Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[CH:6][C:7]([C:9]1[NH:13][C:12]([CH3:14])=[N:11][CH:10]=1)=O.[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH2:26])=[NH:25])[CH:20]=[CH:21][CH:22]=1>C(O)CCC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[NH:23][C:24]1[N:26]=[C:7]([C:9]2[NH:13][C:12]([CH3:14])=[N:11][CH:10]=2)[CH:6]=[CH:5][N:25]=1
Reactant: Cc1ncc(C(=O)C=CN(C)C)[nH]1
Reactant: N=C(N)Nc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Product: Cc1ncc(-c2ccnc(Nc3cccc(Cl)c3)n2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.6 %

Procedure:
Sodium hydride (45 mg of a 60% suspension in mineral oil, 1.12 mmol) was added to a stirred suspension of 5-(3-dimethylaminoprop-2-en-1-oyl)-2-methylimidazole (100 mg, 0.56 mmol) and 3-chlorophenylguanidine (95 mg, 0.56 mmol) in dry 1-butanol (4.0 ml) under nitrogen. The mixture was stirred at ambient temperature for 15 minutes then heated at 126° C. for 26 hours. The reaction mixture was allowed to cool and the volatiles were removed by evaporation. The residue was suspended in water (20 ml) and acetic acid (67 μl) was added and the solution extracted with DCM (3×20 ml). The extracts were combined, dried (NaSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with DCM/MeOH (100:0 increasing in polarity to 92:8) to give the title compound 33 mg, (21%) as a solid. NMR: 2.35 (s, 3H), 6.95 (d, 1H), 7.23 (d, 1M, 7.30 (t, 1H), 7.67 (s, 1H), 7.72 (s, 1H), 8.05 (s, 1H), 8.43 (d, 1H), 9.62 (s, 1H), 12.15 (s, 1H); m/z: 286.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14]1[CH2:17][C:16](=O)[CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[O:14]1[CH2:17][CH:16]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (10.8 g, 1.2 eq, 58.0 mmol) and oxetan-3-one (3.5 g, 1.0 eq, 14 mmol) in 1,2-dichloroethane (100 mL) was stirred at room temperature. Sodium triacetoxyborohydride (16.4 g, 1.6 eq, 77.3 mmol) was added in portions to the above solution and the heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (200 mL) and pardoned with aqueous saturated NaHCO3 solution (100 mL). The layers were separated and the organic layer was washed with brine solution (2×50 mL). The combined organic layers were dried over Na2SO4. Removal of the solvents and purification of the crude mixture by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 0:1 to 1:9) as eluent gave tert-butyl 4-(oxetan-3-yl)piperazine-1-carboxylate in 84% yield.
Reaction SMILES: [CH2:1]([C:3]([OH:24])([CH2:22][CH3:23])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][NH:15]C(=O)C(F)(F)F)[CH:9]=[CH:10][CH:11]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[NH2:15][CH2:14][CH2:13][CH2:12][C:8]1[CH:7]=[C:6]([C:5]#[C:4][C:3]([CH2:22][CH3:23])([OH:24])[CH2:1][CH3:2])[CH:11]=[CH:10][CH:9]=1
Reactant: CCC(O)(CC)CCc1cccc(CCCNC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(O)(C#Cc1cccc(CCCN)c1)CC
Temperature: 45 °C
Reaction time: 4 h

Procedure:
N-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide (12) (0.660 g, 1.93 mmol) was dissolved in MeOH (15 mL), and an aqueous solution of K2CO3 (0.42 g/3 mL) was added. The resulting mixture was stirred at 45° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure then partitioned between EtOAc (50 mL) and water (50 mL). The combined organics were dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (80 to 100% (9:1 EtOAc: 7M NH3 in MeOH):hexanes gradient) gave 1-(3-(3-aminopropyl)phenyl)-3-ethylpent-1-yn-3-ol (13) as a light yellow oil. Yield (0.421 g, 89%): 1H NMR (400 MHz, DMSO-d6) δ 7.15-7.26 (m, 4H), 5.11 (s, 1H), 2.56 (t, J=7.6 Hz, 2H), 2.47 (t, J=5.2 Hz, 2H), 1.55-1.65 (m, 6H), 1.39 (br s, 2H), 0.97 (t, J=7.6 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][S:43]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)(=[O:45])=[O:44])=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NS(=O)(=O)c2ccccc2)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.08 M and 0.16 M in dichloromethane, respectively, 500 μL, 0.042 mmol Example 23e and 0.083 mmol N,N-diisopropylethylamine), and benzenesulfonyl chloride (0.40 M in dichloromethane, 239 μL, 0.096 mmol) were mixed and stirred at ambient temperature overnight. The reaction mixture was concentrated, dissolved in methanol (1 mL) and injected on the reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to yield the title compound as an impure mixture.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](O)(=[O:21])[CH:19]=[CH2:20].S(=O)(=O)(O)O.C1(C=CC(O)=CC=1)O>C1C=CC=CC=1>[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)(=[O:21])[CH:19]=[CH2:20]
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Reactant: C=CC(=O)O
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Yield: 54.3 %

Procedure:
4.8 g of 4-(6-hydroxyhexyloxy)benzoic acid and 5.8 g of acrylic acid were heat-refluxed for 40 hours together with 1 ml of sulfuric acid in the presence of hydroquinone in benzene, followed by distilling-off of the solvent and recrystallization to obtain 3.2 g of the product. (Yield: 55 %)
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[CH:16]=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:23][C:24](=[O:26])[CH3:25])[CH:6]=1)(=[O:3])[CH3:2].CC[O:29]CC.C1C=C(C(O)=O)C(C(OO)=O)=CC=1>CCOCC>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]3[O:29][C@@H:15]3[CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:23][C:24](=[O:26])[CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C=CC[C@H]3[C@H]1CC2
Reactant: CCOCC
Agent: O=C(O)c1ccccc1C(=O)OO
Product: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H]4O[C@@H]4C[C@H]3[C@H]1CC2
Reaction time: 7.5 h

Procedure:
A solution of 350 mg. of 1,3-diacetoxy-8α-estra-1,3,5(10),16-tetraene in 15 ml. of ether is combined with 7 ml. of a 12% strength ether - monoperphthalic acid solution. After allowing the mixture to stand at room temperature for 7.5 hours, the mixture is worked up, yielding 1,3-diacetoxy-16α,17α-epoxy-8α-estra-1,3,5(10)-triene which, in the form of the crude product, is heated to the boiling point with 30 ml. of glacial acetic acid for 2-3 hours. After concentration under vacuum, the residue is heated, for purposes of esterification, with 2 ml. of pyridine and 2 ml. of acetic anhydride for 1.5 hours on a steam bath under N2. After the mixture has been introduced into ice water, it is taken up in methylene chloride and worked up, thus producing, after purification by chromatography on SiO2, 1,3,16β,17α-tetraacetoxy-8α-estra-1,3,5(10)-triene.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][CH2:15]2)[C:8]([O:11]C)=[N:9][CH:10]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][CH2:15]2)[C:8](=[O:11])[NH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COc1ncc(S(C)(=O)=O)cc1CN1CCC(CCc2ccccc2OCC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)c1c[nH]c(=O)c(CN2CCC(CCc3ccccc3OCC3CCCCC3)CC2)c1
Yield: 94.7 %

Procedure:
In ethanol (10 ml) was dissolved 138 mg of 1-[(5-(methylsulfonyl)-2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(cyclohexylmethyloxy)phenyl]ethyl]piperidine. To the mixture was added 1 ml of thionyl chloride, followed by heating under reflux for 2.5 hours. An aqueous sodium carbonate aqueous solution was added to the reaction solution, and the resulting precipitates were collected by filtration, to give 127 mg of the title compound as a white powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[I:14])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:15][C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[C:13]([I:14])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (8.6 g, 24.3 mmol) dissolved in CH2Cl2 was treated with 4 N HCl/dioxane (100 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 and washed with 2 N NaOH. The organic layer was dried over MgSO4 and concentrated to give the product as a solid (6.2 g, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)[CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-tert-Butylphenol (7.52 g, 50 mmol) in anhydrous DMF (40 mL) was added dropwise to NaH (2.2 g, 55 mmol, 60% w/w in mineral oil) at 0° C. under an atmosphere of nitrogen. After five min, ethyl 2-bromopropionate (6.49 mL, 50 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir for 18 h, gradually warming to ambient temperature. The reaction mixture was diluted with ethyl acetate (300 mL) and extracted twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce a colorless oil.
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([O:45][CH3:46])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2OC)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>FC(F)(F)C(O)=O>[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([O:45][CH3:46])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[NH:22]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(OC)c(=O)[nH]2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 80 °C
Reaction time: 9 h
Yield: 62.9 %

Procedure:
Anisole (1 mL) was added to a solution of 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-methoxypyridin-2(1H)-one (65 mg) in trifluoroacetic acid (2 mL), and the mixture was stirred at 80° C. for nine hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give the title compound as a colorless powder (29 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:13]1([CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:26][C:25]3[CH:27]=[CH:28][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)=[CH:3][C:4]=2[C:16]([F:19])([F:18])[F:17])(=[O:10])=[O:9])[CH2:15][CH2:14]1
Reactant: COc1ccc(N)cc1
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2ccc(S(=O)(=O)NCC3CC3)c(C(F)(F)F)c2)cc1
Reaction time: 6 h
Yield: 45 %

Procedure:
A mixture of 4-bromo-N-cyclopropylmethyl-2-trifluoromethylbenzenesulfonamide (295 mg, 0.82 mmol), 4-methoxyaniline (142 mg, 0.92 mmol), Pd(OAc)2 (26 mg, 0.11 mmol), BINAP (70 mg, 0.11 mmol) and cesium carbonate (395 mg, 1.21 mmol) in 15 ml toluene was relaxed for 6 hours. Toluene was evaporated in vacuum and crude oil was purified by Combiflash (PE-THF). Yield 45%
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]#[N:11])[CH:4]=1.[OH-].[K+].C(O)C.[C:25](#[N:29])/[CH:26]=[CH:27]/[CH3:28]>O1CCCC1>[CH3:28][CH:27]([CH2:26][C:25]#[N:29])[C:9]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)([C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:8]=[CH:7][CH:6]=1)[C:10]#[N:11]
Reactant: N#CC(c1cccc(C(F)(F)F)c1)N1CCOCC1
Reactant: C/C=C/C#N
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CC#N)C(C#N)(c1cccc(C(F)(F)F)c1)N1CCOCC1

Procedure:
To a solution of α-(α,α,α-trifluoro-m-tolyl)-4-morpholineacetonitrile in 100 ml. of tetrahydrofuran is added 1.0 ml. of 30% KOH-ethanol solution. To the mixture is added 2.56 g. of crotononitrile and the mixture is stirred at room temperature for 18 hrs. The mixture is concentrated to dryness under vacuum and the residue is dissolved in chloroform. The solution is passed through a column of hydrous magnesium silicate. The eluent is concentrated to an oil (17.3 g) which is crystallized from hexane and recrystallized from CHCL3 -hexane to give 3-methyl-2-morpholino-2-(α,α,α-trifluoro-m-tolyl)glutaronitrile as crystals, m.p. 115°-118° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:43]C1C=CC(C2C=NC(C3CCNCC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:43])=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Clc1ccc(-c2cnc(C3CCNCC3)nc2)cc1
Agent: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 100 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 5-(4-chlorophenyl)-2-piperidin-4-ylpyrimidine (0.123 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)-oxazolidin-2-one (0.269 g), to yield the title compound as a cream foam (0.275 g, 100%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:13]=[C:14]([CH2:17]OC(=O)C(C)(C)C)[S:15][CH:16]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.Cl.C(N1CCNCC1)(C)C.O[N:37]1[C:41]2C=[CH:43][CH:44]=[CH:45][C:40]=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[N:13]=[C:14]([CH2:17][N:37]3[CH2:43][CH2:44][CH2:45][CH2:40][CH2:41]3)[S:15][CH:16]=2)=[O:11])[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)N1CCN(C(=O)c2csc(COC(=O)C(C)(C)C)n2)CC1
Agent: CC(C)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2csc(CN3CCCCC3)n2)CC1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
2,2-Dimethyl-Propionic acid 4-(4-isopropyl-piperazine-1-carbonyl)-thiazol-2-ylmethyl ester. The crude product from Step A (6.42 g, 24.2 mmol), 1-isopropyl-piperazine dihydrochloride (5.36 g., 26.68 mmol) and 1-hydroxybenzotriazole (4.915 g., 36.38 mmol) were dissolved into a mixture of N-methylmorpholine (14.72 g., 101.20 mmol) and DCM (120 mL). The mixture was stirred for 30 min under nitrogen. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.97 g, 36.4 mmol) was added, and the reaction mixture was stirred for 18 h at rt. The reaction was quenched by the addition of 1 M NaOH (25 mL), and was stirred for 1 h. The mixture was diluted with water and extracted with DCM (3×60 mL). The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated to yield dark brown crude oil (6.2 g). The crude product was purified on silica gel column using 30-50% acetone-DCM to give the title compound as a brown oil (3.9 g, 46%). 1H NMR (500 MHz, CDCl3): 7.89 (s, 1H), 5.38 (s, 2H), 3.90-3.84 (m, 2H), 3.81-3.75 (m, 2H), 2.75-2.69 (m, 1H), 2.62-2.50 (m, 4H), 1.27-1.23 (s, 9H), 1.05 (d, J=6.3, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)c(OC)cc2CC1
Yield: 54.2 %

Procedure:
Following a procedure analogous to Example 113, 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (45 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (50 mgs) were combined to give the title compound (46 mgs) as a white foam. 1H-NMR (CDCl3): δ 10.16 (s, 1H), 8.54 (d, J=8.3 Hz, 1H), 8.06 (s, 2H), 7.85 (d, J=15.2 Hz, 2H), 7.47 (s, 1H), 7.41-7.35 (m, 2H), 7.21-7.18 (m, 1H), 6.65 (s, 1H), 6.53 (s, 1H), 3.87 (s, 3H), 3.60-3.57 (m, 2H), 3.40 (s, 3H), 2.91-2.80 (m, 10H). LC/MS: found (M+H)+=520.16; MP: 42-50° C.
Reaction SMILES: [C:1](=[O:13])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2][CH:3](Cl)[CH3:4].[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O-:27])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15].[K+].[I-].[K+]>CN(C=O)C>[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O:27][CH:3]([O:2][C:1]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:13])[CH3:4])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15]
Reactant: CC(Cl)OC(=O)Oc1ccccc1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(=O)Oc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 96 h

Procedure:
1-Chloroethyl phenyl carbonate (prepared according to Synthesis 1986, 627) (2.21 g, 11 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 10 mmol) and potassium iodide (0.17 g, 1 mmol) in dry DMF. After stirring at 50° C. for 6 hours and at room temperature for 4 days the solvent was removed at reduced pressure. The residue was suspended in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 7.3 g. Purity by HPLC: 98%. 1H-NMR (DMSO-d6): delta=1.68 (N(CH3)COCH3); 1.74 (CHCH3); 2.05 (NCOCH3); 2.97 (NCH3); 7.05 (CH); 7.25-7.52 (arom.); 10.14 ppm (NH).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:31])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[O:23]CC2C=CC=CC=2)=[O:13])[C:8]([O:32][CH3:33])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:31])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[OH:23])=[O:13])[C:8]([O:32][CH3:33])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cnc(C(C)(C)C)cc1NC(=O)c1cc2cccc(OCc3ccccc3)c2n1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cnc(C(C)(C)C)cc1NC(=O)c1cc2cccc(O)c2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.3 %

Procedure:
Pd(OH)2 (20% on C, 24 mg) was added to a solution of the above indole (231 mg, 0.52 mmol) in ethanol/ethyl acetate (3:2, 5.0 mL) at room temperature. The solution was placed under a hydrogen atmosphere (1 atm) and stirred at room temperature for 18 h. The mixture was filtered through diatomaceous earth and concentrated in vacuo to provide 7-hydroxy-1-methyl-1H-indole-2-carboxylic acid (2-tert-butyl-5-methoxy-pyridin-4-yl)-amide (199 mg, 99%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][C:13]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[ClH:43]>O>[ClH:43].[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][C:13]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Solvent: O
Product: COc1ccc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Yield: 87 %

Procedure:
N-(6-Methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-amine (94.5 mg, 0.161 mmol) was suspended in a mixture of 2 M aqueous HCl (2.0 mL) and water (6 mL). The mixture was heated at reflux for 1 h and then allowed to cool and stand at room temperature over the weekend. The resulting solid was collected by filtration, washed with water, and dried to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-amine hydrochloride (75.7 mg, 0.141 mmol, 87% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.50 (br. s., 1H); 9.66 (br. s., 1H); 8.60 (s, 1H); 8.52 (d, J=2.54 Hz, 1H); 8.26 (d, J=1.96 Hz, 1H); 8.16 (dd, J=8.80, 2.74 Hz, 1H); 7.87 (d, J=8.22 Hz, 2H); 7.57 (d, J=8.22 Hz, 2H); 6.85 (d, J=8.80 Hz, 1H); 4.13 (s, 2H); 3.85 (s, 3H); 3.17 (s, 3H); 2.84 (s, 3H). m/z (ESI, +ve ion) 502.0 (M+H)+.