Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][CH3:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.CC(O[CH2:19][C:20]1[CH2:29][S:28][C@@H:23]2[C@H:24]([NH2:27])[C:25](=[O:26])[N:22]2[C:21]=1[C:30]([OH:32])=[O:31])=O.O.N>C(#N)C>[NH2:27][CH:24]1[C:25](=[O:26])[N:22]2[C:21]([C:30]([OH:32])=[O:31])=[C:20]([CH2:19][S:1][C:2]3[N:7]4[N:8]=[C:9]([CH2:11][O:12][CH3:13])[N:10]=[C:6]4[N:5]=[C:4]([CH3:14])[CH:3]=3)[CH2:29][S:28][C@H:23]12
Reactant: COCc1nc2nc(C)cc(S)n2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Solvent: CC#N
Solvent: O
Product: COCc1nc2nc(C)cc(SCC3=C(C(=O)O)N4C(=O)C(N)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
In 600 ml of acetonitrile were suspended 30.1 g of 7-mercapto-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine and 38.9 g of 7-aminocephalosporanic acid and 68.7 ml of boron trifluoride - ethyl ether complex was added thereto, and the mixture was stirred at room temperature for 6 hours. One liter of water was added to the reaction mixture and the mixture was adjusted to pH 2 with addition of a conc. aqueous ammonia. The precipitated crystals were collected by filtration, washed with water and with acetone, and then dried to obtain 30 g of the title compound.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OC([C:23]1([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([Br:37])[CH:32]=2)[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]1)=O)C.C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:37][C:33]1[CH:32]=[C:31]([C:23]2([NH2:15])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]2)[CH:36]=[CH:35][N:34]=1
Reactant: CCOC(=O)C1(c2ccnc(Br)c2)COC(C)(C)OC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)OCC(N)(c2ccnc(Br)c2)CO1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
Dipheny phosphoryl azide (14.3 mL, 66.45 mmol) was added to a solution of 5-(2-bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxane-5-carboxylic acid ethyl ester (14.0 g, 44.3 mmol) and triethyl amine (17.24 ml, 133.0 mmol) in toluene (100 ml) at 0° C. The resultant reaction mixture was heated to 80° C. under constant stirring for 7 h. Reaction mixture was concentrated under reduced pressure to remove solvent completely. The residue obtained after concentration was dissolved in THF (100 ml) and cooled to 0° C. 2 N aq. NaOH solution was added drop wise and stirred for 30 min at rt. Reaction mixture was concentrated under reduced pressure to remove THF and the residue obtained was extracted with ethylacetate. Organic layer was washed with water, brine and dried over anhy. Na2SO4. Organic layer was concentrated under reduced pressure to obtain furnished brownish oily material which was solidified at low temperature (<10° C.). Yield=9.5 g (75%). TLC (50% ethyl acetate in hexane) Rf=0.15; LCMS: RtH7=0.083; [M+1]+=287.0 and 289.0.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C@@H:9](/[CH:10]=[CH:11]/[C:12](=[O:14])[NH2:13])[C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:7]1=[O:23].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].C(=O)(O)[O-].[Na+]>C(#N)C.O>[C:12](/[CH:11]=[CH:10]/[C@@H:9]1[NH:6][C:7](=[O:23])[C@@H:8]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:14])[NH2:13]
Reactant: COc1ccc(CN2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2/C=C/C(N)=O)c(OC)c1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C(=O)N[C@H]1/C=C/C(N)=O
Yield: 40.5 %

Procedure:
3.6 g (8.9 mmol) of t-butyl(3R,4S)-1-(2,4-dimethoxybenzyl)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidinecarbamate are dissolved in 80 ml of acetonitrile and 150 ml of water and the solution is treated dropwise under reflux with a solution of 4.9 g (17.8 mmol) of potassium peroxydisulphate in 50 ml of water. The pH is held at 6.5 by the addition of saturated aqueous sodium bicarbonate solution. After 4 hours 40 ml of acetonitrile are distilled off. The crude mixture is subsequently partially evaporated and cooled to +5° C. The crystals obtained are filtered off. The filtrate is washed twice with 100 ml of ether each time. The aqueous phase is saturated with sodium chloride and extracted three times with 300 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate and evaporated. There is obtained a brown residue which yields 920 mg (41%) of t-butyl(3R,4S)-4-[(E)-2 -carbamoylvinyl]-2-oxo-3-azetidinecarbamate after recrystallization from methanol.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[C:13]#[N:14].[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20].O1CCCC1>C(N(CC)CC)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])[C:13]#[N:14]
Reactant: C=COCC
Reactant: COc1cc(C#N)ccc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(C)Oc1ccc(C#N)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two ml trifluoroacetic acid was added slowly to a chilled solution of 20 g of 3-methoxy-4-hydroxybenzonitrile, 50.7 ml of ethyl vinyl ether and 50 ml tetrahydrofuran (THF). The mixture was stirred at room temperature overnight. 7.5 ml of triethylamine was added to the mixture and stirring was continued for several minutes followed by solvent evaporation. The residue was partitioned between 400 ml of ether and 100 ml 1 N NaOH. The remaining ether layer was washed with 100 ml H2O and with 100 ml brine, dried (MgSO4) and evaporated to yield 31.2 gm of crude 3-methoxy-4-(2-ethoxy-1-oxapropyl)benzonitrile.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH:17]C(=O)C)=[CH:16][C:11]=3[N:10]=[C:9]2[C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(O)C>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:21]([CH3:24])([CH3:25])[CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(C)(C)c1nc2cc(NC(C)=O)ccc2n1CC1CCCCC1
Agent: Cl
Solvent: CCO
Product: CCC(C)(C)c1nc2cc(N)ccc2n1CC1CCCCC1
Yield: 127.3 %

Procedure:
N-[1-(Cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide (105.4 mg, 0.309 mmol) was dissolved in ethanol (3 mL) and 2N HCl aqueous solution (2 mL) in a Teflon-capped test tube. The vessel was irradiated by microwave for 45 min. at 120° C. After evaporation and drying in vacuo, 117.8 mg (100%) of the title compound was obtained as a grey white solid. 1H NMR (400 MHz, CD3CD): δ 0.87 (t, J=7.52 Hz, 3H), 1.27 (m, 5H), 1.66 (m, 3H), 1.71 (s, 6H), 1.78 (m, 2H), 2.05 (q, J=7.42 Hz, 2H), 2.13 (m, 1H), 4.53 (d, J=7.62 Hz, 2H), 7.66 (dd, J=8.79, 1.56 Hz, 1H), 7.97 (d, J=1.76 Hz, 1H), 8.17 (d, J=8.79 Hz, 1H). MS (ESI) (M+H)+: 300.05.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]([O:13][C:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH:15]=1)[CH3:12].CN1CCCN(C)C1=O.[CH3:30][O:31][C:32]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:33]=1[CH2:34][NH:35][C:36](=[O:39])[CH2:37]I>C1COCC1>[CH3:30][O:31][C:32]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:33]=1[CH2:34][NH:35][C:36](=[O:39])[CH2:37][CH:17]1[CH2:18][CH2:19][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]1=[O:20]
Reactant: COc1ccc(CNC(=O)CI)c(OC)c1
Reactant: CCOC1=CC(=O)CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC1=CC(=O)C(CC(=O)NCc2ccc(OC)cc2OC)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 55.9 %

Procedure:
To a −78° C. solution of 1.0 M lithium hexamethyldisilazide in THF (0.90 mL) in 4.0 mL THF was added 3-ethoxy-2-cyclohexen-1-one (0.100 mL, 0.687 mmol). After stirring at −78° C. for 40 minutes, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.0 mL, 8.3 mmol) was added. After 5 minutes, N-(2,4-Dimethoxy-benzyl)-2-iodo-acetamide (0.342 g, 1.02 mmol) was added as a solution in 2.0 mL THF. The reaction was kept at −78° C. for one hour, and then quenched with water and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. Purification by column chromatography on silica gel (gradient: 0 to 100% ethyl acetate in dichloromethane) yielded 133.5 mg (56%) of N-(2,4-dimethoxy-benzyl)-2-(4-ethoxy-2-oxo-cyclohex-3-enyl)-acetamide. LCMS (Method E, ESI): RT=1.57 min, m+H=336.2; 1H NMR (400 MHz, CDCl3) δ: 7.17 (d, J=8.1 Hz, 1H), 6.47-6.39 (m, 2H), 6.35 (s, 1H), 5.32 (s, 1H), 4.38-4.30 (m, 2H), 3.90 (dd, J=13.5, 6.5 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 2.77 (dd, J=14.3, 5.6 Hz, 1H), 2.68 (dt, J=10.6, 5.5 Hz, 1H), 2.59-2.48 (m, 1H), 2.37 (ddd, J=12.0, 6.3, 2.9 Hz, 1H), 2.17 (ddd, J=13.1, 11.2, 4.6 Hz, 2H), 1.72 (ddd, J=25.0, 12.6, 4.9 Hz, 1H), 1.36 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCc3c(sc(N)c3C(=O)c3ccccc3)C2)cc1

Procedure:
To a well-stirred and ice-cooled solution of 2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.78 mmol, 0.2 g) in dichloromethane (20 ml) under an argon atmosphere, was added triethylamine (0.162 ml) and then p-toluenesulphonyl chloride (0.93 mmol, 177 mg) portionwise. The suspension was stirred a room temperature for 24 h and the precipitated solid was filtered. The organic solution was evaporated under vacuum to give a solid residue which was chromatographed on silica gel eluting with an ethyl ether and petroleum ether mixture to afford 2-amino-3-benzoyl-6-(4-methylphenylsulphonyl)4,5,6,7-tetrahydrothieno[2,3-c]pyridine.
Reaction SMILES: [CH2:1]([C:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:11][CH3:12])[C:6](=[O:20])[CH2:5]1)[CH:2]=[CH2:3].[OH2:27].O=O>CN(C=O)C.CCOC(C)=O.[Cu]Cl.[Pd](Cl)Cl>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C@@H:10]([N:7]2[CH2:8][CH2:9][C:4]([CH2:1][C:2](=[O:27])[CH3:3])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:5][C:6]2=[O:20])[CH2:11][CH3:12])=[CH:18][CH:17]=1
Reactant: O
Reactant: C=CCC1(c2ccccc2)CCN([C@@H](CC)c2ccc(Br)cc2)C(=O)C1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H](c1ccc(Br)cc1)N1CCC(CC(C)=O)(c2ccccc2)CC1=O
Yield: 78 %

Procedure:
A round-bottom flask was charged with copper(I) chloride (0.3100 g, 3.13 mmol), and a solution of 4-allyl-1-((S)-1-(4-bromophenyl)propyl)-4-phenylpiperidin-2-one (0.3045 g, 0.74 mmol) in DMF (7.5 mL) was added, followed by H2O (2 mL) and palladium(II) chloride (0.0670 g, 0.38 mmol). The reaction mixture was vigorously stirred under a balloon of oxygen for 20 h at rt and diluted with EtOAc, dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 0.2475 g (78%) of 1-((S)-1-(4-bromophenyl)propyl)-4-(2-oxopropyl)-4-phenylpiperidin-2-one. LC-MS Method 3 tR=1.87, 1.93 min, m/z 428, 430 (MH+).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].[N+:18]([O-])(O)=O.C([O-])=O.[K+]>O.C(OCCC)(=O)C.N([O-])=O.[Na+]>[NH2:18][C:8]1[CH:9]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:11]=[C:6]([C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[C:7]=1[OH:17]
Reactant: CCC(C)(C)c1ccc(O)c(C(C)(C)CC)c1
Reactant: O=[N+]([O-])O
Agent: O=C[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: CCCOC(C)=O
Solvent: O
Product: CCC(C)(C)c1cc(N)c(O)c(C(C)(C)CC)c1
Yield: 86.1 %

Procedure:
2,4-Di-tert-pentylphenol (93.8 g, 0.4 mol), sodium nitrite (0.6 g, 0.009 mol), 60 mL of water, and 300 mL of propyl acetate were stirred mechanically in a one liter flask at 15-20°. Nitric acid (37.8 g of 70% acid, 0.42 mol) was added slowly via dropping funnel over 30 min keeping the temperature between 25 and 300. The mixture was then stirred vigorously for an additional hour before draining off the lower aqueous phase. The organic layer was washed with a solution of 21 g of sodium bicarbonate in 300 mL of water, passed through 9 g of activated charcoal, and concentrated under reduced pressure to an oil. Palladium catalyst (5 g of 5% Pd/C, 50% wet with water) was added to the oily nitrophenol dissolved in 240 mL of isopropyl alcohol. The mixture was heated with a 55° water bath before slowly adding over 1 h a solution of potassium formate (135 g, 1.6 mol) in 130 mL of water while keeping the temperature under 65°. After stirring an additional hour at 55-60°, the mixture was diluted with 300 mL of propyl acetate and 200 mL of warm water and filtered to remove catalyst. The catalyst was washed with 75 mL of propyl acetate and 75 mL of water. The combined propyl acetate layer was separated, washed with water and then brine, concentrated, and diluted with 200 mL of heptane to crystallize the product. After filtering and drying, 85.9 g (86%) of 2-amino-4,6-di-tert-pentylphenol were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[N:9][C:10]([OH:11])=[C:5]2[CH:4]=[N:3]1.[I:12]N1C(=O)CCC1=O.F[B-](F)(F)F.[H+].C(=O)(O)[O-].[Na+]>C(#N)C.O>[I:12][C:4]1[C:5]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[OH:11])[N:2]([CH3:1])[N:3]=1
Reactant: Cn1ncc2c(O)ncnc21
Reactant: O=C1CCC(=O)N1I
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [H+]
Solvent: O
Solvent: CC#N
Product: Cn1nc(I)c2c(O)ncnc21
Temperature: 25 °C

Procedure:
1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (5.50 g, 36.6 mmol) was combined with N-iodosuccinimide (97%, 12.7 g, 54.8 mmol) and tetrafluoroboric acid (50% solution in water, 23.0 mL, 183 mmol) in acetonitrile (50 mL) and the reaction mixture was heated to reflux for 5 hours. After cooling to room temperature, the reaction mixture was poured portion-wise into water (50 mL) containing sodium bicarbonate (18.6 g, 220 mmol). When gas evolution had ceased, the mixture was filtered, and the dark solid was washed successively with saturated aqueous sodium thiosulfate solution (25 mL) and water (2×25 mL). The resulting solid was dried under vacuum overnight at 50° C. to afford the product as a cream-colored solid. Yield: 9.35 g, 33.9 mmol, 93%. LCMS m/z 277.0 (M+1). 1H NMR (500 MHz, DMSO-d6) δ 3.87 (s, 3H), 8.07 (s, 1H), 12.08 (v br s, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([C:38](O)=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[NH2:49][CH:50]([C:55]1[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=1)[CH2:51][CH2:52][CH2:53][OH:54].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC(N(C)C)=O.CCOC(C)=O>[C:45]([O:44][C:42]([NH:41][C:35]1([C:38](=[O:39])[NH:49][CH:50]([C:55]2[CH:56]=[CH:57][C:58]([Cl:61])=[CH:59][CH:60]=2)[CH2:51][CH2:52][CH2:53][OH:54])[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37][CH2:36]1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: NC(CCCO)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (5.24 g, 13.77 mmol) was added in one portion to 1-(tert-butoxycarbonyl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylic acid (Intermediate 70) (4.31 g, 12.5 mmol), 4-amino-4-(4-chlorophenyl)butan-1-ol (Intermediate 16) (2.5 g, 12.5 mmol) and DIPEA (6.56 mL, 37.6 mmol) in DMA (62.6 mL) under nitrogen. The resulting solution was stirred at 60° C. for 3 hours and evaporated to dryness. The crude reaction mixture was dissolved in 100 mL EtOAc and then basified with saturated NaHCO3 (150 mL) and the organic fraction dried over MgSO4, filtered and evaporated to dryness. The organic fraction was purified by flash silica chromatography (eluent 0-10% 7N ammonia in MeOH/DCM). Pure fractions were then evaporated to afford tert-butyl 4-(tert-butoxycarbonylamino)-4-(1-(4-chlorophenyl)-4-hydroxybutylcarbamoyl)piperidine-1-carboxylate (5.06 g, 77%) as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][N:27]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:26]1
Reactant: CC1(C)CCCNC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: CC1(C)CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 3,3-dimethylpiperidine (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 40-65% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (33 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (s, 6 H) 1.45 (s, 6 H) 1.50 (t, J=6.06 Hz, 2 H) 1.80 (br. s., 2 H) 3.51 (s, 2 H) 3.65 (t, J=5.05 Hz, 2 H) 6.33 (d, J=2.02 Hz, 1 H) 7.39 (s, 1 H) 7.60 (d, J=8.34 Hz, 2 H) 8.00 (d, J=8.34 Hz, 2 H) 8.08 (d, J=2.02 Hz, 1 H) 10.85 (s, 1 H). ESI-MS: m/z 408.3 (M+H)+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH:12][C:13](OC(C)(C)C)=O)=[C:7]([N+:20]([O-:22])=[O:21])[CH:6]=1)(=[O:4])=[O:3].[C:23]1(=O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30]C=2)[CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)(C(F)(F)F)=O.ClCCl>[C:13]1(=[N:12]/[NH:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:6][C:7]=2[N+:20]([O-:22])=[O:21])/[CH2:30][CH2:29][CH2:28][C:27]2[C:32]/1=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: CC(C)(C)OC(=O)NNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: O=C1CCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(N/N=C2\CCCc3ccccc32)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A room temperature solution of Example 73A (145 mg,0.44 mmol) in 1:1 TFA/dichloromethane (10 mL) was stirred for 4 hours and concentrated. The concentrate was dissolved in ethanol (2 mL), treated with 3,4-dihydro-1(2H)-naphthalenone (8.2 mg, 0.06 mmol) and pyridinium p-toluenesulfonate (2 mg, 0.008 mmol), heated to reflux, stirred for 2 hours, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 359 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[N:11]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[C:3]=1[C:28]#[N:29].[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32].O>CS(C)=O.C(N(C(C)C)CC)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][S:33]([CH2:30][CH2:31][CH3:32])(=[O:35])=[O:34])[N:11]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[C:3]=1[C:28]#[N:29]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN)n3)nc(N)c2C#N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCCS(=O)(=O)NCc1cccc(CSc2nc(N)c(C#N)c(-c3ccc(NC(C)=O)cc3)n2)n1
Reaction time: 0.5 h

Procedure:
To a suspension of 0.1 g of the compound of Example 32 in 5 mL of DMSO, 0.25 mL of diisopropylethylamine was added, and 0.04 mL of 1-propanesulfonyl chloride was added dropwise under stirring. After 30 minutes, water was added to the reaction mixture, and the resulting crystal was filtrated, and dried under reduced pressure to give 80 mg of N-[4-(6-amino-5-cyano-2-{6-[(propane-1-sulfonylamino)methyl]pyridin-2-ylmethylsulfanyl}pyrimidin-4-yl)phenyl]acetamide as a white powder.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.O=[C:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]1.[BH3-]C#N.[Na+]>CO>[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:14][CH2:15][N:16]([CH:30]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29]4)[CH2:17][CH2:18]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: Cc1nn(-c2ccccc2)c2nc(C3CCNCC3)[nH]c(=O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nn(-c2ccccc2)c2nc(C3CCN(C4CCN(C(=O)OC(C)(C)C)C4)CC3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-methyl-1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (500 mg, 1.45 mmol, 1.00 equiv) in methanol (50 mL) at room temperature. To the resulting mixture was then added tert-butyl 3-oxopyrrolidine-1-carboxylate (804 mg, 4.35 mmol, 3.00 equiv), in portions at room temperature, followed by NaBH3CN (456 mg, 7.24 mmol, 5.00 equiv) at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), the organic layers combined and concentrated under vacuum to yield tert-butyl 3-(4-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-1-yl)pyrrolidine-1-carboxylate as a white solid.
Reaction SMILES: C(O)(=O)C.C1COCC1.[Br:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)=[CH:13][C:12]=1[CH2:29][C:30]([N:32]1[CH:37]=[CH:36][C:35](=[O:38])[CH2:34][CH:33]1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)=[O:31]>O>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][CH2:19][CH2:20][OH:21])=[CH:13][C:12]=1[CH2:29][C:30]([N:32]1[CH:37]=[CH:36][C:35](=[O:38])[CH2:34][C@H:33]1[C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1)=[O:31]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc(CC(=O)N2C=CC(=O)CC2c2ccc(F)cc2)c(Br)cc1F
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1C=CN(C(=O)Cc2cc(OCCO)c(F)cc2Br)[C@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
A mixture of acetic acid (4.5 ml), water (1.5 ml) and THF (1.5 ml) was added to a flask containing 1-(2-{2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetyl)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (0.048 g, 0.082 mmol). The mixture was stirred at room temperature for 16 hours. Water was added and the product was extracted with EtOAc. The extract was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness. Purification by flash chromatography (EtOAc) gave (S)-1-{2-[2-bromo-4-fluoro-5-(2-hydroxy-ethoxy)-phenyl]-acetyl}-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (0.032 g) as a white foam.