Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:21](=[O:24])[CH2:22][CH3:23])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Reactant: CCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (3 ml) was suspended 60% sodium hydride (20 mg). The compound 1 (124 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, propionyl chloride (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-propionylquinoline (compound 3, 21 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:28])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O:35][C:36]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][CH:47]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:19]=2[N:18]([CH2:52][C:49]2[CH:48]=[CH:47][C:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH2:39][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:51][CH:50]=2)[C:17]1=[O:28])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc(F)ccc2NC1=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3cc(F)ccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]propanamide (Step E) and 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 35, Step G) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CDCl3): δ 1.39 (s, 9H), 1.48 (s, 3H), 1.51 (s, 3H), 1.78 (m, 1H), 2.35-2.70 (m, 3H), 4.18 (d, 7 Hz, 2H), 4.42 (m, 1H), 4.58 (m, 1H), 4.75 (d, 16 Hz, 1H), 5.05 (s, 2H), 5.27 (d, 16 Hz, 1H), 5.35 (s, 1H), 6.88 (dd; 8, 6 Hz; 1H), 6.98 (m, 1H), 7.09 (d, 6 Hz,1H), 7.14-7.35 (m, 13H), 7.40 (d, 8 HZ, 1H). FAB-MS: calculated for C41H45FN4O6 708; found 709 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]([NH2:11])=O)=[N:2]1.[Cl-].[Na+].P(Cl)(Cl)(Cl)=O>C(#N)C>[NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]#[N:11])=[N:2]1
Reactant: NC(=O)c1n[nH]c2c1CCC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1n[nH]c2c1CCC2
Temperature: 80 °C

Procedure:
1,4,5,6-Tetrahydro-cyclopentapyrazole-3-carboxylic acid amide (0.210 g, 1.39 mmol) was added to anhydrous acetonitrile (12 cm3), heated to 80° C. and sodium chloride (2.0 g, 34-mmol) added. After 15 minutes phosphorus oxychloride (0.128 g, 0.83 mmol) was added and the solution heated to 80° C. overnight, cooled, filtered, and the collected solid washed with acetonitrile. Solvent was removed from the combined solutions under reduced pressure and the resulting solid purified by preparative HPLC to give 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carbonitrile as a deep purple coloured solid (0.031 g, 0.23 mmol, 17%). δH (CD3OD): 2.79 (t like, 2H, J=7.3), 2.73 (t like, 2H, J=7.1), 2.65-2.55 (m, 2H); m/z (ES+): 134 [M+H]+.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[CH3:32][C:33]1[N:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[O:39][C:36]2[CH:37]=[N:38][C:33]([CH3:32])=[CH:34][CH:35]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(O)cn1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2nc3c(c(=O)n(CCCOC4CCCCO4)c(=O)n3C)n2Cc2ccc(Cl)cc2)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.195 mmol, intermediate 14) in DMF (5 mL) was added 6-methylpyridin-3-ol (24 mg, 0.22 mmol) followed by potassium carbonate (76 mg, 0.55 mmol) and the mixture was stirred at 85° C. for 3 h. The mixture was cooled and partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed with saturated aqueous ammonium chloride, dried and concentrated to give 7-(4-chlorobenzyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (79 mg, 75% yield) as yellow solid. LCMS retention time 2.297 min; LCMS MH+-THP 456.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[NH:17][C:16]([C@@H:18]2[CH2:23][C@@H:22]3[C@@H:20]([CH2:21]3)[N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:15][CH:14]=1)(C)C>CO>[C:12]([C:13]1[NH:17][C:16]([C@@H:18]2[CH2:23][C@@H:22]3[C@@H:20]([CH2:21]3)[N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:15][CH:14]=1)#[CH:11]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc([C@@H]2C[C@H]3C[C@H]3N2C(=O)OC(C)(C)C)[nH]1
Temperature: 50 °C
Yield: 97.3 %

Procedure:
Potassium carbonate (194 mg, 1.40 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (970 mg, 2.81 mmol) in MeOH (30 mL) and the reaction was stirred under nitrogen and then heated at 50° C. (bath temp) for 4 h. The reaction was concentrated to ˜5 mL of volume, diluted with DCM (˜40 mL) and washed with ½ sat brine (˜20 mL). The organics were dried (MgSO4) filtered and concentrated to a tan solid. This material was purified by BIOTAGE® Horizon (40 g SiO2, loaded with DCM, 35-45% EtOAc/hexanes) to yield (1R,3S,5R)-tert-butyl 3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (747 mg) as a light yellow solid. LC-MS retention time 2.866 min; m/z 272.12 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 7.18 (br. s., 1H), 4.59 (br. s., 1H), 3.36-3.64 (m, 2H), 2.46 (dd, J=13.2, 8.9 Hz, 1H), 2.18-2.31 (m, 1H), 1.64-1.74 (m, 1H), 1.18-1.45 (m, 9H), 0.83 (dt, J=8.5, 5.8 Hz, 1H), 0.56 (br. s., 1H).
Reaction SMILES: C(OC(=O)[NH:7][O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(C)(C)C.O1CCOCC1.[ClH:24]>CO>[ClH:24].[ClH:24].[N:11]1([CH2:10][CH2:9][O:8][NH2:7])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NOCCN1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NOCCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a solution of (2-morpholin-4-yl-ethoxy)-carbamic acid tert-butyl ester (118 mg, 0.48 mmol) in MeOH (1 mL) is added 4 M dioxane solution of HCl (2.4 mL, 9.60 mmol) at room temperature. The resulting solution is stirred for 16 hours at room temperature. After addition of additional HCl (2.4 mL) followed by stirring for 4 hours, the reaction mixture is concentrated in vacuo to give yellow solids (82 mg, 78%).
Reaction SMILES: Cl.Cl.[CH:3]1([NH2+:9][C:10]2[C:14]3([CH2:19][CH2:18][NH2+:17][CH2:16][CH2:15]3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[Br:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O.C(Cl)Cl>ClCCCl>[Br:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][N:17]1[CH2:16][CH2:15][C:14]2([N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:12](=[O:27])[N:11]=[C:10]2[NH:9][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:19][CH2:18]1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C1N=C([NH2+]C2CCCCC2)C2(CC[NH2+]CC2)N1c1cccc(F)c1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1N=C(NC2CCCCC2)C2(CCN(Cc3cccc(Br)c3)CC2)N1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 600 mg (1.44 mmol) 4-(cyclohexylammonio)-1-(3-fluorophenyl)-2-oxo-1,3-diaza-8-azoniaspiro[4.5]dec-3-ene dihydrochloride, 376 μL (2.16 mmol) diisopropylethylamine, and 427 mg (2.01 mmol) triacetoxy sodium borohydride in 20 mL DCE was added dropwise a 4 mL DCE solution of 251 μL (2.16 mmol) 3-bromobenzaldehyde and the resulting heterogeneous mixture was stirred at rt overnight under a nitrogen atmosphere. The reaction mixture was treated with 50 mL CH2Cl2 and washed with 20 mL saturated NaHCO3 (aq), 20 mL brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by automated flash chromatography (0-5% MeOH in CH2Cl2 over 25 m) afforded the product as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.75 (d, J=8.15 Hz, 1H), 7.45 (m, 2H), 7.36 (m, 1H), 7.22 (m, 1H), 7.15 (d, J=7.69 Hz, 1H), 7.02 (m, 3H), 3.97 (m, 1H), 3.50 (s, 2H), 2.76 (m, 2H), 2.43 (m, 2H), 2.09 (m, 4H), 1.95 (m, 2H), 1.75 (m, 2H), 1.68 (m, 1H), 1.41 (m, 2H), 1.23 (m, 3H). High resolution mass spec (FT/ICR): calc M+H=513.1660. found 513.1697
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]=1[CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+].Cl>CO>[CH2:18]([C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:16][CH3:17])=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1c(/C=C/C(=O)OC)ccc2cc(OC)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1c(/C=C/C(=O)O)ccc2cc(OC)ccc12
Yield: 98.8 %

Procedure:
A solution of (E)-3-(1-butyl-6-methoxy-2-naphthalenyl)-2-propenoic acid methyl ester (1.7 g) in methanol (10 mL) was treated with 2N sodium hydroxide (4.5 mL) and the mixture was stirred at reflux for 1 hour. The warm reaction mixture was acidified by the addition of 1N hydrochloric acid (9.2 mL). After the mixture cooled, the resulting solid was filtered off to provide 1.6 g of (E)-3-(1-butyl-6-methoxy-2-naphthalenyl)-2-propenoic acid. Crystallization of a portion from methanol gave the analytical specimen, mp 163°-164° C. Anal. Calcd for C18H20O3 : C, 76.03; H, 7.09 Found: C, 76.31; H, 7.32
Reaction SMILES: C(NC)(C)C.C([Li])CCC.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[CH2:24][CH2:23][CH2:22]2.Cl>O1CCCC1>[OH:29][C:25]1([CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13])[C:26]2[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:28][CH:27]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CCOC(C)=O
Agent: CNC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCc2cc(OC)ccc21
Yield: 90.8 %

Procedure:
A solution of 1.41 g (19 mmoles) of isopropylmethylamine in 10 ml of tetrahydrofuran was cooled to -78°, and 6.6 ml 1.1 equiv~1.67 M (11 mmoles) of n-butyllithium was added dropwise. After fifteen minutes at -78°, a solution of 0.88 g (10 mmoles) of ethyl acetate in 3 ml of tetrahydrofuran was added dropwise. After stirring for ten minutes at -78° a solution of 1.76 g (10 mmoles) of 6-methoxy-1-tetralone in 5 ml of tetrahydrofuran was added. After ten minutes the mixture was acidified with 10% hydrochloric acid and concentrated to dryness. The residue was extracted into diethyl ether, and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude material was chromatographed on silica gel to give 2.4 g of the title compound as an oil. Structure assignment was confirmed by the proton nmr spectrum.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:26]=[CH:25][C:20]2[S:21][CH:22]=[C:23]([CH3:24])[C:19]=2[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:26]=[CH:25][C:20]4[S:21][CH:22]=[C:23]([CH3:24])[C:19]=4[CH:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Cc1csc2ccc(Br)cc12
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1csc2ccc(N3CCN(c4cnccc4C4CC4)C3=O)cc12
Yield: 58.2 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 5-bromo-3-methylbenzo[b]thiophene (122.4 mg, 0.541 mmol), 1,4-dioxane (5 mL), copper iodide (9.3 mg, 0.049 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (5.6 mg, 0.049 mmol) and potassium phosphate (313 mg, 1.477 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 100 mg of the product (58% yield).
Reaction SMILES: [C:1]1([C:25]#[C:26][CH2:27][CH2:28][CH2:29][OH:30])[CH:6]=[C:5]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12])[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:3][C:2]=1[C:19]#[C:20][CH2:21][CH2:22][CH2:23][OH:24]>CO.[Pd]>[C:5]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[C:1]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[C:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:3][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: OCCCC#Cc1cc(C#CCCCO)c(C#CCCCO)cc1C#CCCCO
Agent: [Pd]
Solvent: CO
Product: OCCCCCc1cc(CCCCCO)c(CCCCCO)cc1CCCCCO
Reaction time: 4 h
Yield: 94.2 %

Procedure:
5,5′,5″,5′″-(1,2,4,5-benzentetrayl)tetrakis-4-pentyn-1-ol (2.01 g, 4.95 mmol) was dissolved in methanol (30 mL) and 10% Pd/C (5% w/w) was added. The resulting mixture was hydrogenated on a Parr hydrogenation apparatus (45 psig) for 4 hrs. The catalyst was removed by filtration through a Celite pad. The filter cake was rinsed with methanol, and the combined organic liquors were concentrated under reduced pressure. The crude product was purified by column chromatography (CHCl3:MeOH, 10:1) to afford 1.97 g of the title compound. Yield: 95%. 1H NMR (300 MHz, CDCl3) δ 6.81 (s, 3H), 3.62 (t, J=6.3 Hz, 6H), 2.57 (t, J=7.5 Hz, 6H), 1.53-1.70 (m, 12H), 1.38 (m, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ 142.5, 126.1, 63.1, 36.1, 32.9, 31.5, 25.7 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:19])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O-:23])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([CH:20]=[O:23])[CH:7]=3)[CH:7]=[CH:6][CH:5]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(Nc2cccc(Br)c2)c2ccccc2n1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(Nc2cccc(-c3cccc(C=O)c3)c2)c2ccccc2n1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To a suspension of 71 (294 mg, 0.94 mmol) in toluene (9.6 mL) under N2 were sequentially added saturated NaHCO3 (aq. 3.8 mL), a solution of 72 (199 mg, 1.33 mmol) in EtOH (6.7 mL), and PdCl2(Ph3P)3 (32 mg, 0.046 mmol). The reaction was heated at 80° C. for 21 hours before it was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate (40 mL) and washed with water (15 mL), brine (15 mL). The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 73 as a yellow solid (219 mg, 68.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([C:35]2[S:36][C:37]([NH:43]C(OC(C)(C)C)=O)=[C:38]([C:40](O)=[O:41])[N:39]=2)[CH2:30]1)=O)(C)(C)C>>[NH2:43][C:37]1[S:36][C:35]([CH:31]2[CH2:32][CH2:33][CH2:34][NH:29][CH2:30]2)=[N:39][C:38]=1[C:40]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH2:14])[CH2:9]1)=[O:41]
Reactant: CC(C)(C)OC(=O)Nc1sc(C2CCCN(C(=O)OC(C)(C)C)C2)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2N)C1
Product: Nc1sc(C2CCCNC2)nc1C(=O)Nc1cnccc1N1CCCC(N)C1
Yield: 51 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate and 2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid. Obtained the desired product as a white solid (6.4 mg, 51%). 1H NMR (500 MHz, DMSO) δ 9.38 (s, 1H), 8.37 (s, 1H), 8.19 (d, J=5.1 Hz, 1H), 7.28 (s, 2H), 7.11 (d, J=5.1 Hz, 1H), 3.14 (dd, J=28.4, 11.4 Hz, 2H), 2.94 (dd, J=51.3, 24.0 Hz, 4H), 2.65 (dd, J=27.1, 13.0 Hz, 2H), 2.50-2.40 (m, 1H), 2.05 (s, 1H), 1.97-1.56 (m, 5H), 1.47 (d, J=11.2 Hz, 1H), 1.24 (d, J=8.3 Hz, 2H). ESIMS m/z=402.1 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[C:22]([NH:24][C:25](NC2C=C(C)N=C(C)C=2)=[O:26])[CH:21]=[C:20]([CH3:36])[N:19]=1>O1CCOCC1>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:25]([NH:24][C:22]2[CH:23]=[C:18]([CH3:17])[N:19]=[C:20]([CH3:36])[CH:21]=2)=[O:26])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(=O)Nc2cc(C)nc(C)c2)cc(C)n1
Reactant: NCCN1CCC(Cc2ccccc2)CC1
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)NCCN2CCC(Cc3ccccc3)CC2)cc(C)n1

Procedure:
A suspension of 2-(4-benzylpiperidino)-1-ethanamine (Example B1, 54.6 mg, 0.25 mmol), TEA (35 μL, 0.25 mmol) and 1,3-bis-(2,6-dimethyl-pyridin-4-yl)-urea (Example B1, 67.6 mg 0.25 mmol) in dioxane (2 mL) is heated at reflux for 24 h. The solvent is evaporated and the residue purified by HPLC to provide the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])(=[O:9])[CH:6]([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[C:5]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([Cl:3])=[O:14])(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(=O)c1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)C(=O)c1cccc(C(=O)Cl)c1

Procedure:
100 ml of toluene and 5 g of thionyl chloride were added to the crude product of m-isobutyrylbenzoic acid obtained in the above step (1), and the mixture was reacted under refluxing for 1 hour. After completion of the reaction, excess thionyl chloride was distilled off to obtain a toluene solution of crude m-isobutyrylbenzoic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].Cl[CH2:11][CH2:12][OH:13].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][CH2:11][CH2:12][OH:13]
Reactant: NCc1cccc(F)c1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCNCc1cccc(F)c1

Procedure:
Combine 3-fluorobenzylamine (31.1 g, 0.248 mol), 2-chloroethanol (10 g, 0.124 mol) and water (30 g, 1.66 mol) and heat on a steam-bath for ˜5 hours. Add sodium hydroxide (15 g, 0.373 mol) to the cooled solution and heat the resulting mixture on a steam-bath for ˜30 minutes. Add water (˜50 mL) to dissolve the inorganic salts and extract the two-phase mixture twice with 25 mL and 13 mL portions of benzene. Combine the extracts and remove the water by co-distillation with benzene through a modified Claisen flask. The final desired compound may be purified with further distillation.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C@:16]12[CH2:33][CH2:32][C@H:31]3[C@@H:21]([CH2:22][CH2:23][C:24]4[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:34])[CH:25]=4)[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[C:35](O)=[O:36].C(N(CC)CC)C.C1(S(Cl)(=O)=O)C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:35]([C@H:17]2[CH2:18][CH2:19][C@H:20]3[C@H:21]4[C@H:31]([CH2:32][CH2:33][C@:16]23[CH3:15])[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]2)[CH2:23][CH2:22]4)=[O:36])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
0.108 ml of benzhydrylamine was added to a solution of 100 mg of androsta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of 4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml of methylene chloride. 0.060 ml of benzenesulfonyl chloride was divided into three portions and added to this reaction mixture at intervals of 30 minutes at room temperature, whilst stirring. One hour after finishing the addition of benzenesulfonyl chloride, the reaction mixture was diluted with methylene chloride, washed with 1N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was crystallized from acetone to give 130.1 mg (yield 85%) of the title compound, having the same properties as the product of Preparation 17.