Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH:12]=[CH:11][CH:5]([CH:6]=[C:7]1[CH2:8][CH2:9][OH:10])[C:4]([CH3:14])([CH3:13])[C:3]2=[O:15].[H][H]>[Pd].C(O)(C)C>[CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([CH2:6][CH:7]1[CH2:8][CH2:9][OH:10])[C:4]([CH3:14])([CH3:13])[C:3]2=[O:15]
Reactant: [H][H]
Reactant: CC12C=CC(C=C1CCO)C(C)(C)C2=O
Agent: [Pd]
Solvent: CC(C)O
Product: CC1(C)C(=O)C2(C)CCC1CC2CCO
Temperature: 150 °C
Reaction time: 48 h

Procedure:
An autoclave is charged with 26.8 grams of 1,3,3-trimethyl-6-(2-hydroxyethyl)bicyclo(2.2.2)-octa-5,7-dien-2-one prepared according to the process of Example XVI, 2 grams 5% palladium/carbon catalyst, and 300 ml isopropyl alcohol. The autoclave is then sealed and pressurized with hydrogen to 400 psig, heated to 150° C. and maintained at that temperature, with stirring, for a period of 48 hours. At the end of this period of time, the autoclave is opened and the reaction mass is removed. The reaction mass is filtered, and the excess isopropyl alcohol is stripped therefrom. The reaction product (the title product) is distilled at 64°-65° C. at a pressure of 0.2 mm Hg (yield: 12.3 g). Its structure, confirmed by NMR and mass spectral analyses is as follows: ##STR36##
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C(=O)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39](SC)=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:26][CH:25]=1>O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:9][CH2:10]3)=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CSc1nc2cncnc2n1Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1ccc(Cn2c(OC3CCN(Cc4ccccc4)CC3)nc3cncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A mixture of 12.6 parts of 1-(phenylmethyl)-4-piperidinol, 3.2 parts of a sodium hydride dispersion 50% and 200 parts of N,N-dimethylacetamide was stirred for 1 hour at room temperature. 18 Parts of 9-[(4-fluorophenyl)methyl]-8-(methylthio)-9H-purine were added portionwise and upon completion, stirring was continued for 4 hours at room temperature. The reaction mixture was poured into water. The product was filtered off and taken up in trichloromethane. The organic layer was washed with water and filtered over diatomaceous earth. The filtrate was dried, filtered and evaporated. After crystallization from acetonitrile, the product was filtered off and dried, yielding 16.75 parts (61.1%) of 9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]oxy]-9H-purine; mp. 117.0° C. (compound 5).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([O:16]CC)=O.[BH4-].[Na+].II.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:7]=[C:6]2[C:14]1=[O:16]
Reactant: CCOC(=O)c1cc2ccccc2n1CC(=O)NC
Agent: Cl
Agent: II
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CN1CCn2c(cc3ccccc32)C1=O
Temperature: 0 °C
Yield: 31.4 %

Procedure:
To a mixture of ethyl 1-(2-(methylamino)-2-oxoethyl)-1H-indole-2-carboxylate (0.86 g), NaBH4 (0.39 g) in 33 mL of THF stirred at 0° C. under a N2 atmosphere, a solution of Iodine (1.26 g, 10 mL THF) was added dropwise. The resulting mixture was reacted at 65° C. for 24 hr. The reaction was worked up by the addition of HCl (con., 1.5 mL) and heated at 65° C. for 4 hr. Then the mixture was neutralized by saturated NaHCO3 solution and the aqueous phase was extracted with EtOAc (2×60 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by Combiflash (0-100% EtOAc/hexane) to afforded 208 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:27]1([CH2:26][CH2:25][CH2:24][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3([CH2:8][NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:16][CH:17]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: ClCCCN1CCCCC1
Reactant: Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(NCC2(c3ccc(OCCCN4CCCCC4)cc3)CCOCC2)nc1
Yield: 76.3 %

Procedure:
4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (200 mg, 0.704 mmol), 3-chloropropylpiperidine hydrochloride (152 mg, 0.775 mmol) and potassium carbonate (204 mg, 1.48 mmol) were stirred in DMF (1 ml) at 45° C. for 24 hours until complete. The reaction was then partitioned between ethyl acetate (40 ml) and water (40 ml). The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to give a solid. The solid was purified by preparative HPLC to give the title compound (220 mg, 76%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.44-1.55 (m, 2H), 1.64-1.78 (m, 4H), 1.85-2.00 (m, 2H), 2.08-2.18 (m, 4H), 2.52-2.70 (m, 6H), 3.48 (d, 2H), 3.52-3.62 (m, 2H), 3.78-3.85 (m, 2H), 4.02 (t, 2H), 6.21 (d, 1H), 6.50 (t, 1H), 6.90 (d, 2H), 7.24 (d, 2H), 7.34 (t, 1H), 8.01 (d, 1H). LRMS APCI+ m/z 410 [MH]+.
Reaction SMILES: Cl.CN[O:4][CH3:5].C[Al](C)C.C([C@H:17]1COC(=O)[N:18]1[C:23]([C@@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:28][N:27]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:26]1)=[O:24])C1C=CC=CC=1>C(Cl)Cl>[CH3:5][O:4][N:18]([CH3:17])[C:23]([C@@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:28][N:27]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:26]1)=[O:24]
Reactant: CNOC
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a suspension of N,O-dimethylhydroxylamine hydrochloride (3.61 g, 0.037 mol) in DCM (40 mL) at RT was added trimethylaluminium (2.0M solution in heptane, 18.5 ml, 0.037 mol) dropwise and stirring was continued for one hour. To this mixture was added a solution of (S)-4-benzyl-3-[(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonyl]-oxazolidin-2-one (9.47 g, 0.0186 mol) in DCM (50 mL) over 10 minutes. Stirring was continued for three hours. The reaction was quenched by an addition of aq. Potassium sodium tartarate solution and extracted with ethyl acetate. The separated organic layer was washed with brine and dried on Na2SO4 and concentrated under vacuo. Purification by column chromatography (SiO2, EtOAc/H, 2:3) yielded 6.58 g (90%) of the title compound as a light yellow oil. ES-MS m/e: 393.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][NH2:12])=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[NH:25][N:24]=[C:23]([CH:26]3[CH2:28][CH2:27]3)[CH:22]=2)[CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[C:3]([CH2:11][NH:12][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[C:23]([CH:26]4[CH2:28][CH2:27]4)[NH:24][N:25]=3)[CH:17]=[CH:16][N:15]=2)=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1
Reactant: NCc1cc2nc[nH]c2cc1Cl
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cc2[nH]cnc2cc1CNc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A tube was charged with 252 (110 mg, 0.608 mmol), 53 (143 mg, 0.608 mmol), and DIPEA (235 mg, 1.823 mmol) in IPA (3 mL), sealed and heated 120° C. for 18 h with stirring. The reaction was cooled to RT and concentrated in vacuo. The crude product was purified by preparative HPLC to afford 72 mg (31.3%) of I-94 as white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:29][CH:30]([CH3:32])[CH3:31])[S:10]([C:13]2[CH:14]=[CH:15][C:16]([C:23]#[C:24][Si](C)(C)C)=[C:17]([CH:22]=2)[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11])=[CH:5][CH:4]=1)[CH3:2].[OH:33]S(O)(=O)=O>CC(C)=O>[C:23]([C:16]1[CH:15]=[CH:14][C:13]([S:10](=[O:11])(=[O:12])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH2:29][CH:30]([CH3:31])[CH3:32])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:33])[CH3:24]
Reactant: O=S(=O)(O)O
Reactant: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C#C[Si](C)(C)C)c(C(=O)OC)c2)cc1
Solvent: CC(C)=O
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(C)=O)c(C(=O)OC)c2)cc1

Procedure:
A mixture of methyl 5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2-((trimethylsilyl)ethynyl)benzoate (320 mg, 0.678 mmol), mercuric sulphate (201 mg, 0.678 mmol), H2SO4 (1.357 mL, 1.357 mmol) and acetone (6 mL) was heated at reflux for 4 hours. The mixture was partitioned between ammonium chloride solution (10%, 20 mL) and dichloromethane (DCM) (2×25 mL) then organics separated, dried (MgSO4) and evaporated onto florisil. The crude material was purified by silica (Si) chromatography (0-100% dichloromethane-cyclohexane gradient) to give the title compound as a colourless gum, 110 mg. LCMS [LCMS1] Rt 1.33 min, m/z (ES+) 418 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>CN(C=O)C>[CH2:1]([N:3]([C:11](=[O:13])[CH3:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1ccc(O)cc1

Procedure:
Two g of p-ethylaminophenol (0.0146 moles) were dissolved in 50 ml DMF. To this was added 2.98 g of acetic anhydride (0.0292 moles). The mixture was heated at 60° for three hours and then poured over crushed ice. Sodium carbonate was added until a pH of approximately 10 was achieved. The solution and precipitated oil were extracted with chloroform, dried over anhydrous magnesium sulfate, and then evaporated to dryness leaving a residual oil. To this oil was added 5% sodium hydroxide, and the mixture was heated at 60° for one hour. The solution was cooled and then extracted with chloroform. The remaining aqueous phase was acidified with dilute HCl to achieve a pH of approximately 4, and then extracted with chloroform. The liquid was dried over anhydrous magnesium sulfate, and then evaporated to dryness. The residual brown solid material was recrystallized from an ethanol-water mixture to yield N-ethyl-4'-hydroxyacetanilide (melting point 183°-185° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1>[N:28]([CH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[CH:11]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(CO)cc1Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Yield: 97.5 %

Procedure:
A solution of 2-chloro-4-(hydroxymethyl)benzoic acid, methyl ester (11.09 g, 55.3 mmol), diphenylphosphoryl azide (22.58 g, 82.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.57 g, 56.3 mmol) in tetrahydrofuran was stirred overnight at room temperature. Silica gel was added and the solvent was evaporated. The residue was chromatographed (10% ethyl acetate/hexanes) to give 4-(azidomethyl)-2-chlorobenzoic acid, methyl ester (12.17 g, 98%) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:28]1([C:34](=[O:45])[CH2:35][C:36](=O)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:37](/[C:36](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:35]/[C:34](=[O:45])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCCCCCCC(=O)CC(=O)c1ccccc1
Product: CCCCCCC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared as described above for the preparation of Example 2, from 102 mg (0.28 mmol) of Intermediate 45 and 69 mg (0.28 mmol) of Intermediate 19 to yield 77 mg of Example 45: TLC (EtOAc/MeOH , 713): Rf=0.56; 1H NMR (DMSO-d6, 400 MHz) δ11.55 (d, 1H, J=9.6), 7.86 (d, 2H, J=6.8), 7.76 (d, 2H, J=6.4), 7.46. (m, 3H), 7.38 (m, 3H), 7.10 (d, 2H, J=8.4), 6.78 (d, 2H, J=8.4), 5.5 (s, 1H), 4.10 (t, 2H, J=6.6), 4.0 (m, 1H), 3.16 (m, 1H), 2.86 (t, 2H, J=6.5), 2.69 (dd, 1H, J=13.6, 9.6), 2.31 (s, 3H), 1.87 (m, 2H), 1.25-1.1 (m, 10H), 0.78 (t, 3H, J=6.8); low resolution MS (ES+)m/e 595.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:14]=NC=[CH:17][CH:18]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[N:24]1C=CC(CC(=O)C)=C[CH:25]=1>>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:24]=[CH:25][CH:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5]
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccnc1
Reactant: CC(=O)Cc1ccncc1
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccncc1

Procedure:
Compound 17 was prepared as described for the preparation of Compound 16 using commercially available (4-pyridyl)acetone.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[C:11]([CH2:17][CH3:18])[CH:10]=1.O.[N:20]#[C:21]Br>CCO.CCO.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:17][CH3:18])[C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: N#CBr
Reactant: CCc1cc(Cl)nnc1NN
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1cc(Cl)nn2c(N)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
(6-Chloro-4-ethylpyridazin-3-yl)hydrazine trifluoroacetate (W3.003; 1.35 g) were initially charged in EtOH (25 ml) and water (4 ml) while stirring at RT. Thereafter, cyanogen bromide (997 mg), dissolved in EtOH/water (5/2 ml), was cautiously added dropwise. After stirring at RT for 8 h and standing overnight, the mixture was stirred at 55° C. for another 4 h. Subsequently, the solvent was concentrated and the residue was admixed with water. Once it had been alkalized with saturated potassium carbonate solution, the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 918 mg of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1Cl.Cl.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C.CN(C=O)C>CC(O)C>[NH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:6]2[N:5]([CH2:4][C:3]3[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=3[Br:1])[C:13]3[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=3[N:7]=2)[CH2:27]1
Reactant: NC1CCCNC1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2Br)n(C)c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(nc(N3CCCC(N)C3)n2Cc2ccccc2Br)n(C)c1=O

Procedure:
7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (10A) (100 mg, 0.26 mmol) and 3-aminopiperidine dihydrochloride (226 mg, 1.31 mmol) were dissolved in 2-propanol (20 ml), triethylamine (0.109 ml, 0.78 mmol) and DMF (5 ml) and subjected to microwaves (method F, 130° C., 300 W) for ten hours. The solvents were evaporated and the crude product was purified by preparative HPLC, (method A1, Rt=7.52 min.) to give the title compound as a brown oil.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[Yb]>C(Cl)Cl>[OH:1][C@@H:2]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1)[CH2:3][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Yb]
Solvent: ClCCl
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73 g, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield tert-butyl 4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate as a clear oil (9.5 g, 23 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1Br
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Product: Cc1ccccc1N1CCC(S(=O)(=O)c2ccc(C(C)(C)C)cc2)CC1
Yield: 44.1 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2-bromotoluene (53 μl, 0.43 mmol) to afford the title compound (59 mg), a yellow solid, in 44% yield.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[CH2:11][NH2:12])[CH2:2]1)[CH2:8]2.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[CH2:11][NH:12][C:23]([C:18]3[NH:19][C:20]4[C:16]([CH:17]=3)=[CH:15][C:14]([F:13])=[CH:22][CH:21]=4)=[O:24])[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: NCC1C2CC3CC1CN(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: O=C(NCC1C2CC3CC1CN(C3)C2)c1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of Example 2B (50 mg, 0.30 mmol) was dissolved in pyridine (5 mL). 5-Fluoroindole-2-carboxylic acid (65 mg, 0.36 mmol), 1-hydroxybenzotriazole (51 mg, 0.38 mmol), 4-di(methylamino)pyridine (9.2 mg, 0.08 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) were added to the reaction mixture. The reaction was stirred at 25° C. for 18 hours. The reaction mixture was filtered through a glass frit. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 Å Prep-Pak® cartridge column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the free base of the title compound. The solid was dissolved in 10:1 ether/methanol (5 mL) and treated with fumaric acid (10 mg/mL solution in 10:1 ether/methanol). The precipitate was filtered and dried under vacuum to afford the title compound as a fumarate: 1H NMR (methanol-d4, 500 MHz) δ 1.95-2.02 (m, 2 H), 2.11-2.20 (m, 4 H), 2.20-2.28 (m, 2 H), 3.37-3.43 (m, 2 H), 3.51 (br s, 2 H), 3.62 (d, J=7.93 Hz, 2 H), 3.76-3.83 (m, 2 H), 6.69 (s, 2.6 H; C4H4O4), 7.00 (dt, J=9.15, 2.44 Hz, 1 H), 7.03 (s, 1 H), 7.26 (dd, J=9.46, 2.44 Hz, 1 H), 7.41 ppm (dd, J=8.85, 4.58 Hz, 1 H); MS (ESI) m/z 328 (M+H)+; Anal. Calcd. for C19H22FN3O.1.3C4H4O4.0.1NH4OAc: C, 60.3; H, 5.79; N, 8.93. Found: C, 59.98; H, 5.76; N, 9.19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH3:26])=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1.Cl[C:29]1[CH:34]=CN(CC2N3C=CC=CC3=NC=2C2C=CC(Cl)=CC=2)C(=O)N=1.N1CCCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:34][CH2:29][CH2:26][CH2:25]3)=[N:20][C:19]2=[O:27])=[CH:6][CH:7]=1
Reactant: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Reactant: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Solvent: C1CCNC1
Product: O=c1nc(N2CCCC2)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the experimental for compound 132 from 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one and pyrrolidine. M/e+ 406 for C22H21ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.44 (d, J=6.6 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.28 (m, 1H), 6.86 (td, J=6.9, 1.1 Hz, 1H), 6.73 (d, J=7.3 Hz, 1H), 5.57 (s, 2H), 5.49 (d, J=7.7 Hz, 1H), 3.65 (t, J=6.6 Hz, 2H), 3.28 (t, J=6.6 Hz, 2H), 1.90 (m, 4H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[F:11].ClC1C(C)=C(N=[C:23]=[O:24])C=CC=1C#N>>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[F:11])=[C:23]=[O:24]
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Reactant: N#Cc1ccc(N)c(F)c1Cl
Product: N#Cc1ccc(N=C=O)c(F)c1Cl

Procedure:
4-Isocyanato-3-fluoro-2-chlorobenzonitrile was prepared from 4-amino-3-fluoro-2-chlrorbenzonitrile (9B) in a manner similar to that described in Example 1 for the preparation of 1G.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:17][CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][CH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16][CH2:17]2)=[O:13])=[C:5]3[NH:18][CH:19]2[CH2:20][CH2:21][CH:22]([CH2:25][N:26]([CH3:27])[CH3:28])[CH2:23][CH2:24]2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CC1CCC(Nc2c(C(=O)C3CCC3)cnc3ccc(Cl)nc23)CC1
Product: CN(C)CC1CCC(Nc2c(C(=O)C3CCC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)nc23)CC1
Yield: 88.1 %

Procedure:
Following general procedure II, (6-chloro-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)(cyclobutyl)methanone (65 mg, 0.16 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.24 mmol) to afford the desired product (72 mg, 77%) as light yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.93 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.02 (s, 1H), 7.88 (dd, J=11.5, 2.0 Hz, 1H), 5.74-5.64 (m, 1H), 4.29-4.19 (m, 1H), 3.12-3.07 (m, 2H), 2.95 (s, 6H), 2.52-2.41 (m, 4H), 2.39-2.34 (m, 2H), 2.24-2.12 (m, 1H), 2.09-1.98 (m, 2H), 1.98-1.89 (m, 1H), 1.78-1.66 (m, 2H), 1.49-1.35 (m, 2H); ESI MS m/z 511 [M+H]+; HPLC>99% (AUC), tR=10.52 min.