]([O:23][C:17]([C:18]1[C:19](=[O:20])[O:1][C:2]([CH3:16])([CH3:15])[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:22])[CH3:25]
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CCOC(=O)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 62.6 %

Procedure:
A mixture of 2-hydroxy-2-methyl-1-(4-(methylsulfonyl) phenyl)propan-1-one (2.87 g, 11.8 mmol), ethyl hydrogen malonate (2.02 g, 15.3 mmol), CMC (6.51 g, 15.4 mmol) and DMAP (0.35 g, 2.8 mmol) was dissolved in 100 mL of CH2Cl2. The mixture was stirred for 14 h at room temperature, then DBU (4 mL, 27 mmol) was added, stirred 1 h, then partitioned between CH2Cl2 and 1M HCl. The organic layer was washed with brine, filtered through cotton and evaporated. Purification by flash chromatography (90% ether/Hex) provided 2.50 g of the title compound.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:31]2[CH2:33][CH2:32]2)[CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:34])[CH:2]=[CH2:3].[H-].[Na+].I[CH2:39][CH3:40]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH:31]2[CH2:33][CH2:32]2)[CH2:25][N:26]([CH2:39][CH3:40])[S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: CCI
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(C)(=O)=O)C2CC2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CN(CC)S(C)(=O)=O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)methanesulfonamide (Example 289, Step A, 86 mg, 0.161 mmol) in DMF (1.5 ml) was added sodium hydride (16.06 mg, 0.401 mmol) at rt and the reaction was stirred at rt for 30 minutes. To this reaction was added iodoethane (0.058 mL, 0.723 mmol) and the reaction was stirred at rt for 2 hours. The reaction was diluted with EtOAc, washed with water and sat. NaCl, dried with Na2SO4 and then concentrated. The crude was used on next reaction.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[NH2:11])[CH3:2].[CH2:12](C(CC)(CC)C([O-])([O-])[O-])[CH3:13]>C(O)C>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=2[N:11]=[C:12]1[CH3:13])[CH3:2]
Reactant: CCNc1ccc(F)cc1N
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CCO
Product: CCn1c(C)nc2cc(F)ccc21

Procedure:
To 2.92 g of N-ethyl-4-fluorophenylenediamine in 15 ml of ethanol was added 3.49 ml of triethylorthoacetate and the reaction refluxed for 6 hours. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic phase was separated, dried and the solvent removed to give 2.87 g of product as a brown oil.