Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1)[CH2:8][C:9]([CH2:16][CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C(O)=O)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]>CS(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1)[CH2:8][CH:9]([CH2:16][CH2:17][CH2:18][S:19][C:20]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)(C(=O)O)C(=O)O)cc(C(C)(C)C)c1
Solvent: CS(C)=O
Product: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cc(C(C)(C)C)c1
Yield: 93.6 %

Procedure:
A solution of 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-2-[3-[(triphenylmethyl)thio]propyl]-malonic acid XI (6.71 g, 11 mmol) in DMSO (10 ml) was stirred at 130° C. for 1.5 hours. The solvent was removed under reduced pressure and water was added to the residual oil. The precipitate was filtered off, washed with water, and dried under vacuum to afford 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-5-[(triphenylmethyl)thio]-pentanoic acid XII (5.86 g, 10.3 mmol, 94%) as a white solid: 1H NMR (CD3OD) δ 1.3 (s, 9H), 1.3-1.5 (m, 4H), 2.1 (m, 2H), 2.4 (m, 1H), 2.7 (m, 1H), 2.8 (m, 1H), 7.1-7.4 (m, 16H), 7.7 (s, 1H), 7.9 (s, 1H); 13C NMR (CD3OD) δ 27.4, 31.7 (3C), 32.3, 32.7, 35.6, 39.2, 48.4, 67.7, 125.7, 127.7, 128.6, 128.9, 130.8, 131.6, 132.0, 140.8, 146.3, 152.7, 170.3, 178.8.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([NH:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:7])[CH3:6])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:20])[C:5]([N:8]([C:31](=[O:32])[C:30]1[CH:34]=[C:35]([CH3:37])[CH:36]=[C:28]([CH3:27])[CH:29]=1)[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)NNC(=O)OCc1ccccc1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(C)N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
2-(N′-benzyloxycarbonyl-hydrazino)-2-methyl-propionic acid ethyl ester (28 g, 0.1 mol) was dissolved in 50 mL CH2Cl2 and cooled on ice. A solution of 20.7 g K2CO3 in 30 mL of water was added. A solution of 3,5-dimethylbenzoyl chloride (17 g, 0.1 mol) in 50 mL of CH2Cl2 was added drop-wise over a period of 1 hour, maintaining the temperature at 0-5° C. The mixture was stirred for 1 hour on an ice bath, and then at room temperature overnight. TLC indicated the reaction was complete. The aqueous layer was removed in a separatory funnel and the organic phase was washed with water and then brine, and then dried over Na2SO4. The solvent was removed on a rotary evaporator. The residue was slurried in hexane, filtered, and then air-dried. 2-[N′-Benzyloxycarbonyl-N-(3,5-dimethyl-benzoyl)-hydrazino]-2-methyl-propionic acid ethyl ester was obtained as a white solid (35 g), giving a single spot by TLC. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.4 (s, 1H), 7.3 (m, 3H), 7.15 (m, 2H), 7.1. (s, 2H), 7.0 (s, 1H), 5.2 (d, 1H), 5.0 (d, 1H), 4.2 (m, 2H), 2.25 (s, 6H), 1.78 (s, 3H), 1.64 (s, 3H), 1.28 (t, 3H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH2:28]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)=[CH:6][CH:5]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc(NCc2ccccc2)cc1

Procedure:
The title compound is prepared from N-(4-aminophenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-acetamide dihydrochloride (Example 181) and benzaldehyde according to the method described in Example 177. Melting Point: 84-106° C. (dec.) (diethylether-ethyl acetate)
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.Cl.[NH2:18][CH2:19][C:20](OCC)=[O:21]>N1C=CC=CC=1>[Cl:16][C:15]1[C:2]2[NH:1][C:20](=[O:21])[CH2:19][N:18]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)CN
Reactant: Nc1c(Cl)cccc1C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CN=C(c2ccccc2)c2cccc(Cl)c2N1
Yield: 65.3 %

Procedure:
A solution of 2-amino-3-chlorobenzophenone (0.730 g, 3.15 mmol) and ethyl glycinate hydrochloride salt (0.660 g, 4.72 mmol) in pyridine (15 mL) was refluxed using a Dean-Stark trap to remove water. After 30 h the reaction was cooled and concentrated. The residue was dissolve in methylene chloride and washed with saturated sodium bicarbonate. The crude product was purified by chromatography (silica gel, 0–30% ethyl acetate in hexane gradient elution) to give the title compound as a solid (0.557 g). 1H NMR (500 MHz, CDCl3) δ 7.83 (br s, 1H), 7.61 (dd, J=1, 8 Hz, 1H), 7.52 (m, 2H), 7.46 (tt, J=1,8 Hz, 1H), 7.39 (t, J=8 Hz, 2H), 7.26 (m, 1H), 7.11 (t, J=8 Hz, 1H), 4.36 (br s, 2H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=O)[O:26]C3C=CC=CC=3)=[CH:20][CH:19]=2)[N:7]=1)(=[O:4])=[O:3].C([N:36](CC)CC)C.NC1N=CC=CN=1>CN(C=O)C>[CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH2:36])=[O:26])=[CH:22][CH:23]=2)[N:7]=1)(=[O:4])=[O:3]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Agent: Nc1ncccn1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(N)=O)cc2)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Phenyl N-[4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]carbamate (110 mg) was dissolved in DMF (2 mL) and triethylamine (0.098 mL) added. 2-Aminopyrimidine (108 mg) was added and the reaction stirred at 40° C. for 2 hours. The crude mixture was purified by prep-HPLC (basic), however, only [4-[4-(Methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]urea was isolated from the mixture (8 mg).
Reaction SMILES: [CH3:1][Si:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:23][OH:24])[C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=1)([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:25](Br)[CH3:26].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O>[CH2:25]([O:24][N:23]=[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][Si:2]([CH3:10])([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)=[CH:14][CH:15]=1)[C:20](=[O:22])[CH3:21])[CH3:26]
Reactant: CC(=O)C(=NO)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCON=C(C(C)=O)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1

Procedure:
13.8 g of 1-(4-[{dimethyl-(4-fluorophenyl)-silyl}methoxy]phenyl)-propane-1,2-dione-1-oxime, 4 ml of ethyl bromide and 9 g of potassium carbonate are stirred in 150 ml of dimethylformamide for 2 hours at room temperature. 200 ml of diethyl ether are added to the reaction mixture, which is then washed with water and saturated sodium chloride solution; the organic phase is dried and the solvent is evaporated off to yield the title product in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[OH-].[NH4+:21]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH2:21])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reaction time: 16 h
Yield: 83.5 %

Procedure:
A solution of 2 g (0.0065 mole) of 3-[2-chloro-4-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1 ml (0.013 mole) of 57% ammonium hydroxide. After stirring for 16 h the reaction mixture was diluted with 100 ml of water and the solid which precipitated was collected by filtration (2.4 g). Recrystallization from benzene/ligroin yielded 1.6 g (83.5%) of white crystals, mp. 156°-159° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][C:9]1([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Cl)[N:21]=1>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[N:21]=2)[CH2:10][C:9]1([CH3:16])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC1(C)CC(O)CCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(Oc2cccc(Cl)n2)CCN1Cc1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
Combine 1-benzyl-2,2-dimethyl-piperidin-4-ol (preparation 9) 1.08 g, 4.92 mmol), N,N-dimethylformamide (20 mL) and 95% sodium hydride (0.12 g, 4.92 mmol) and stir. After 30 min., add 2,6-dichloropyridine (0.67 g, 4.52 mmol), stir and heat at 120° C. After 18 hr., cool to ambient temperature and partition between water (100 mL) and ethyl acetate (100 mL). Separate the organic layer and wash the aqueous layer with ethyl acetate (2×100 mL). Combine the organic layers, wash with water (5×100 mL), wash with aqueous NaCl solution, dry over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 9:1 hexane:ethyl acetate to obtain of the title compound (0.57 g, 38%). Mass spectrum (electrospray): m/z=331.1 (M+1); 1H NMR (CDCl3): 7.5 (dd, 1H), 7.3 (m, 5H), 6.8 (d, 1H), 6.6 (d, 1H), 5.2 (m, 1H), 3.9 (d, 1H), 3.2 (d, 1H), 2.65 (m, 1H), 2.4 (m, 1H), 2.0 (m, 2H), 1.7 (m, 1H), 1.6 (m, 1H), 1.3 (s, 3H), 1.2 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][C:17]([CH3:25])([CH3:24])[NH:18][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].II.CC([O-])=O.[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][C:17]([CH3:25])([CH3:24])[N:18]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)Cc2c(cccc2N2CCN(C(=O)OC(C)(C)C)CC2)CN1
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Solvent: CCO
Product: CC1(C)Cc2c(cccc2N2CCN(C(=O)OC(C)(C)C)CC2)C=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
To a solution of 78C (170 mg, 0.49 mmol) in EtOH (2 mL) was added iodine (281 mg, 2.21 mmol) and NaOAc (60 mg, 0.73 mmol) and the reaction mixture was heated to 80° C. After 3 h, the solvent was evaporated and the residue was quenched with 10% sodium thiosulphate solution and extracted twice with EtOAc and the combined organics were washed with H2O. The organic layer was extracted with 2 mL of 0.5 N HCl solution and the combined aqueous layers were basified with ammonia solution and extracted with EtOAc twice. The combined organics were washed with H2O, brine and dried over Na2SO4, filtered and concentrated to give 78D (90 mg, 53.2%). MS (ESI) m/z: 344.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N: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)=[C:6]3[CH:12]=[N:11][NH:10][C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[K+].[I:28]I>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([N: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)=[C:6]3[C:12]([I:28])=[N:11][NH:10][C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C3CC3)cnc3[nH]ncc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C3CC3)cnc3[nH]nc(I)c23)CC1
Temperature: 60 °C
Yield: 102.1 %

Procedure:
A mixture of tert-butyl 4-(5-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.44 g, 4.19 mmol) and powdered potassium hydroxide (0.692 g, 10.5 mmol) in DMF (20 mL) was treated with iodine (2.13 g, 8.39 mmol), and the mixture was heated at 60° C. for 5 hours. The mixture was diluted with EtOAc (200 mL) and successively washed with saturated Na2S2O3 solution (2×20 mL) and water (2×50 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo to provide the crude tert-butyl 4-(5-cyclopropyl-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (2.01 g, 4.28 mmol, 100%) yield) as a solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Cl)=[N:15][C:14]([Cl:19])=[CH:13][CH:12]=2)=[O:7])(=[O:3])[CH3:2].[CH3:20][N:21]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1)[CH3:22]>>[C:1]([O:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([CH2:23][N:21]([CH3:22])[CH3:20])[CH2:25][CH2:26]1)=[N:15][C:14]([Cl:19])=[CH:13][CH:12]=2)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Product: CC(=O)OCC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure I, 2-(4,6-dichloro-1,5-naphthyridin-3-yl)-2-oxoethyl acetate (101 mg, 0.33 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexan amine (67 mg, 0.43 mmol) to afford the desired product (90 mg, 65%) as an off-white solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:9]=2[N:10]=1)[CH2:2][CH3:3].CCN(C(C)C)C(C)C.Cl.[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][CH:28]([OH:34])[CH2:27]2.O>C(O)CCC>[CH3:14][N:11]1[C:9]2[N:10]=[C:5]([NH:4][CH2:1][CH2:2][CH3:3])[N:6]=[C:7]([N:33]3[CH:26]4[CH2:32][CH2:31][CH:30]3[CH2:29][CH:28]([OH:34])[CH2:27]4)[C:8]=2[CH:13]=[CH:12]1
Reactant: CCCNc1nc(Cl)c2ccn(C)c2n1
Reactant: OC1CC2CCC(C1)N2
Agent: Cl
Solvent: CCCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1nc(N2C3CCC2CC(O)C3)c2ccn(C)c2n1
Temperature: 125 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
To a solution of 2-(n-propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (CXXIV) (1.0 g, 4.5 mmol) in n-butanol (10 mL) were added DIPEA (1.0 g, 7.8 mmol) and 8-aza-bicyclo[3.2.1]octan-3-ol hydrochloride (1.1 g, 6.7 mmol). The mixture was stirred at 125° C. for 16 h. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution, and dried over anhydrous Na2SO4. The solvents were removed in vacuo and the resultant residue was purified by flash column chromatography (pet ether/EtOAc=6/1) to yield 8-(7-methyl-2-(propylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (CLIV) (800 mg, 57% yield) as a yellow solid. LCMS (ESI) m/z=316 (M+H)+.
Reaction SMILES: [I-:1].[CH3:2][C:3]1([CH3:48])[O:8][C:7]2[CH:9]=[CH:10][C:11]([C@@H:13]([OH:47])[CH2:14][N:15](C(=O)OCC3C=CC=CC=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:28]=[C:29]([N+:33]([CH3:36])([CH3:35])[CH3:34])[CH:30]=[CH:31][CH:32]=3)=[CH:12][C:6]=2[CH2:5][O:4]1>C(O)C>[I-:1].[CH3:2][C:3]1([CH3:48])[O:8][C:7]2[CH:9]=[CH:10][C:11]([C@@H:13]([OH:47])[CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:28]=[C:29]([N+:33]([CH3:36])([CH3:35])[CH3:34])[CH:30]=[CH:31][CH:32]=3)=[CH:12][C:6]=2[CH2:5][O:4]1
Reactant: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCOCc3cccc([N+](C)(C)C)c3)C(=O)OCc3ccccc3)ccc2O1
Agent: [I-]
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc([N+](C)(C)C)c3)ccc2O1
Yield: 4.3 %

Procedure:
A solution of 3-{12-[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-13-oxo-15-phenyl-2,5,14-trioxa-12-azapentadec-1-yl}-N,N,N-trimethylbenzenaminium iodide (195 mg) in ethanol (15 ml) was hydrogenated over 10% paladium on carbon (194 mg) for 5 h. The mixture was filtered through celite and the solvent evaporated in vacuo. The residue was purified by mass directed autopreparative HPLC to give the title compound (7 mg). LCMS RT=2.13 min.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[S:44][C:43]([CH3:45])=[N:42][C:41]=1[CH3:46]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[S:44][C:43]([CH3:45])=[N:42][C:41]=2[CH3:46])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: Cc1nc(C)c(CCl)s1
Agent: Cl
Product: Cc1nc(C)c(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)s1
Yield: 100.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 5-(chloromethyl)-2,4-dimethylthiazole (0.49 g) as starting materials, 5-benzyloxy-N-({1-[(2,4-dimethylthiazol-5-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.92 g) was obtained.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)([O-])C.[K+].[C:25]1([C:31]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:32]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[CH:48]=[CH:47][C:46]([CH2:49]Br)=[CH:45][CH:44]=3)[N:34]=[N:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C.O>CN(C)C(=O)C>[C:57]1([C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:32]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[CH:48]=[CH:47][C:46]([CH2:49][N:7]([C:8]4[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=4)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:45][CH:44]=3)[N:34]=[N:33]2)[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: CCCCC(=O)Nc1cccc(C(=O)OCC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1)c1cccc(C(=O)OCC)c1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a solution of ethyl 3-aminobenzoate (5.02 g) in N,N-dimethylacetamide (DMA, 50 ml) was added dropwise pentanoyl chloride (4.0 ml), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was stirred for 1 hr. The mixture was partitioned and extracted by adding ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give ethyl 3-(N-pentanoyl)aminobenzoate (7.55 g). To a solution of the obtained amide compound in DMA (100 ml) was added potassium tert-butoxide (4.09 g), and the mixture was stirred for 30 min. To the reaction mixture was added [4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methylbromide (18.6 g), and the mixture was stirred at 50° C. for 3 hrs. The reaction mixture was added to ethyl acetate-water and, after partitioning and extraction, the extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with hexane-ethyl acetate:3-2 v/v) to give the object compound (20.6 g, yield 93.6%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[N+:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N+:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]2[O:21][C:1]([OH:2])=[N:23][N:22]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2nnc(O)o2)cc1
Reaction time: 3.5 h

Procedure:
1,1′-Carbonyldiimidazole (3.86 g; 23.81 mmol; 1 eq.) is added to a 0° C. solution of 4-nitrobenzohydrazide (4.31 g; 23.81 mmol; 1 eq.) and triethylamine (4.95 ml; 35.71 mmol; 1.50 eq.) in DMF (150 ml). The reaction mixture is stirred between 0° C. and rt for 3.5 hours. Solvents are removed under vacuo affording an orange oil which is solubilized in DCM and washed with HCl 0.1 M. The organic phase is concentrated. The resulting precipitate is recovered by filtration, affording 5-(4-nitrophenyl)-1,3,4-oxadiazol-2-ol as a white solid (4.50 g; 91%).
Reaction SMILES: [CH3:1]S(C)(=O)=C.[CH3:6][O:7][CH:8]([CH2:21][CH3:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH:19]2[CH:16]([CH2:17][C:18]2=[O:20])[CH2:15][CH2:14]1>CS(C)=O>[CH3:6][O:7][CH:8]([CH2:21][CH3:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH:19]2[CH:16]([CH2:17][C:18]32[CH2:1][O:20]3)[CH2:15][CH2:14]1
Reactant: CCC(CCCCC1CCC2CC(=O)C12)OC
Reactant: C=S(C)(C)=O
Solvent: CS(C)=O
Product: CCC(CCCCC1CCC2CC3(CO3)C12)OC
Temperature: 40 °C

Procedure:
A 250 ml, 3-necked round bottomed flask is equipped with a magnetic stirrer. The reaction is conducted under a positive nitrogen pressure, maintained with an oil filled bubbler. The reaction vessel is charged with dimethyloxosulfonium methylide (36 ml of 0.932M solution, 0.034 moles) in dimethyl sulfoxide. 4-(5-Methoxyheptyl)bicyclo[3.2.0]heptan-6-one (7.7 g, 0.032 moles) is added neat to the stirring solution by a syringe. The reaction vessel is heated in a 40° C. water bath for 60 minutes and then a sample is removed and analyzed by infra-red spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][S:31]([NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][N:26]([CH:27]([CH3:29])[CH3:28])[C:39](=[O:40])[C:38]3[CH:42]=[CH:43][C:35]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:36][CH:37]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CNC(C)C)cc1OC
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CN(C(=O)c2ccc(NS(C)(=O)=O)cc2)C(C)C)cc1OC

Procedure:
In a manner similar to Preparation 3, react 4-(3-chlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-N-(1-methylethyl)-2-piperazinemethanamine with 4-[(methylsulfonyl)amino]benzoyl chloride to obtain the title compound.