Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[N:34]1[CH:39]=[CH:38][C:37]([CH:40]([S:42][C:43]2[C:48]([C:49]([OH:51])=O)=[CH:47][CH:46]=[CH:45][N:44]=2)[CH3:41])=[CH:36][CH:35]=1.[Cl:52][C:53]1[CH:59]=[CH:58][C:56]([NH2:57])=[CH:55][CH:54]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:52][C:53]1[CH:59]=[CH:58][C:56]([NH:57][C:49]([C:48]2[C:43]([S:42][CH:40]([C:37]3[CH:36]=[CH:35][N:34]=[CH:39][CH:38]=3)[CH3:41])=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:51])=[CH:55][CH:54]=1
Reactant: CC(Sc1ncccc1C(=O)O)c1ccncc1
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Sc1ncccc1C(=O)Nc1ccc(Cl)cc1)c1ccncc1
Yield: 14 %

Procedure:
N,N-Diisopropylethylamine (0.29 mL, 1.7 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (330 mg, 0.87 mmol) were added to a solution of 2-[1-(4-pyridyl)ethylthio]pyridine-3-carboxylic acid (200 mg, 0.77 mmol, Reference compound No. 5-1) and 4-chloroaniline (110 mg, 0.85 mmol) in N,N-dimethylformamide (2.0 mL), then the mixture was stirred at room temperature for 13 hours. Ethyl acetate (30 mL) was added to the reaction mixture, the ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution (30 mL) twice and brine (30 mL) twice, then dried over anhydrous magnesium sulfate. The resulting residue by evaporated under reduced pressure was purified by silica gel column chromatography to give 41 mg of the target compound as a colorless solid. (Yield 14%)
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][N+:19]([O-:21])=[O:20])[CH2:14][CH2:13]1.CO.[O-:24][C:25]#[N:26].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:26][C:25]([NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][N+:19]([O-:21])=[O:20])[CH2:14][CH2:13]1)=[O:24]
Reactant: NCCN1CCC(O[N+](=O)[O-])CC1
Reactant: N#C[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(=O)NCCN1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.53 g. 1-(2-aminoethyl)-4-nitroxypiperidine fumarate are dissolved in 15 ml. methanol and 5 ml. water. 1.62 g. Potassium cyanate is added thereto and the reaction mixture is stirred overnight at ambient temperature. A pH value of 10 is adjusted by the addition of potassium carbonate. The reaction mixture is extracted with ethyl acetate and the extracts are dried with anhydrous sodium sulphate. After evaporation and trituration of the residue with diethyl ether, the resultant crystals are filtered off with suction. There is obtained 1 g. of the title compound, i.e. 86% of theory; m.p. 114°-116° C.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH:15]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(C(Cl)Cn2ccnc2)cc1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
965 mg of methyl 4-mercaptobenzoate were dissolved in 6 ml of dry dimethylformamide. 250 mg of a 55% w/w suspension of sodium hydride in mineral oil were added to the resulting solution, whilst ice-cooling, and the mixture was then stirred at room temperature for 30 minutes. A solution of 1.1 g of 1-[2-chloro-2-(4-fluorophenyl)ethyl]imidazole dissolved in 16 ml of dry dimethylformamide was added to the resulting mixture. The mixture was then heated at 70° to 75° C. for 2.5 hours. At the end of this time, the resulting mixture was treated and purified similarly to the procedure described in Example 1, to give 866 mg of the title compound as a powder.
Reaction SMILES: C([S:4][CH2:5][C:6]([CH3:24])([CH3:23])[C:7]([N:9]1[C@H:19]([C:20]([OH:22])=[O:21])[CH2:18][C:11]2([C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])[CH2:10]1)=[O:8])(=O)C.N>>[SH:4][CH2:5][C:6]([CH3:24])([CH3:23])[C:7]([N:9]1[C@H:19]([C:20]([OH:22])=[O:21])[CH2:18][C:11]2([C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])[CH2:10]1)=[O:8]
Reactant: CC(=O)SCC(C)(C)C(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O
Agent: N
Product: CC(C)(CS)C(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia to yield (8S)-7-(3-mercapto-2,2-dimethyl-1-oxopropyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylic acid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.CCOCC.O>CN(C=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: c1ccc(Oc2ccc(OCCN3CCCC3)cc2)cc1
Reaction time: 15 h
Yield: 92.9 %

Procedure:
A solution of 4-phenoxyphenol (0.56 g, 3.0 mmol), 1-(2-chloroethyl)-pyrrolidine HCl (0.51 g, 3.0 mmol) and powdered K2 CO3 (1.2 g, 8.7 mmol) in 30 mL DMF was stirred at 80°-90° C. for 15 hours. The solution was cooled, poured into Et2O and water and the ether layer washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give 0.79 g of a brown oil. The crude product was flashed chromatographed on silica gel using a gradient of 2:1 hexane/EtOAc to 100% EtOAc to provide the title compound (0.65 g, 76.5%) as a light yellow oil:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][C:21](=O)[CH3:22])=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:34][CH2:35][C@H:36]([OH:45])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][CH:21]([NH:34][CH2:35][C@H:36]([OH:45])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:22])=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc2c(c1)cc(C(=O)OCc1ccccc1)n2Cc1ccc([N+](=O)[O-])cc1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(Cc1ccc2c(c1)cc(C(=O)OCc1ccccc1)n2Cc1ccc([N+](=O)[O-])cc1)NC[C@H](O)COc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 1-(4-nitro-benzyl)-5-(2-oxo-propyl)-1H-indole-2-carboxylic acid benzyl ester (540 mg, 1.22 mmol) and 1-amino-3-phenoxypropan-2(S)-ol (245 mg, 1.46 mmol) in dichloroethane (20 ml) was added powdered sodium sulfate (1.73 g, 12.2 mmol), and the mixture was stirred for about one hour at room temperature under nitrogen. Acetic acid (87.9 mg, 0.084 ml, 1.46 mmol) and sodium triacetoxyborohydride (388 mg, 1.83 mmol) were added. After about 6 hours, additional sodium triacetoxyborohydride (194 mg, 0.915 mmol), acetic acid (0.2 ml, 3.5 mmol) and 1-amino-3-phenoxypropan-2(S)-ol (122 mg, 0.73 mmol) were added, and the mixture was stirred for about two days at room temperature under nitrogen. The reaction was then diluted with methylene chloride, washed with dilute sodium bicarbonate and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was flash chromatographed on silica (55 g), eluting with 5% methanol/methylene chloride, to give the title compound (500 mg) as a mixture of diastereomers.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C@@H:4]([C:19]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:20])[CH2:3]1.O[Li].O>>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)[C@@H:4]([C:19]([NH:21][C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[CH3:23])=[O:20])[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)CCN2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CC(F)CCN1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Yield: 69.8 %

Procedure:
The title compound (E14) (42 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-((1S)-1-((2R)-4-fluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (D133) (62 mg). (LiOH H2O: 4 eq; reaction time: 5 hrs)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6]OS(=O)(=O)[N:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[CH:24][NH:25]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C>[NH:25]1[C:26]2[C:22](=[C:21]([N:15]3[CH2:20][CH2:19][N:18]([CH2:6][C@@H:2]([CH3:1])[NH:3][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH2:17][CH2:16]3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: CC#N
Product: C[C@H](CN1CCN(c2cccc3[nH]ccc23)CC1)Nc1ccccn1
Temperature: 60 °C
Yield: 67.5 %

Procedure:
A solution of (R)4-methyl-3-pyridin-2-yl-[1,2,3]-oxathiazolidine-2,2-dioxide (4.04 g 0.019 moles) prepared according to Example 1 and 4-piperazinoindole (3.80 g 0.019 moles) in acetonitrile (200 ml) was heated to 60° C. for 0.5 h then evaporated in vacuo. The residue was taken up into dilute hydrochloric acid (100 ml), warmed to 60° C. for 0.5 h, cooled, washed with ethyl acetate (2×100 ml), made basic with potassium carbonate, extracted into dichloromethane (3×100 ml), dried (MgSO4) then evaporated in vacuo to give a brown glass. This was purified on a silica column eluting with 10% propan-2-ol in dichloromethane to give (R)-1-(4-indolyl)-4-[2-methyl-2-(2-pyridinylamino)ethyl]piperazine (4.3 g) as a clear glass.
Reaction SMILES: C([NH:8][C:9]1[C:14]([F:15])=[C:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([F:21])=[C:11]([F:22])[N:10]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:8][C:9]1[C:14]([F:15])=[C:13]([NH:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:12]([F:21])=[C:11]([F:22])[N:10]=1
Reactant: CC(C)(C)Nc1c(F)c(F)nc(NCc2ccccc2)c1F
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)Nc1c(F)c(N)nc(F)c1F
Reaction time: 6 h

Procedure:
To 13 ml of acetic acid were added 4.0 g of the crude 2-benzylamino-4-(t-butyl)amino-3,5,6-trifluoropyridine as described above together with 0.43 g of 10% palladium on carbon, and the mixture was hydrogenated at 60° C. for 6 hours. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure to obtain the title compound as a brown crude oil.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([CH2:7][NH:8]C(OCC2C=CC=CC=2)=O)[CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1>CO>[NH2:8][CH2:7][C@@H:6]1[C@H:2]([OH:1])[CH2:3][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](CN)[C@H](O)C1

Procedure:
Dissolve 1,1-dimethylethyl(3S,4S)-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.75 g, 2.14 mmol) in methanol (10 mL). Add 20% PdOH (catalytic) and subject to H at 55 PSI on a Parr hydrogenation apparatus. The solution was filtered through a plug of celite and concentrated under reduced pressure to yield an oil. (0.712 g, quantitative) LCMS: m/z 133.2 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:30])[NH:24][C:25]([CH3:29])=[N:26]2)=[CH:21][C:20]=1[N+:31]([O-:33])=[O:32]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:19]3[CH:28]=[C:27]4[C:22]([C:23](=[O:30])[NH:24][C:25]([CH3:29])=[N:26]4)=[CH:21][C:20]=3[N+:31]([O-:33])=[O:32])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1nc2cc(Cl)c([N+](=O)[O-])cc2c(=O)[nH]1
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Sc3cccc4cnccc34)c([N+](=O)[O-])cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 150 mg (0.9 mmol), DMF 5 ml, potassium carbonate 250 mg (1.8 mmol) and 7-chloro-2-methyl-6-nitro-3,4-dihydro-4-quinazolinone 200 mg (0.8 mmol) was stirred at room temperature for 2 hours, and 7-(5-isoquinolylsulfanyl)-2-methyl-6-nitro-3,4-dihydro-4-quinazolinone 260 mg (83.7%) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:16][CH:18]3[CH2:19][O:20]3)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: ClCC1CO1
Reactant: CC1(C)CCC(c2ccc(O)cc2)CC1
Product: CC1(C)CCC(c2ccc(OCC3CO3)cc2)CC1

Procedure:
The title compound was prepared from 4-(4,4-dimethylcyclohexyl)-phenol and epichlorohydrin according to the procedures employed for the preparation of the compound in Step 1 of Example 2.
Reaction SMILES: CC1(C)O[C@@H](CC[O:9]/[N:10]=[C:11]2\[NH:12][C@@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=3)[CH2:14][C:15]3[N:16]=[C:17]([NH2:22])[N:18]=[C:19]([CH3:21])[C:20]\2=3)CO1.Cl>>[NH2:22][C:17]1[N:18]=[C:19]([CH3:21])[C:20]2=[C:15]([CH2:14][C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=3)[NH:12]/[C:11]/2=[N:10]\[OH:9])[N:16]=1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC[C@H]3COC(C)(C)O3)N2)n1
Agent: Cl
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/O)N2)n1

Procedure:
Deprotection of 86h was achieved by treating with diluted HCl as described in Example 85 to yield Compound 37.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:21]([O-:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>>[CH2:23]([O:22][P:21]([O:25][CH2:26][CH3:27])([C:2]([OH:1])([CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:28])[CH3:24]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)C(=O)CCN1C(=O)c2ccccc2C1=O
Product: CCOC(=O)C(O)(CCN1C(=O)c2ccccc2C1=O)P(=O)(OCC)OCC

Procedure:
A mixture of 13.76 g (0.05 mole) of ethyl 2-oxo-4-phthalimidobutanoate in 31 g (0.225 mole) of diethyl phosphite is stirred at 20°-30° for several days. The excess diethyl phosphite is removed on a rotary evaporator under vacuum at a bath temperature of 50°-70° to give the crude product. This is purified by chromatography on silica gel using chloroform/methanol as eluant.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][F:13])=[CH:8][C:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:6]([F:20])[CH:5]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36](O)=[O:37])[N:27]=1>>[Cl:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][F:13])=[CH:8][C:7]([N:14]2[CH2:15][CH2:16][N:17]([C:36](=[O:37])[CH2:35][N:28]3[C:29]4=[N:30][CH:31]=[CH:32][CH:33]=[C:34]4[C:26]([C:22]4[NH:21][CH:25]=[CH:24][N:23]=4)=[N:27]3)[CH2:18][CH2:19]2)=[C:6]([F:20])[CH:5]=1
Reactant: FCCOc1cc(N2CCNCC2)c(F)cc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: Cl
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2cc(OCCF)c(Cl)cc2F)CC1

Procedure:
The title compound was prepared following Protocol A. 1-[4-Chloro-2-fluoro-5-(2-fluoroethoxy)phenyl]-piperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (2% to 3.5% MeOH in CH2Cl2) to provide 1-{4-[4-chloro-2-fluoro-5-(2-fluoroethoxy)phenyl]piperazin-1-yl}-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6; H, J=8.0, 1.8 Hz), 8.67 (d, 0.4; H, J=6.4 Hz), 8.57-8.55 (m, 1H), 7.30-7.25 (m, 1H), 7.11-7.06 (m, 2H), 6.63 (d, 0.6H, J=7.6 Hz), 6.57 (d, 0.4H, J=7.6 Hz), 6.54 (d, 1H, J=7.6 Hz), 5.45 (s, 0.7H), 5.43 (s, 1.3H), 4.83-4.80 (m, 1H), 4.71-4.68 (m, 1H), 4.31-4.18 (m, 2H), 3.82-3.76 (m, 3H), 3.50 (t, 1H, J=5.2 Hz), 3.23-3.04 (m, 4H); LC/MS m/z (M+H)+ 502.4.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][OH:7])(=[O:4])=[O:3].ClCCl.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(C(C)C)CC)(C)C>O>[S:12]([O:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:14])(=[O:13])[CH3:11]
Reactant: CS(=O)(=O)CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Combine 2-methylsulfonylethanol (7.7 g, 62 mmol) and dichloromethane (50 mL). Cool in an ice bath. Add methanesulfonyl chloride (7.81 g , 68.2 mmol). Add diisopropylethylamine (8.0 g, 62 mmol). After the addition of diisopropylethylamine, warm to ambient temperature. After 12 hours, add water and separate the layers. Extract the organic layer with a saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter and evaporate in vacuo to give the title compound: mp; 55-57° C.
Reaction SMILES: BrC1C=CC([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C:18]3([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=CC=1.Cl.Cl.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][C:39](N3CCNCC3)=[N:40][CH:41]=2)=[CH:32][CH:31]=1.COC(C1(S(Cl)(=O)=O)CCOC(C)C1)=O>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[N:40][C:39]([N:8]3[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C:18]4([C:24]([OH:26])=[O:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)(=[O:15])=[O:16])[CH2:10][CH2:9]3)=[N:38][CH:37]=2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(Br)cc3)CC2)CCOCC1
Agent: COC(=O)C1(S(=O)(=O)Cl)CCOC(C)C1
Agent: Cl
Product: O=C(O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCOCC1
Yield: 81 %

Procedure:
Prepared according to the method for the preparation of 4-[4-(4-bromophenyl) -piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid, from 5-(4-fluorophenyl)-2-piperazin-1-ylpyrimidine dihydrochloride (0.27 g), and 4-chlorosulfonyl -methyltetrahydropyran-4-carboxylic acid methyl ester (0.25 g), to yield the title compound as white solid (0.31 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)CC)(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A round-bottomed flask was charged with 2,4,5-trichloropyrimidine (5 mL, 43.6 mmol), ethyl 2-aminobenzoate (7.6 g, 46.0 mmol), di-isopropyl-ethylamine (8.3 mL, 48.0 mmol) and ethanol (60 mL). The flask was fitted with a reflux condenser and the reaction was heated to reflux and stirred for 18 h. A white solid appeared in the reaction mixture. The reaction was cooled to room temperature, and the solid was filtered off and washed with ethanol (100 mL), ethanol/hexane (1:1, 200 mL) and hexane (200 mL) to afford the product (10.2 g, 32.7 mmol, 75% yield) as a white solid. MS: M(C13H11Cl2N3O2)=312.15, (M+H)+=312.0 and 314.0.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4](=[O:10])[C:5]([O:7]CC)=O)#[N:2].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=1.[O-]CC.[Na+]>>[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:5](=[O:7])[C:4](=[O:10])[CH:3]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:1]#[N:2])[C:26]#[N:27])=[CH:21][CH:20]=1
Reactant: CSc1ccc(CC#N)cc1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: CSc1ccc(C(C#N)C(=O)C(=O)C(C#N)c2ccccc2)cc1

Procedure:
As described in Example 1, ethyl 3-cyano-3-phenylpyruvate is reacted with p-methylthiophenylacetonitrile in an alcoholic solution of sodium ethoxide to give 2-(p-methylthiophenyl)-5-phenyl-3,4-dioxoadiponitrile. The latter is refluxed in a mixture of water, glacial acetic acid and concentrated sulfuric acid to give a mixture of 4- and 4'-methylthiopulvinic acid which is then refluxed in acetic anhydride to result in the formation of 4-methylthiopulvinic acid lactone.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:60][CH3:61])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[C:53]([CH3:58])=[N:54][CH:55]=[CH:56][CH:57]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[C:53]([CH3:58])=[N:54][CH:55]=[CH:56][CH:57]=2)[C:47]1=[O:59])[CH:41]([CH3:40])[CH2:60][CH3:61])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccnc2C)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccnc2C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
A solution containing the product from Example 2C (1.1 g, 2.07 mmol) in THF (20 mL) was treated with the product from Example 15C (0.87 g, 2.07 mmol), DEPBT (0.93 g, 3.11 mmol), and N,N-diisopropylethylamine (1.8 mL, 10.33 mmol), stirred at 25° C. for 3 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with a gradient starting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate to give the title compound (1.17 g, 69% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (m, 18 H), 1.29 (m, 1 H), 1.53 (m, 2 H), 1.80 (m, 1 H), 2.48 (s, 3 H), 2.72 (m, 3 H), 2.96 (m, 3 H), 3.50 (s, 3 H), 3.65 (m, 1 H), 3.84 (d, J=9.93 Hz, 1 H), 3.94 (d, J=11.03 Hz, 1 H), 4.15 (m, 2 H), 4.32 (s, 2 H), 4.67 (d, J=7.35 Hz, 1 H), 6.64 (d, J=9.93 Hz, 1 H), 7.09 (m, 5 H), 7.22 (m, 3 H), 7.31 (m, 2 H), 7.52 (dd, J=7.72, 1.47 Hz, 1 H), 7.86 (m, 5 H), 8.36 (dd, J=4.78, 1.47 Hz, 1 H), 8.63 (d, J=4.41 Hz, 1 H).