Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C.Cl>O>[C:4]([C:3]1[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:2]=1[N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCNC
Reactant: CCOc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCN(C)c1cc(OCC)c([N+](=O)[O-])cc1C(=O)O

Procedure:
A mixture of 24.5g 2-chloro-4-ethoxy-5-nitrobenzoic acid, 22.7g methyl tetradecylamine (distilled) and 35.0 ml triethylamine were heated on a steam bath for 5 hours and then poured into two liters of water and made acid with HCl. The reaction product was filtered and washed with water, and recrystallized twice from methanol/water.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:3]1=2.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:20][S:21]([O:19][CH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2COc2ccc(CCO)cc21
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A stirred chilled (-5° C.) solution of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol (5.08 g, 0.02 mol) and anhydrous pyridine (28 ml) was treated over 60 seconds with methanesulfonyl chloride (2.74 g, 0.024 mol). A mild exotherm was noted and a precipitate separated with continued cooling and stirring for 15 minutes after addition of the methanesulfonyl chloride was completed. Additional methanesulfonyl chloride (1.37 g, 0.012 mol) was added over 30 seconds and after stirring for 15 minutes the cooling bath was removed. After stirring 2 hours at ambient temperature, the mixture was decanted into 400 ml of ice cold water. The aqueous phase was decanted and the residual oil was stirred with water (300 ml). The water was decanted and the residual semisolid was triturated with ether. The resultant solid was collected, washed with ether and dried in vacuo to afford 4.92 g of crude material. Recrystallization from acetonitrile (15 ml) afforded 2.60 g (39.1 %) of crystals, m.p. 108°-110° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[OH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>CO>[CH2:16]([O:15][C:9]1[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=1[Br:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: Oc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C

Procedure:
To a mixture of MeOH (50 mL) and K2CO3 (49.36 g, 357 mmole) at r.t was dripped commercially available 2-bromobenzene-1,4-diol (15 g, 79 mmole) in MeOH (25 mL), followed by the syringe addition of benzyl bromide (14.93 g, 10.38 mL). The resulting mixture was refluxed for 8 hours. The reaction was cooled to RT and poured into saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate (2×150). The combined organic phases were washed with aqueous NaHCO3 solution (2×150 mL), aqueous 1N HCl solution (2×150 mL), and brine (2×150 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was subjected to flash chromatography (Silica, 10% Ethyl acetate/Hexane). ESLRMS m/z 280.9 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCN(S(F)(F)[F:18])CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:18])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc(Br)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(4-bromophenyl)propan-2-ol (8.3 g, 38.59 mmol) in 100 mL of CH2Cl2 was added DAST (6.1 mL, 46.31 mmol) at −78° C. The reaction was stirred to rt overnight, and quenched with 100 mL of water at 0° C. The product was extracted with EtOAc, and the extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous MgSO4, and concentrated to give 1-bromo-4-(1-fluoro-1-methylethyl)benzene, which was used without further purification.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:26](=[O:27])[N:12]2[C:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:14]([CH3:18])[CH2:15][S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl.[W]>[C:1]([NH:9][CH:10]1[C:26](=[O:27])[N:12]2[C:13]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[C:14]([CH3:18])[CH:15]([Br:35])[S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1Br

Procedure:
11.7 g (30 mmoles) of t-butyl 7-benzamido-3-methyl-3-cephem-4-carboxylate 1-oxide were dissolved in 250 ml of methylene chloride and the solution was kept under nitrogen and cooled in ice while 5.3 ml (45 mmoles) of triethylamine and 6.4 g (36 mmoles) of N-bromosuccinimide were subsequently added. The resulting solution was irradiated with a 150 W tungsten lamp for 20 minutes and the dark-brown solution was washed with dilute hydrochloric acid (pH 1) and with water. After drying over magnesium sulfate, the solution was concentrated by evaporation to approximately 100 ml. To the solution of t-butyl 7-benzamido-2-bromo-3-methyl-3-cephem-4-carboxylate 1-oxide thus obtained were added 100 ml of acetic acid and the resulting solution was held under nitrogen and was cooled in ice and irradiated with a 150 W tungsten lamp. 7.15 g (40 mmoles) of N-bromosuccinimide were added thereto followed after 4 hours by another 1.78 g (10 mmoles) of the same compound. Then, the solution was irradiated with a 150 W tungsten lamp for another 3 hours. Part of the solution thus obtained (52%), which contained t-butyl 7-benzamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylate 1-oxide, was washed 4 times with 100 ml of water. After drying over magnesium sulfate, the solution was concentrated by evaporation to approximately 25 ml. Then, 5 ml of methanol were added thereto and the solution was treated with activated charcoal. After addition of 1,2-dichloroethane, the solution was evaporated to dryness and the residue was dissolved in diethyl ether. The product was precipitated with n-heptane to obtain 6.8 g (79.4%) of t-butyl 7-benzamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylate 1-oxide.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[CH2:13][CH2:12][N:11]3[C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[C:23]([S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])[CH:22]=4)(=[O:20])=[O:19])=[N:15][N:16]=[C:10]3[CH2:9]2)[CH2:3][CH2:2]1.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[C:60]([CH:65]=O)=[CH:61][CH:62]=[CH:63][CH:64]=2)=[CH:55][CH:54]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[CH2:65][N:1]2[CH2:7][CH2:6][CH2:5][CH:4]([N:8]3[CH2:13][CH2:12][N:11]4[C:14]([NH:17][S:18]([C:21]5[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH2:29][CH2:30][N:31]6[CH2:32][CH2:33][O:34][CH2:35][CH2:36]6)=[C:23]([S:45]([C:48]([F:49])([F:50])[F:51])(=[O:47])=[O:46])[CH:22]=5)(=[O:19])=[O:20])=[N:15][N:16]=[C:10]4[CH2:9]3)[CH2:3][CH2:2]2)=[CH:57][CH:58]=1
Reactant: O=S(=O)(Nc1nnc2n1CCN(C1CCCNCC1)C2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nnc2n1CCN(C1CCCN(Cc3ccccc3-c3ccc(Cl)cc3)CC1)C2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
To a vial containing N-(7-azepan-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonamide (62 mg, 0.080 mmol) and 4′-chloro-biphenyl-2-carbaldehyde (52.1 mg, 0.241 mmol) was added methanol (2.5 mL) under nitrogen. The reaction was stirred in an ice bath for 10 minutes and then acetic acid (5.51 μL, 0.096 mmol) was added. After stirring in the ice bath for an additional 15 minutes, sodium cyanoborohydride (40.3 mg, 0.642 mmol) was added. The reaction was then allowed to warm to ambient temperature and stir for 72 hours. The reaction mixture was concentrated, filtered and purified via flash chromatography on silica gel (10-50% methanol in CH2Cl2) to afford the title compound (50 mg, 64% yield).
Reaction SMILES: [P:1]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([O:3][CH2:4][CH2:5][NH2:6])=[O:2].CCN(CC)CC.[Cl:24][CH2:25][CH:26]1[C:34]2[C:33]3[CH:35]=[CH:36][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:38][C:32]=3[C:31]([N+:43]([O-:45])=[O:44])=[CH:30][C:29]=2[N:28](C(=O)C(F)(F)F)[CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.CO>[P:1]([O:3][CH2:4][CH2:5][NH:6][S:39]([C:37]1[CH:36]=[CH:35][C:33]2[C:34]3[CH:26]([CH2:25][Cl:24])[CH2:27][NH:28][C:29]=3[CH:30]=[C:31]([N+:43]([O-:45])=[O:44])[C:32]=2[CH:38]=1)(=[O:41])=[O:40])([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:2]
Reactant: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Reactant: CC(C)(C)OP(=O)(OCCN)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OP(=O)(OCCNS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl)OC(C)(C)C
Yield: 90.6 %

Procedure:
A solution of amine 226 (203 mg, 0.80 mmol) and Et3N (0.11 mL, 0.80 mmol) in THF (2 mL) was added to solution of 116 (306 mg, 0.67 mmol) in THF (8 mL) at 0° C. After 5 min the cooling bath was removed and after 10 min Cs2CO3 (0.44 g, 1.3 mmol) and MeOH (4 mL) were added. After a further 25 min the mixture was diluted with water and extracted with CH2C2 (×3). The combined extracts were dried and evaporated and the residue was purified by chromatography, eluting with EtOAc/petroleum ether (1:1 then 2:1) to give di(tert-butyl) 2-({[1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}amino)ethyl phosphate (227) (351 mg, 91%) as a red-orange foam: 1H NMR [(CD3)2SO] δ 8.59 (d, J=1.6 Hz, 1H), 8.04 (d, J=8.9 Hz, 1H), 7.95 (br s, 1H, 7.79 (dd, J=8.9, 1.8 Hz, 1H, 7.77 (s, 1H), 6.74 (s, 1H), 4.28-4.20 (m, 1H), 3.95-3.86 (m, 2H), 3.83-3.72 (m, 4H), 2.99 (t, J=6.0 Hz, 2H), 1.35 (s, 18H). HMS (FAB) calcd. for C23H3335ClN3O8PS (M+) m/z 577.1415, found 577.1412.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.CS(O[CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[O:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[CH2:14][N:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1
Reactant: ON=C1CCNCC1
Reactant: CS(=O)(=O)OCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: ON=C1CCN(CC2CCCO2)CC1
Reaction time: 48 h
Yield: 535.9 %

Procedure:
A mixture of piperid-4-one oxime (46 g; 0.04 moles), 2-tetrahydrofurylmethyl methanesulphonate (79.3 g; 0.44 moles) and anhydrous potassium carbonate (56.5 g; 0.40 moles) in methyl isobutyl ketone (625 ml), was boiled under reflux with stirring for 48 hours. After cooling, the reaction mixture was washed with brine, dried (Na2SO4), and the solvent removed in vacuo. The residue was crystallised from diisopropyl ether to give 1-(2-tetrahydrofurylmethyl)-piperid-4-one oxime (42.5 g), m.p. 104°-106°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:36])[CH2:11][C:12]([C:14]1[C:15](O)=[C:16]([CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH:25]2[CH2:30][O:31]C(=O)C)[C:17]([O:22][CH3:23])=[CH:18][C:19]=1[O:20][CH3:21])=[O:13].C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:36][C:15]2[C:14]([C:12](=[O:13])[CH:11]=1)=[C:19]([O:20][CH3:21])[CH:18]=[C:17]([O:22][CH3:23])[C:16]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c(C2CCN(C)C2COC(C)=O)c(O)c1C(=O)CC(=O)c1ccc(C#N)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(C#N)cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Reaction time: 3 h

Procedure:
To a solution of n-BuLi (1.6 M solution in hexane, 17 mL, 27 mmol) in THF (50 mL), maintained at 0° C. under nitrogen atmosphere, hexamethyldisilazane (5.7 mL, 27 mmol) was added dropwise and stirred for 15 min. To this, a solution of the compound of example (36)(5.6 g, 10 mmol) in THF (50 mL) was added drop wise, maintaining the temperature at 0° C. After the addition, the reaction was allowed to warm to room temperature and stirred for 2.5 hrs. The reaction mixture was acidified with dilute HCl, and basified with 10% sodium bicarbonate to pH 8-9. The aqueous layer was extracted with chloroform (3×75 mL). The organic layer was washed with water (50 mL), brine (50 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and dried under vacuum to yield acetic acid 3-{3-[3-(2-chloro-4-cyano-phenyl)-3-oxo-propionyl]-2-hydroxy-4,6-dimethoxy-phenyl}-1-methyl-pyrrolidin-2-ylmethyl ester as oil (6.1 g). This ester was dissolved in conc. HCl (60 mL) and stirred for 3 hrs. to effect cyclisation. At the end of 3 hrs, the reaction mixture was basified with solid NaHCO3 to pH 8-9. The aqueous layer was extracted with chloroform (50×3 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and dried over vacuum. The residue was purified by column chromatography with 3% methanol in chloroform and 0.01% ammonia as eluent to yield the compound, (+)-trans-2-(2-chloro-4-cyano-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one, as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>C1COCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=2)=[CH:5]1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccccc12)c1cccnc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Tryptamine (640 mg, 4.0 mmol) was initially introduced into abs. THF (30 ml). TEA (596 μl, 4.3 mmol) and nicotinic acid chloride hydrochloride (770 mg, 4.3 mmol) was then added and the mixture was stirred at RT for 5 h. The mixture was concentrated to dryness i. vac. The residue was taken up in EA (20 ml) and the mixture was washed with saturated NaHCO3 solution (2×20 ml) and with NaCl solution (2×20 ml). The organic phase was dried over Na2SO4 and concentrated i. vac. Yield: 482 mg (45%)
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[F:16][C:17]([F:23])([F:22])[CH2:18][C:19](=O)[CH3:20].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Br:7][C:6]1[C:2]2[NH:1][C:19]([CH3:20])([CH2:18][C:17]([F:23])([F:22])[F:16])[NH:15][C:13](=[O:14])[C:3]=2[S:4][C:5]=1[C:8]1[CH:9]=[N:10][NH:11][CH:12]=1
Reactant: NC(=O)c1sc(-c2cn[nH]c2)c(Br)c1N
Reactant: CC(=O)CC(F)(F)F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CC1(CC(F)(F)F)NC(=O)c2sc(-c3cn[nH]c3)c(Br)c2N1
Yield: 23.6 %

Procedure:
A mixture of 3-amino-4-bromo-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide (90 mg, 0.313 mmol), 4,4,4-trifluorobutan-2-one (395 mg, 3.13 mmol), CSA (7.28 mg, 0.031 mmol), MgSO4 (37.7 mg, 0.313 mmol) and DMA (2 mL) was microwave-irradiated at 150° C. for 3 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc). The obtained solid was triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (29.2 mg, 24%) as a white solid:
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH2:12]O)([CH3:3])[CH3:2].[C:14](OCC)(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].N1CCCCC1>C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>[CH:1]([N:4]1[C:5]2[C:6](=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[CH:12]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]1=[O:21])([CH3:2])[CH3:3]
Reactant: Cc1cccc(NC(C)C)c1CO
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)c1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2c(C)cccc2n(C(C)C)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.5 %

Procedure:
A mixture of 2-(isopropylamino)-6-methylbenzaldehyde (22.4 g, 127 mmol, step 2 in preparation 2), diethyl malonate (22.3 g, 139 mmol), piperidine (1.29 g, 15.2 mmol), and benzoic acid (572 mg, 4.7 mmol) in benzene (500 mL) was refluxed with stirring for 4 days. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:15˜1:2) to give 19.6 g (57%) of the title compound as a yellow solid.
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:7]=[C:8]([CH2:16][C:17]([OH:19])=[O:18])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)=O.[OH-].[Na+]>CO.Cl>[SH:5][C:6]1[CH:7]=[C:8]([CH2:16][C:17]([OH:19])=[O:18])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: CN(C)C(=O)Sc1cc(CC(=O)O)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cc(S)cc(C(F)(F)F)c1

Procedure:
The product from step (ii) (0.49 g) was dissolved in methanol (10 ml) and 2M NaOH (10 ml) and stirred at RT overnight. The mixture was diluted with 2M HCl, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to an solid (0.30 g)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:25]=[CH:24][C:14]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)[C:3]=12>C(O)(C(F)(F)F)=O.ClCCl>[NH2:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:28][CH2:27]3)[N:9]=2)=[CH:25][CH:24]=1
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(CNC(=O)OC(C)(C)C)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C2CCC(n3nc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 10.8 %

Procedure:
1H-pyrazolo[3,4-d]pyrimidin-4-amine (850 mg, 1.93 mmol), tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate (1.25 equiv., 812 mg, 2.41 mmol), tetrakis-(triphenylphosphine)palladium (135 mg) and sodium carbonate (2.5 equiv., 511 mg, 4.83 mmol) in degassed water (10 mL) and DME (30 mL) was heated and stirred at 85° C. for 16 h. The solvent was removed under reduced pressure to give a brown foam which was purified by column chromatography over silica gel using 10% methanol and 1% ammonium hydroxide in dichloromethane as the eluent. Trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzyl)carbamate was formed as an off white foam (800 mg, 80%). A solution of tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzyl)carbamate (800 mg) in TFA (4 mL) and dichloromethane (4 mL) was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the oily residue was basified with saturated aqueous sodium hydrogen carbonate solution and the aqueous layer washed with dichloromethane (3×20 mL). The aqueous layer was concentrated and DMF added (20 mL). The salts were removed by filtration and the DMF was removed in vacuo. The residue was purified by column chromatography over silica gel using 10% methanol in dichloromethane as the eluent to afford 3-[4-(aminomethyl)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid (70 mg, 11%). m-Tolyl isocyanate (1.1 equiv., 13.7 mg, 0.1 mmol) was added to a solution of 3-[4-(aminomethyl)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (35 mg, 0.083 mmol) in pyridine (0.5 mL) and then stirred for 2 days. The reaction mixture was purified using mass actuated preparative RP-HPLC (Micromass/Gilson, Hypersil BDS C18, 5 μm, 100×21.2 mm column; 0-100% acetonitrile and 0.05M ammonium acetate, buffered to pH 4.5, over 12.5 min at 25 mL/min) to give trans-N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzyl)-N′-(3-methylphenyl)urea (17 mg, 37%); 1H NMR (DMSO-d6, 400 MHz) δ 1.46 (2H, m), 2.05 (4H, m), 2.18 (2H, m), 2.25 (3H, s), 2.33 (4H, m), 2.45-2.53 (8H, m), 4.38 (2H, br d), 4.65 (1H, m), 6.52 (1H, t), 6.66 (1H, d), 7.10 (1H, t), 7.19 (1H, brd), 7.26(1H, br s), 7.46(2H, d), 7.63 (2H, d), 8.23 (1H, s) and 8.51 (1H, s) and m/z (MH+) 554.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:24][N:25]=[C:26]=[O:27]>C(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]2[CH2:23][CH2:22][N:21]([C:26]([NH:25][CH3:24])=[O:27])[CH2:20][CH2:19]2)[C:26]([NH:25][CH3:24])=[O:27])=[CH:12][CH:13]=1
Reactant: CN=C=O
Reactant: Fc1ccc(CNC(c2ccc(F)cc2)C2CCNCC2)cc1
Solvent: ClCCl
Product: CNC(=O)N1CCC(C(c2ccc(F)cc2)N(Cc2ccc(F)cc2)C(=O)NC)CC1

Procedure:
A solution of 2.06 g (6.5 mmol) of α-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-4-piperidinemethanamine and 3.1 g (54.4 mmol) of methyl isocyanate in 300 mL of CH2Cl2 was stirred at room temperature for 18 h. The solvent was removed in vacuo to give a white solid. The solid was recrystallized from methylene chloride/ether to give 2.65 g (94.8%) of a white, crystalline solid containing 0.15 mole of CH2Cl2, mp 120°-162° C.