Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:10]([CH3:14])[C:11]=2[CH:12]=O)=[CH:3][CH:2]=1.[ClH:21].[NH2:22][OH:23].N1C=CC=CC=1>CO>[ClH:21].[ClH:21].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:10]([CH3:14])[C:11]=2[CH:12]=[N:22][OH:23])=[CH:3][CH:2]=1
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1C=NO
Yield: 42.5 %

Procedure:
A mixture of 2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde (0.14 g), hydroxylamine hydrochloride (0.04 g), and pyridine (0.04 mL) in MeOH (3 mL) was heated at reflux temperature for 16 hours. After cooling, the volatiles were removed by evaporation. The resulting residue was dissolved in 10% methanolic HCl (5 mL) and the solution was concentrated in vacuo again. The resulting solid was washed with water (50 mL) and CH2CI2 (30 mL) to provide the title compound (0.045 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[I:21]I.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13]([I:21])=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Reactant: II
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a cooled (−78° C.) solution of (2-fluoro-phenyl)-carbamic acid tert-butyl ester (38.0 g, 180 mmol) in THF (700 mL) under nitrogen was added tert-butyllithium (1.7 M, 240 mL, 408 mmol). The mixture was stirred for 1 h at −78° C. and then a solution of iodine (60.8 g, 240 mmol) in THF (150 mL) was added slowly. The reaction mixture was stirred for further 1 h. Saturated aqueous ammonium chloride (100 mL) was added slowly and the mixture was warmed to RT. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic fractions were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography (5% ethyl acetate:hexanes) to afford 39.1 g (65%) of the title compound as a while solid. 1H NMR (300 MHz, CDCl3): δ 1.50 (s, 9H), 5.98 (br. s, 1H), 6.92-6.99 (m, 1H), 7.08-7.15 (m, 1H), 7.62 (dt, J=7.8, 1.2 Hz, 1H).
Reaction SMILES: [SH:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][C:8]=2[NH2:11])[N:3]=1.[O:12]=[C:13]([CH2:25]Br)[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[C:20]([C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][C:13](=[O:12])[CH2:25][S:1][C:2]2[NH:10][C:9]3[C:4](=[N:5][CH:6]=[N:7][C:8]=3[NH2:11])[N:3]=2)=[CH:17][CH:18]=1)([OH:22])=[O:21]
Reactant: O=C(CBr)COc1ccc(C(=O)O)cc1
Reactant: Nc1ncnc2nc(S)[nH]c12
Product: Nc1ncnc2nc(SCC(=O)COc3ccc(C(=O)O)cc3)[nH]c12

Procedure:
From 8-mercapto-adenine and p-(2-oxo,3-bromo propyloxy)-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([OH:8])=O.[C:21](OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=[O:8])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC(NC(=O)CCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Product: COC(=O)CC(NC(=O)CCc1ccccc1)C(C)=O
Temperature: 90 °C

Procedure:
2-(3-Phenyl-propionylamino)-succinic acid 4-methyl ester (10 g, 36 mmol), pyridine (50 mL) and acetic anhydride (45 mL) were combined in a 500 mL flask. The reaction mixture was heated at 90° C. for 2 h and then cooled to ambient temperature. After concentrating the reaction mixture under reduced pressure, DI water was added (100 mL). The reaction mixture was partitioned between water and CH2Cl2 (200 mL). The organic phase was washed with 1N HCl (50 mL), dried (MgSO4), filtered, and concentrated. The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.31-7.20 (m, 5H), 6.79 (br d, J=7.6 Hz, 1H), 4.72 (X of ABX, 1H), 3.65 (s, 3H), 3.01-2.93 (m, 3H), 2.71-2.62 (m, 3H), 2.11 (s, 3H); MS (EI) 278.1 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([N:6]2[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(C(C)(C)C)cc2)C[C@H](C)N1
Temperature: 100 °C
Yield: 37.3 %

Procedure:
To a solution of cis-2,6-dimethylpiperazine (1 g, 8.7 mmol) in toluene (35 mL) was added 4-(tert-butyl)bromobenzene (1.86 g, 8.7 mmol), followed by BINAP (0.81 g, 1.3 mmol) and 1-BuONa (1.5 g, 15.6 mmol) in one portion each. The resulting mixture was degassed twice. To the mixture was added Pd2(dba)3 (0.79 g, 0.87 mmol) in one portion and the mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×100 mL), washed with water (1×100 mL), and brine (1×50 mL), dried over Na2SO4 and concentarted in vacuo. The residue was purified by silica gel column chromatography (0-20% MeOH in dichloromethane) to afford 0.8 g 1-(4-tert-Butyl-phenyl)-cis-3,5-dimethyl-piperazine. 1H NMR (400 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 6.88-6.86 (m, 2H), 3.49-3.46 (m, 2H), 3.08-3.00 (m, 2H), 2.33-2.27 (m, 2H), 2.15 (1H, br), 1.29 (s, 9H), 1.13 (d, 6H).
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(N(CC)CC)C.[CH:25]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:29]=1[O:30][C:31](Cl)=[O:32])([CH3:27])[CH3:26]>ClCCl.CN(C1C=CN=CC=1)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:25]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:29]=1[O:30][C:31]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:32])([CH3:27])[CH3:26]
Reactant: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccccc1O
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Oc1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
To a cooled (0° C.) solution of benzyl salicylate (0.77 g, 3.3 mmol) in dichloromethane (6 mL) was added triethylamine (0.52 mL, 3.7 mmol) and a catalytic amount of DMAP. To this mixture a suspension of compound (104) (0.9 g, 3.7 mmol, crude product from last step) in dichloromethane (4 mL) was further added. The reaction was allowed to warm to room temperature slowly and stirred for 14 h. The reaction mixture was then diluted with 10% aqueous citric acid solution (10 mL) and extracted with ethyl ether (2×40 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by radial chromatography on silica gel (eluting with ethyl acetate/hexane) to afford 0.8 g (57% yield over two steps) of the title compound (105).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:20][O:19][C:13]1[CH:18]=[CH:17][C:16]([C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccccc1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Yield: 51.9 %

Procedure:
The diaryl product was obtained using the same synthetic methods as shown in Example 25, step 5, using 2-(4-methoxyphenyl)acetic acid (5.0 g, 30.1 mmol, 1.00 equiv) and anisole (16 g, 148.1 mmol, 5.00 equiv) as reactants. Purification via silica gel column (ethyl acetate/petroleum ether (1:10)) afforded 4.0 g (52%) of 1,2-bis(4-methoxyphenyl)ethanone as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)[CH3:2].[NH4+].O[N:29]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:29])=[O:15])=[CH:9]2)[CH3:2]
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 0 °C
Yield: 81.9 %

Procedure:
To an ice-cooled and stirred mixture of 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (0.54 g) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole ammonium salt (0.33 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.42 g). After stirred at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate and brine, dried (MgSO4), filtered, and concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (441 mg, 82%) as pale yellow crystals. MS 376 (MH+).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Nc1nc2c(Br)cccn2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Temperature: 110 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
A suspension of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (5.33 g, 25 mmol), 3,4-difluorophenylboronic acid (5.92 g, 37.5 mmol) and 2M aqueous sodium carbonate solution (62.5 mL, 125 mmol) in 1,4-dioxane (250 mL) was treated with 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.02 g, 1.25 mmol) at room temperature and then stirred for 18 hours at 110° C. The reaction was cooled to room temperature and separated between water (312 mL) and ethyl acetate (500 mL). The aqueous layer was extracted with further ethyl acetate (500 mL). The organic layers were washed with saturated aqueous sodium chloride solution (300 mL), combined, dried over sodium sulfate, filtered off and evaporated. The brown solid was trituration with diethyl ether (130 mL) and dichloromethane (25 mL) to yield the title compound as a light brown solid (6.33 g, 97%). MS ISP (m/e): 247.2 (100) [(M+H)+].
Reaction SMILES: OC[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>O1CCCC1>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:13](=[O:14])[CH2:12][C:11](=[O:15])[CH3:10])[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
28 ml (0.25 mol) 1-(2-hydroxyethyl)piperazine was added dropwise to a solution of 20 g of diketene (0.24 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 33.70 g (0.18 mol, 77% yield) of a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[F:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1F>CN(C=O)C>[F:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1[N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1c1ccc([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 468 mg (5.5 mmol) of 2-pyrrolidone (Fluka, Buchs, Switzerland) in 10 ml of DMF at 0° C. are added 240 mg (5.5 mmol) of 55% NaH in oil. The reaction mixture is stirred for 30 min at 0° C. and for 30 min at rt. After this time, 795 mg (5 mmol) of 3,4-difluoronitrobenzene (Aldrich, Buchs, Switzerland) are added and the reaction mixture is stirred for 1 h at rt. The reaction mixture is quenched with 1 M aqueous HCl and extracted with EtOAc (2×). The organic layers are washed with aqueous sat. NaHCO3 and with brine (3×), dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel (hexane-EtOAc 5:1 to 1:3) to give the title compound as a solid. ES-MS: 225 (M+H)+; analytical HPLC: tret=2.99 minutes (Grad 1).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]([F:44])=[CH:31][N:30]=1>>[Cl:28][C:29]1[C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:33][C:32]([F:44])=[CH:31][N:30]=1
Reactant: CC1(C)OB(c2cc(F)cnc2Cl)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc(F)cnc2Cl)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 287 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a slightly rose powder. UPLC-MS (Condition 3), tR=1.09 min, m/z=513.2/515.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.67-1.96 (m, 2H) 2.86-3.50 (m, 4H) 4.14-4.29 (m, 1H) 7.33 (d, J=8.78 Hz, 2H) 7.85 (d, J=9.15 Hz, 2H) 7.97-8.02 (m, 1H) 8.02-8.21 (m, J=8.42, 2.93 Hz, 1H) 8.55 (t, J=3.11 Hz, 1H) 8.81 (dd, J=7.68, 2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].Br[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: COCCBr
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: COCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 3 g (7.9 mmol) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate, 0.54 g (13.5 mmol) of NaH in 60% of mineral oil and 1.04 mL (11.08 mmol) of bromoethylmethyl ether. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 1.3 g (39% of yield) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.CCN(CC)CC.[Cl:23][CH2:24][C:25](Cl)=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]2[O:7][C:25]([CH2:24][Cl:23])=[N:9][N:8]=2)=[CH:4][N:3]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(CCl)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-chloro-4-(isopropylamino)nicotinohydrazide (10) (500 mg, 2 mmol) in DCM (10 mL), Et3N (6 mmol, 3 equiv.) and 2-chloroacetyl chloride (3 mmol, 1.5 equiv.) were added and stirred at room temperature for 4 h. Added tosyl chloride (3.2 mmol, 1.5 equiv.) was added at stirred overnight at room temperature. The reaction mixture was diluted with DCM. The DCM layer was washed with 10% NaHCO3 solution followed by water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and EtOAc:Pet. ether as eluent to afford the desired compound, 2-chloro-5-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-N-isopropylpyridin-4-amine LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.95 min; LCMS (ES-API), m/z 287.6 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][CH:13]([NH2:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][CH:13]([CH3:12])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(N)CCc1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1O
Product: Cc1cc(C(=O)NC(C)CCc2ccccc2)ccc1O

Procedure:
Prepared in a similar manner to example 4 using 4-hydroxy-3-methyl-benzoic acid and 1-methyl-3-phenyl-propylamine. MS (M+H, 284.2).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][N:5]=1.[Li]CCCC.CN(C)[CH:18]=[O:19]>CCOCC>[Br:3][C:4]1[CH:9]=[C:8]([CH:18]=[O:19])[CH:7]=[CH:6][N:5]=1
Reactant: CN(C)C=O
Reactant: Brc1ccnc(Br)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2,4-dibromo-pyridine (1.90 g, 8.02 mmol) in dry Et2O (40 mL) was treated with n-BuLi (3.36 mL of a 2.5M solution in hexanes, 8.42 mmol) at −78° C. The reaction mixture was stirred at this temperature for 30 min. N,N-Dimethyl-formamide (0.78 mL, 10.03 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h and stirred at this temperature for 20 min. The reaction was quenched by the addition of sat. aq. NH4Cl (30 mL). The layers were separated and the aq. layer extracted with Et2O (3×50 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a white solid. TLC:rf (1:1 hept-EA)=0.44.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13](Cl)[N:12]2[N:16]=[CH:17][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>C(O)C.CCOC(C)=O>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:28][CH:25]2[CH2:27][CH2:26]2)[N:12]2[N:16]=[CH:17][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: N#CCCCCc1cnn2c(Cl)nc(SCc3ccccc3)nc12
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CCCCCc1cnn2c(NC3CC3)nc(SCc3ccccc3)nc12
Yield: 65 %

Procedure:
A solution of compound (5) and cyclopropylamine (1.2 g. 17.7 mmol) in anhydrous ethanol (10 mL) was stirred for 0.5 h at ambient temperature. The mixture was then diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO3 and brine and dried over anhydrous Na2 SO4. Removal of the solvent provided 5-(2-benzylsulfanyl-4-cyclopropylamino-pyrazolo[1,5-a][1,3,5]triazin-8-yl)-pentanenitrile (6) (4.3 g. 65% in two steps).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3].Br[CH2:19][CH2:20][CH2:21][P:22]([O:27][CH2:28][CH3:29])(=[O:26])[O:23][CH2:24][CH3:25]>>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH2:19][CH2:20][CH2:21][P:22](=[O:26])([O:27][CH2:28][CH3:29])[O:23][CH2:24][CH3:25])[CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]cnc2n(CCC)c1=O
Reactant: CCOP(=O)(CCCBr)OCC
Product: CCCn1c(=O)c2c(ncn2CCCP(=O)(OCC)OCC)n(CCC)c1=O

Procedure:
The title substance was prepared from 1,3-dipropylxanthine and diethyl 3-bromopropanephosphonate analogously to Example 1 and chromatographed on silica gel (eluent: ethyl acetate/methanol 20:1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:41])=[C:22]([CH2:24][S:25]([CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)(=[O:27])=[O:26])[N:23]=3)=[CH:15][CH:14]=2)=[O:12])[CH:3]=1.[OH-].[Na+].O>ClCCl>[CH3:41][C:21]1[O:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:11]([NH:10][CH2:9][CH2:8][C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)=[O:12])=[CH:18][CH:17]=2)=[N:23][C:22]=1[CH2:24][S:25]([CH:28]1[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1)(=[O:27])=[O:26]
Reactant: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Excess hydrogen chloride gas was bubbled into a solution of tert-butyl 4-((2-(4-((2-(pyridin-3-yl)ethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate (840 mg, 1.48 mmol, 1.00 equiv) in dichloromethane (20 mL) maintained at 0° C. in a water/ice bath. The reaction mixture was stirred at 0° C. for another 2 h. The pH value of the solution was adjusted to 10 with 1M sodium hydroxide solution. Water (400 mL) was then added and the resulting solution was extracted with 5×200 mL of dichloromethane. The combined organic layers was washed with 2×600 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 420 mg (61%) of 4-(5-methyl-4-((piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(2-(pyridin-3-yl)ethyl)benzamide as a white solid. LC-MS: (ES, m/z): 469 [M+H]+, 320, 235. 1HNMR (400 MHz, CD3OD, ppm) δ 8.47 (s, 1H), 8.42-8.40 (d, 1H), 8.09-8.07 (d, 2H), 7.90-7.88 (d, 2H), 7.81-7.79 (d, 1H), 7.42-7.39 (t, 1H), 4.45 (s, 2H), 3.70-3.66 (t, 2H), 3.43-3.39 (m, 3H), 3.03-2.99 (t, 2H), 2.88-2.82 (m, 2H), 2.50 (s, 3H), 2.34-2.31 (d, 2H), 1.91-1.88 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH3:22][C:23]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([N+:30]([O-:32])=[O:31])[C:23]=2[CH3:22])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OC)cc(Oc2ccc(C=O)cc2)c1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: C=CCOc1cc(OC)cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 90B and 2-methyl-3-nitroaniline were processed as in Example 6A to provide the title compound. MS (ESI−) m/z 419 (M−H)−.