Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1(O)[CH2:20][CH2:19][C:11]2(OCC(C)(C)C[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:8]1[CH2:20][CH2:19][C:11](=[O:12])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COC2(CCC(O)(Cc3ccccc3)CC2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.1 %

Procedure:
To a solution in toluene (44.0 mL) of the compound (1.28 g) obtained in step (1) above, p-toluenesulfonic acid monohydrate (84.0 mg) was added and thereafter the mixture was refluxed for 3 hours with a Dean-Stark apparatus. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50). A suspension of the resulting purified product (935 mg) and 20% palladium hydroxide/carbon (93.5 mg) in methanol (11.3 mL) was stirred at room temperature for 5 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure. To a solution of the resulting residue (938 mg) in tetrahydrofuran (34.3 mL), 1 mol/L hydrochloric acid (9.30 mL) was added at 0° C. and the mixture was stirred at room temperature for 14.5 hours. After concentrating the stirred mixture under reduced pressure, three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine. After passage through a phase separator, the washed organic layers were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-50:50) to give the titled compound as a colorless oil (225 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=2)[C:15]([OH:17])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[NH:22][NH2:23]>>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=2)[C:15]([NH:23][NH:22][C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[O:17])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: O=C(CCc1ccccc1)Nc1cc(C(=O)O)ccn1
Product: O=C(CCc1ccccc1)Nc1cc(C(=O)NNC(=O)OCc2ccccc2)ccn1
Yield: 53 %

Procedure:
In the same manner as in Reference Example 1 and using 2-[(3-phenylpropanoyl)amino]isonicotinic acid instead of benzothiazole-6-carboxylic acid and benzyl carbazate instead of tert-butyl carbazate, the title compound (yield 53%) was obtained as colorless amorphous.
Reaction SMILES: Cl[CH:2]1[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]3=2)=[CH:5][CH:4]=[CH:3]1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[CH:16]1[C:10]2[CH:9]=[CH:8][C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH:12]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:11]=2[CH:13]=[CH:14][CH:15]=1
Reactant: ClC1C=CC=C2C=CC=c3ccccc3=C21
Reactant: C1CNCCN1
Solvent: ClC(Cl)Cl
Product: C1=Cc2ccccc2C(N2CCNCC2)c2ccccc21
Reaction time: 48 h
Yield: 100 %

Procedure:
The chlorodibenzocycloheptene intermediate thus prepared was dissolved in 50 milliliters of chloroform, the solution added dropwise to a solution of 41.3 grams (480 millimoles) of piperazine in 150 milliliters of chloroform and the resulting mixture stirred for two days. At the end of this time, the mixture was washed successively with 20 percent sodium hydroxide, water, and brine, then dried over potassium carbonate. The drying agent was filtered off and the solvent vaporized to obtain 6.70 grams (100 percent yield) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperazine product as residue. A portion of the product was recrystallized from acetonitrile to obtain a purified product, m.p. 139°-141° C. Elemental analyses of the product after drying for 24 hours at 65° C. at 20 millimeters of mercury pressure were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[CH:3]=1.O.[NH2:11][NH2:12]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:11][NH2:12])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1cc(Cl)cc(Cl)c1
Temperature: 180 °C
Yield: 60 %

Procedure:
A mixture of 1,3,5-trichlorobenzene (2.53 g), hydrazine hydrate (3.48 g, 5 molar equivalents) and pyridine (12 ml) was heated in an autoclave (purged with argon) for 6 hours at 180° C. The mixture was cooled, the excess hydrazine decanted and the organic phase evaporated in vacuo to give the title compound in 60% yield. It was shown that 65% of the starting material had been consumed, thus indicating that the reaction had occurred with high selectivity.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)O1.C([O-])([O-])=O.[K+].[K+].C1COCC1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC1(C)OB(c2cnc3ccccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cncc(-c2cnc3ccccc3c2)c1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
1.11 g (4.7 mmol) of 3,5-dibromo-pyridin, 1.0 g (3.92 mmol) of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline, 0.45 g of tetrakis(triphenylphosphine)palladium(0), 7.84 ml of 2 M K2CO3 and 1.26 g of tetrabutylammoniumbromide were added to a 100 ml round-bottom flask in an argon atmosphere, and 30 ml of THF and 15 ml of toluene were added thereto. Then, the mixture was refluxed at 100° C. for 16 hours. When the mixture solution turned dark brown, water was added thereto and the mixture was subject to extraction using chloroform. Then, an organic layer extracted therefrom was dried using anhydrous magnesium sulfate and filtered. A solvent was removed and the resultant was separated using a silica gel column chromatography to obtain 1.1 g of white solid 3-(5-bromo-pyridin-3-yl)-quinoline which was identified by an atmospheric pressure chemical ionization (APCI) using LCMS (SHIMADZU, LCMS-IT-TOF). As a result, a main peak was observed at [M+H]+=285.
Reaction SMILES: Cl[S:2]([C:5]1[C:13]2[C:9](=[N:10][O:11][N:12]=2)[C:8]([F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1.Cl>C1C=CC=CC=1.C(Cl)(Cl)Cl>[F:14][C:8]1[C:9]2=[N:10][O:11][N:12]=[C:13]2[C:5]([S:2]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(F)c2nonc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccccc1)c1ccc(F)c2nonc12

Procedure:
1.0 g of the compound obtained in Example 1 and 1 g of phenol were dissolved in 5 ml of benzene. Next, after dripping in a chilled mixed solution of 5 ml of benzene and 1 ml of pyridine, the solution was allowed to react for 4 hours at room temperature. After dripping in 50 ml of chilled 10% hydrochloric acid, the solution was extracted with benzene, water washed, and then dried with magnesium sulfate and reduced pressure concentrated. The remaining solid was subjected to chloroform mobile phase; silica gel column chromatography (2 cm ×60 cm) to prepare 2 ml fractions. These were then subjected to thin layer chromatography (silica gel, chloroform) and the fractions with an Rf range in the vicinity of 0.73 were collected. After reduced pressure condensation, the substance was recrystallized using n-hexane. The resulting 0.4 g of white needle shaped crystals had a melting point of between 120° to 121° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:35][CH:36]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:37][NH:38][C:39]([CH:41]1[CH2:46][CH:45]([CH3:47])[CH2:44][CH2:43][CH:42]1[CH:48]([CH3:50])[CH3:49])=[O:40]>O.C(OCC)(=O)C.C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:11](=[O:13])[NH:35][CH:36]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:37][NH:38][C:39]([CH:41]1[CH2:46][CH:45]([CH3:47])[CH2:44][CH2:43][CH:42]1[CH:48]([CH3:50])[CH3:49])=[O:40])[CH3:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC1CCC(C(C)C)C(C(=O)NCC(N)c2ccccc2)C1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CCC(C(C)C)C(C(=O)NCC(NC(=O)C(C)NC(=O)OC(C)(C)C)c2ccccc2)C1
Reaction time: 3 h
Yield: 25.5 %

Procedure:
A 15 mL reaction vessel equipped with a stir bar was charged with THF (15 mL), Boc-(R)-alanine (52 mg, 0.273 mmoles), HOBt (37.87 mg, 0.273 mmoles), EDCI (53 mg, 0.273 mmoles) and TEA (37 μl, 0.273 mmoles). The reaction mixture was stirred for 15 min. whereupon 2-isopropyl-5-methyl-cyclohexanecarboxylic acid (2-amino-2-phenyl-ethyl)-amide (75 mg, 0.248 mmol) was added and stirred for an additional 3 h. Ethyl acetate (10 mL) and H2O (10 mL) were added to the reaction mixture. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with 1N HCl (2×10 mL), H2O (1×10 mL), sat NaHCO3 (3×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20% ethyl acetate/hexane for elution) provided the title compounds as colorless solid (30 mg).
Reaction SMILES: CS(Cl)(=O)=O.C1CCNCC1.[CH2:12]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]([F:50])([F:49])[C:29]1[CH:30]=[C:31]([CH:46]=[CH:47][CH:48]=1)[C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:37])=[O:33].C1(N=C=O)C=CC=CC=1>C(Cl)(Cl)Cl.CC#N>[CH2:12]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:43]2[CH2:44][CH2:45][CH:40]([CH2:39][NH:38][C:36](=[O:37])[CH2:35][NH:34][C:32](=[O:33])[C:31]3[CH:46]=[CH:47][CH:48]=[C:29]([C:28]([F:50])([F:49])[F:27])[CH:30]=3)[CH2:41][CH2:42]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccc(Cc2ccccc2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of methanesulfonyl chloride (4.2 mg, 0.037 mmol) in CHCl3 (1.0 mL) and (piperidinomethyl)polystyrene (54 mg, 2.7 mmol base/g resin) were added to a solution of 4-(benzyl)benzyl alcohol (8.7 mg, 0.044 mmol) in CHCl3 (1.0 mL). The reaction mixture was stirred at 25° C. for 15 h. A solution of 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (15.1 mg, 0.044 mmol) in CH3CN (1.0 mL) and KI (2 mg) were added to the reaction mixture and the mixture was stirred at 65° C. for 5 h. Phenyl isocyanate (5.2 mg) was added to the cooled reaction mixture and the mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH3OH (20 mL). Product was eluted off using 2 N NH3 in CH3OH (6 mL) and concentrated to afford 1-(4-benzylbenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 926) as a pale yellow oil (5.6 mg, 29%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 524.1 (M++H, C30H32F3N3O2).
Reaction SMILES: [CH2:1]([C:3]1[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:22])[CH:4]=1)[CH3:2].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([C:3]1[C:12]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=3)=[CH:29][CH:30]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:22])[CH:4]=1)[CH3:2]
Reactant: Cn1ccc(-c2ccc(CBr)cc2)n1
Reactant: CCc1cc(O)c(C(=O)OC)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(O)c(C(=O)OC)cc1Cc1ccc(-c2ccn(C)n2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of methyl 4-ethyl-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.41 g), 3-(4-(bromomethyl)phenyl)-1-methyl-1H-pyrazole (0.44 g), sodium carbonate (0.28 g), tetrakis(triphenylphosphine)palladium(0) (0.15 g), DME (15.0 mL) and water (5.0 mL) was stirred overnight at 90° C. under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.26 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:11]([CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCCOc1ccccc1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCOc2ccccc2)CC1

Procedure:
1-(2-Phenoxyethyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-2-phenoxyethane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9][C:8]1=[O:26].FC(F)(F)C(O)=O>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9][C:8](=[O:26])[N:7]2[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=1
Reactant: CCOC(=O)/C=C/c1cc(=O)n(CC2OCCO2)c2cc(OC)ccc12
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C/c1cc(=O)n(CC=O)c2cc(OC)ccc12
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To 0.16 g of ethyl (2E)-3-(1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate, 2 mL of 90% aqueous trifluoroacetic acid solution was added and stirred for 2 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluent; chloroform) to give 84 mg of ethyl (2E)-3-(7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinolin-4-yl)acrylate as a yellow oil. (2) To 3 mL of a dichloromethane solution containing 84 mg of ethyl (2E)-3-(7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinolin-4-yl)acrylate, 98 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 14 μL of acetic acid were added and stirred for 1 hour. To the reaction mixture, 81 mg of sodium triacetoxyborohydride was added and stirred for 2 hours. Water, ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=100:1] to give 0.11 g of ethyl (2E)-3-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:17]([NH:29][CH:30]3[CH2:35][CH2:34][N:33](CC4C=CC=CC=4)[CH2:32][CH2:31]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].C(Cl)Cl>CO.O.[Pd]>[C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:17]([NH:29][CH:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCN(Cc4ccccc4)CC3)c3ncn(C4CCCC4)c3n2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCNCC3)c3ncn(C4CCCC4)c3n2)CC1

Procedure:
Add to a solution of {4-[6-(1-benzyl-piperidin-4-ylamino)-9-cyclopentyl-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (8a, 40.2 g, 68 mmol) in 400 mL of methanol, a suspension of Pd black (2 g) in a small amount of water. Then add a solution of ammonium formate (13.3 g, 215 mmol) in 100 mL of water, and heat at a gentle reflux overnight. TLC shows the presence of starting material (TLC, silica plates, 4:1 DCM:methanol; Rf: starting material 0.75, product 0.15). Add an additional 5 g of ammonium formate and reflux 24 hours. Remove the catalyst by filtration through Celite® and concentrate the filtrate. Dissolve the residue in DCM and extract with water. Remove the white precipitate by filtration through a pad of Celite®, wash the filtrate with brine, dry over sodium sulfate and filter. Concentrate the filtrate and purify the residue on silica gel (500 g) using DCM:methanol (4:1) to give 33.4 g of trans-{4-[9-cyclopentyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9a) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][CH:7]=1.[OH-].[NH4+].[H][H]>C(O)C.[Pd]>[CH3:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:5]1[N:4]=[N:3][CH:2]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: Cc1ccccc1Cc1ccc(Cl)nn1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Cc1cccnn1
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
A solution of 3-chloro-6-(2-methylbenzyl)pyridazine (34 g.) in ethanol (370 ml.) containing aqueous ammonium hydroxide solution (s.g. 0.880; 38 ml.) was treated with hydrogen in the presence of palladium on charcoal (5% Pd) at ambient temperature and normal atmospheric pressure for 1.5 hours. After filtration, the filtrate was evaporated to dryness and the residue extracted with chloroform (3 × 100 ml.). The chloroform solution was washed with water, dried over magnesium sulphate and evaporated to dryness. The light brown solid thus obtained was triturated with n-hexane to give 3-(2-methylbenzyl)pyridazine (26 g.), m.p. 88°-89° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4](Br)[CH:3]=1.C([Mg]Cl)(C)C.[CH3:16][O:17]B(OC)OC.C(OO)(=O)C.C(=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:17][CH3:16])[C:5]([F:9])=[CH:6][C:7]=1[F:8]
Reactant: Fc1cc(F)c(Br)cc1Br
Reactant: COB(OC)OC
Agent: CC(=O)OO
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(Br)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
To a solution of 1,3 dibromo-4,6-difluorobenzene (10.0 g, 37 mmol) in THF (50 mL) at −20° C. was added isopropyl magnesium chloride (2.0M in THF, 42 mmol) and the resulting solution warm to 0° C. and stirred for 30 minutes. Trimethylborate (4.7 g, 45 mmol) was added and the mixture stirred at ambient temperature for 1 hour. The solution was recooled to −20° C. and peracetic acid (32%, 50 mmol) was added and the solution was stirred for 30 minutes at ambient temperature. The solution was then quenched with sodium bisulfite (5% solution, 75 mL) and then acidified with 6 N hydrochloric acid and extracted with ethyl ether (2×75 mL). Combined extracts were dried (sodium sulfate) and concentrated. The crude phenol was dissolved in acetonitrile (40 mL) and potassium carbonate (10 g, 74 mmol) and iodomethane (5.7 g, 40 mmol) were added and stirred at ambient temperature for 20 hours. The solution was concentrated and the residue taken into water (50 mL) and extracted with ethyl ether (2×75 mL) and the combined extracts were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by chromatography (hexanes) to give 1-bromo-2,4-difluoro-5-methoxybenzene (2.0 g, 8.6 mmol): LC/MS (m/z=223).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(Cl)[Cl:16]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([Cl:16])=[O:14]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)Cc1ccc2ccccc2c1
Product: O=C(Cl)Cc1ccc2ccccc2c1

Procedure:
2-Naphthylacetyl chloride is prepared according to the method described in Example 8 using 2-naphthylacetic acid (2.47 g, 13.3 mmol) to give a yellow solid which is dissolved in chloroform (15 mL). This solution is added to a solution of (±)-trans-[2-(4-methyl-1-piperazinyl)]cyclohexanol (2.5 g, 12.6 mmol) in chloroform (10 mL), and the mixture is refluxed for 11 hours under nitrogen. The solvent is removed in vacuo, and the residue is partitioned between 1M hydrochloric acid (100 mL) and ether (60 mL). The ether layer is separated and the aqueous is washed with more ether (2×30 mL), and then basified by the addition of 50% sodium hydroxide solution. This is then extracted with ether (4×30 mL), and the combined ether extracts are washed repeatedly with water to remove any unreacted aminoalcohol. The ether containing the product is then dried over sodium sulfate, and the solvent is removed to leave the crude free ester. The free ester is dissolved in ether/dichloromethane (35 mL, 4:3) and converted to the dihydrochloride salt by treatment with an excess of HCl in the same solvent. The resulting solid is washed with ether and recrystallised from hot methanol to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:19]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:18]=1.[NH4+].[Cl-]>CO.C1COCC1.O.[Fe]>[NH2:19][C:3]1[C:2]([Br:1])=[CH:18][C:6]2[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH:10]3[CH2:12][CH2:11]3)[O:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1c(C2CC2)oc2cc([N+](=O)[O-])c(Br)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOC(=O)c1c(C2CC2)oc2cc(N)c(Br)cc12
Yield: 86.4 %

Procedure:
A mixture of crude compound ethyl 5-bromo-2-cyclopropyl-6-nitrobenzofuran-3-carboxylate (8.5 g, 25 mmol), iron filings (4.1 g, 75 mmol) and NH4Cl (8 g, 150 mmol) in MeOH-THF—H2O (2:2:1, 100 mL) were stirred at reflux for 3 hours. After being filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish the pure product of ethyl 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylate (7.00 g, yield: 91%). 1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 6.75 (s, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.11 (s, 2H), 2.94˜2.99 (m, 1H), 1.43 (t, J=7.2 Hz, 3H), 1.19˜1.21 (m, 2H), 1.12˜1.15 (m, 2H). MS (M+H)+: 324/326.