Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH2:2]([N+:4]1(C)[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH3:3].[CH2:12]([O:14][C@H:15]1[CH2:20]C[C@H](N)[CH2:17][CH2:16]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH2:12]([O:14][C@H:15]1[CH2:20][CH2:3][C@H:2]([N:4]2[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]2)[CH2:17][CH2:16]1)[CH3:13]
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: CCO[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCO[C@H]1CC[C@H](N2CCC(=O)CC2)CC1
Temperature: 80 °C

Procedure:
A mixture of 1-ethyl-4-piperidone methiodide (D9, 27 g), trans-4-ethoxycyclohexylamine (D65, 8.16 g, 0.065 mol), potassium carbonate (13.5 g), water (100 mL), and ethanol (200 mL) was heated for 3 hours at 80° C., then cooled overnight. The mixture was partitioned with aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was separated, washed with brine and solvent removed to give the title compound as an amber coloured oil (13.2 g).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][CH2:11][C:12]1([CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17](OC)=[O:18])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO>O1CCCC1>[CH2:3]([O:10][CH2:11][C:12]1([CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][OH:18])[CH2:13][CH2:14]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](CC1(COCc2ccccc2)CC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1(COCc2ccccc2)CC1

Procedure:
4.3 g of lithium borohydride are added in portions to a solution of 30.9 g of 1-benzyloxymethyl-1-[2(S)-tert-butoxycarbonylamino-2-methoxycarbonyleth-1-yl]cyclopropane in 300 ml of tetrahydrofuran, while stirring. The mixture is stirred at room temperature for a further 2 h, 500 ml of methanol are then slowly added dropwise, the mixture is concentrated almost to dryness and the residue is taken up in methylene chloride. The organic phase is washed with 1N hydrochloric acid. Further customary working up gives the pure title compound: Rf (B)=0.50.
Reaction SMILES: [CH2:1]([C:4]1([C:13]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[O:17])([CH3:15])[CH3:14])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH:2]=[CH2:3].[H][H]>[Pd].C(O)C>[CH2:1]([C:4]1([C:13]([C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[O:17])([CH3:15])[CH3:14])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCC1(C(C)(C)C(=O)Oc2ccc(N)cc2)C(=O)NC(=O)NC1=O
Agent: [Pd]
Solvent: CCO
Product: CCCC1(C(C)(C)C(=O)Oc2ccc(N)cc2)C(=O)NC(=O)NC1=O
Reaction time: 1 h

Procedure:
A solution of 750 g. of 5-allyl-5-(p-aminophenyloxycarbonyl-isopropyl)barbituric acid in 15 ml. of ethanol containing 100 mg. of 10% palladium-on-carbon as catalyst was subjected to hydrogenation at room temperature and atmospheric pressure. After one hour, the required amount (180 ml.) of hydrogen had been taken up. The reaction mixture was filtered through Celite, and the filtrate was evaporated to dryness. The residue was chromatographed on 13 g. of silica gel with ethyl acetate as the eluent. Fractions containing the desired product were evaporated. The remaining solid was recrystallized from chloroform/ether to afford 620 mg. (89%) of the ester, m.p. 212°-215°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:13]3[N:22]=[CH:21][C:20]4[N:19]([CH3:23])[C:18](=[O:24])[C@:17]5([CH2:28][CH3:29])[CH2:25][CH2:26][CH2:27][N:16]5[C:15]=4[N:14]=3)[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([C@@:17]12[CH2:25][CH2:26][CH2:27][N:16]1[C:15]1[N:14]=[C:13]([N:9]3[CH:10]=[CH:11][N:12]=[C:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)[CH:3]=3)[N:22]=[CH:21][C:20]=1[N:19]([CH3:23])[C:18]2=[O:24])[CH3:29]
Reactant: OB(O)c1cccnc1
Reactant: CC[C@@]12CCCN1c1nc(-n3ccnc3-c3cccc(Br)c3)ncc1N(C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CC[C@@]12CCCN1c1nc(-n3ccnc3-c3cccc(-c4cccnc4)c3)ncc1N(C)C2=O
Yield: 37.5 %

Procedure:
(S)-2-(2-(3-bromophenyl)-1H-imidazol-1-yl)-6a-ethyl-5-methyl-6a,7,8,9-tetrahydropyrrolo[2,1-h]pteridin-6(5H)-one (Example 252, 0.118 mmol, 0.053 g) was added to a solution of 3-pyridyl boronic acid (0.593 mmol, 0.072 g), Na2CO3 (0.593 mmol, 0.063 g), and Pd(PPh3)4 (0.029 mmol, 0.034 g) in 1 mL of DME and 0.5 mL of H2O. The reaction mixture was microwaved for 40 minutes at 135° C. The reaction mixture was diluted with 15 mL of DCM, washed with 5 mL of H2O, dried with Na2SO4, filtered and concentrated. The resulting residue was purified by reverse phase HPLC to give the title compound as a white solid (0.020 g, 38%); 1H NMR (400 MHz, CDCl3) δ: 9.18 (s, 1H), 8.77 (m, 1H), 8.70 (m, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.87 (m, 1H), 7.82 (m, 1H), 7.73 (s, 1H), 7.56 (m, 3H), 3.38 (m, 3H), 3.29 (m, 1H), 2.24 (m, 2H), 2.00 (m, 2H), 1.77 (m, 1H), 1.62 (m, 1H), 0.78 (t, J=7.4 Hz, 3H); LCMS: 452.3 m/z (M+H)+; ret. Time: 3.758 min (Analytical Method C).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[NH2:31])[CH2:20][CH:19]2[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].C(=O)([O-])[O-].[Na+].[Na+].[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[NH:31][C:42](=[O:43])[CH2:41][O:40][CH3:39])[CH2:20][CH:19]2[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Reactant: COCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
The solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol (1.0 g, 2.24 mmol) obtained in Step 2 in 30 ml of tetrahydrofuran was cooled to 0° C. Sodium carbonate (350 mg, 3.36 mmol) and methoxyacetyl chloride (0.53 mg, 5.82 mmol) was added to the reaction mixture, which was then stirred for 4 hours. 20 ml of ice water was added to the reaction mixture, which was then concentrated and extracted with 50 ml of ethyl acetate. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was crystallized with ethyl acetate to give 1.1 g of the titled compound.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:28]=[C:27]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[C:26]([Cl:39])=[C:25]3[C:20]=2[CH2:21][CH2:22][CH2:23][O:24]3)[O:7][C@@H:6]1[CH2:40][O:41]C(=O)C)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Cl:39][C:26]1[C:27]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][CH:35]=2)=[CH:28][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:40][OH:41])[O:7]2)=[C:20]2[C:25]=1[O:24][CH2:23][CH2:22][CH2:21]2
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(C4CC4)cc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H]1O[C@@H](c2cc(Cc3ccc(C4CC4)cc3)c(Cl)c3c2CCCO3)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a suspension of acetate 180 (152 mg, 0.24 mmol) in MeOH (5 mL) was added NaOMe (25 wt % in MeOH, 0.05 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (reverse phase) to provide the compound E155 (37 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10].I[CH2:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCOCC1>[CH3:1][O:2][C:3](=[O:50])[CH2:4][N:5]([CH2:52][CH2:53][CH3:54])[CH2:6][CH2:7][NH:8][C:9]([C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CCC)CC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 66.9 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-methoxy-2-oxoethylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (28 mg, 0.041 mmol), 1-iodopropane (55.4 mg, 0.326 mmol) and potassium carbonate (11.27 mg, 0.082 mmol) in acetonitrile (2 mL) and dioxane (2.000 mL) was heated up for 8 hours. LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a white solid (20 mg, 67%). LCMS: m/e 729.47 (M+H)+, 2.96 min (method 1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[F:22])=[CH:10][C:9]=1[NH2:23])(C)(C)C.CC1(C)O[C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=[O:40])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:30]([C:32]3[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=3)[C:35]#[N:36])[CH2:29][C:28](=[O:40])[NH:23][C:9]=2[CH:10]=1
Reactant: COc1cccc(F)c1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(F)c1-c1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
Prepared from (3-amino-2′-fluoro-6′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G44) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a white solid (47 mg).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH2:5]([C:12]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][NH:18][CH:19]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[CH2:5]([C:12]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:2][C:3]#[N:4])[CH:19]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CCBr
Reactant: COc1ccc(C(NCCCOc2ccc(Cl)cc2Cc2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(C(c2ccc(OC)cc2)N(CC#N)CCCOc2ccc(Cl)cc2Cc2ccccc2)cc1
Temperature: 90 °C
Yield: 96.7 %

Procedure:
Bromoacetonitrile (0.575 mL, 8.25 mmol) is added to a stirred solution of [3-(2-benzyl-4-chloro-phenoxy)-propyl]-[bis-(4-methoxy-phenyl)-methyl]-amine (2.76 g, 5.50 mmol) and diisopropylethylamine (1.44 mL, 8.25 mmol) in anhydrous 1,4-dioxane (20 mL) at ambient temperature under nitrogen. The mixture is heated at 90° C. for 4 hours. At ambient temperature, EtOAc (100 mL) and half-saturated aqueous NaHCO3 solution (100 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 5-16% EtOAc in hexane) to give 2.88 g (5.32 mmol, 97% yield) of the title compound as oil. ESIMS: m/z 541 [(M+H)+, 35Cl], 543 [(M+H)+, 37Cl]. Analysis for C33H33ClN2O3: calcd: C, 73.25; H, 6.15; N, 5.18; found: C, 73.05; H, 6.28; N, 5.02.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:16])[CH:4]([N+:13]([O-])=O)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>CO.[Ni]>[NH2:13][CH:4]([CH:3]([OH:16])[CH2:2][F:1])[CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)(C)OC(=O)CC(C(O)CF)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(N)C(O)CF
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.3 %

Procedure:
To a solution of t-butyl 5-fluoro-4-hydroxy-3-nitropentanoate (950 mg, 4.0 mmol) in MeOH (20 mL) was added Raney Ni (about 200 mg), the mixture was shaken under H2 (30-35 psi) at rt for 18 h. It was filtered and the catalyst was washed with MeOH (2×10 mL). The MeOH solution was evaporated and the residue was purified by chromatography over silica gel (EtOAc-MeOH, 10:1) to give 840 mg (96%) of the titled compound as a yellowish viscous oil. 1HNMR (CDCl3), 1.450 (s, 9H), 2.12 (bs, 3H, OH and NH2), 2.28-2.38 (m, 1H), 2.47-2.57 (m, 1H), 3.24-3.30 (m, 1H), 3.54-3.76 (m, 1H), 4.38-4.48 (m, 1H), 4.54-4.61 (m, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH:6]=[N:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)C.C([O-])C.[Na+].Cl>C(O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[C:4](=[O:3])[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:6][NH:7]1
Reactant: CCOC(=O)C(C=NNc1ccccn1)c1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1c(-c2cccnc2)c[nH]n1-c1ccccn1
Reaction time: 0.5 h

Procedure:
3.95 g (13.9 mmol) of the compound from Example 3A are initially introduced into 80 ml ethanol under argon and 945 mg (13.9 mmol) sodium ethanolate are added in portions at RT. After stirring for 30 min, 13.9 ml 1 M hydrochloric acid are added dropwise. The precipitate which has separated out is filtered off with suction, washed with cold ethanol (20 ml) and with water (twice with 20 ml each time) and dried in vacuo. 2.80 g (85% of th.) of the title compound are obtained.
Reaction SMILES: CN(C)[P:3](N(C)C)N(C)C.[NH:11]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[N:11]12[PH:3]34[N:18]([CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][CH2:24]1)[CH2:17][CH2:16][CH2:15][N:14]4[CH2:13][CH2:12]2
Reactant: C1CNCCNCCCNCCNC1
Reactant: CN(C)P(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: C1CN2CCN3CCCN4CCN(C1)[PH]234

Procedure:
A stirred mixture of 4.90 g (30 mmol) of hexamethylphosphorous triamide, 6.00 g (30 mmol) of 1,4,8,11-tetraazacyclotetradecane, and 30 ml of dry toluene is heated to 80°-90°, under nitrogen for 16 hr, then refluxed for 8 hr. The hot solution is filtered under N2 and concentrated, and the residue is sublimed at 60°-70° (0.3 mm) to give 5.45 g (80%) of waxy, white solid 1,4,8,11-tetraaza-15-phosphatetracyclo[6.6.1.04,15.011,15 ]pentadecane.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:12][Si:13]([C:16]#[C:17][Si](C)(C)C)([CH3:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:16]#[C:17][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)Cl
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCC(=O)C#C[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
To 500ml of CH2Cl2 was added 53ml (294 mmol) of nonanoyl chloride and 50g (293.4 mmol) of bis(trimethylsilyl) acetylene. The reaction mixture was cooled in an ice bath and 40g (300 mmol) of AlCl3 was added portionwise with stirring over 1/2 hour. After stirring for an additional hour, the reaction mixture was quenched with ice. Water was added to the reaction mixture and it was extracted 3x with 200ml aliquots of diethyl ether. The combined extracts were washed 2x with 50ml aliquots of saturated NaHCO3, 1 x with brine, and then dried (MgSO4). The solvent was removed in vacuo to give a brown oil which was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>CN1C(=O)CCC1>[CH:30]1([N:27]2[CH2:28][CH2:29][CH:24]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:10]4[C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=[C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:44](=[O:47])[CH2:45][CH3:46])[CH2:3]5)[N:9]=4)=[CH:23][CH:22]=3)[CH2:25][CH2:26]2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: NC(=O)c1ncc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCC(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C4CCN(C5CCCC5)CC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (436) (40 mg, 0.075 mmol) was dissolved in 3 mL NMP. To it were added DIEA (80 μL, 0.45 mmol) and then propionyl chloride (20 μL, 0.23 mmol). The mixture was stirred at RT for 30 min, quenched with 0.3 mL TFA, and directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and nest MeCN to isolate the title compound, (R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-propionamidopiperidin-1-yl)pyrazine-2-carboxamide (438), as HCl salt (23 mg). LC-MS (ESI): m/z (M+1) 520.6. UV: λ=267, 276, 305, 335, 372 nm. Proton NMR (CD3OD): δ 7.62 (1H, s), 7.59 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.19 (1H, m), 4.01 (1H, m), 3.91 (1H, m), 3.72 (2H, d, J=12.0 Hz), 3.55 (1H, m), 3.42 (1H, m), 3.38 (1H, m), 3.12 (2H, m), 2.86 (1H, m), 2.22-1.64 (18H, m), 1.12 (3H, t, J=7.5 Hz) ppm.
Reaction SMILES: C([O:5][C:6](=[O:28])[C:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])([C:15]1[S:19][N:18]=[C:17]([CH3:20])[N:16]=1)C(OC(C)(C)C)=O)(C)(C)C>FC(F)(F)C(O)=O>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:7]([C:15]1[S:19][N:18]=[C:17]([CH3:20])[N:16]=1)[C:6]([OH:28])=[O:5])#[N:27]
Reactant: Cc1nsc(C(CCCCCC#N)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nsc(C(CCCCCC#N)C(=O)O)n1

Procedure:
To stirred trifluoroacetic acid (20 mL) was added 2-(5-cyanopentyl)-2-(3-methyl[1,2,4]thiadiazol-5-yl)malonic acid di-tert-butyl ester (2021051) (0.75 g, 1.83 mmol) and the resultant mixture was stirred at room temperature for 1.5 h. The TFA was then removed under reduced pressure, while the temperature of the water bath was maintained below 25° C. The resultant oil was dissolved in dichloromethane (20 mL) and made basic with the careful addition of triethylamine, while keeping the reaction temperature below 20° C. The dichloromethane solution of 7-cyano-2-(3-methyl[1,2,4]thiadiazol-5-yl)heptanoic acid (2021052) was then immediately used in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[NH2:16][C:17]1N=C(C)C=[C:19](C)[CH:18]=1.CN(CCN(C)C)C.[Li]CCCC.BrCCCN1[Si](C)(C)CC[Si]1(C)C.[Cl-].[NH4+]>C(OCC)C.CCCCCC>[CH3:7][C:4]1[N:3]([C:8]2[N:9]=[C:10]([CH2:15][CH2:19][CH2:18][CH2:17][NH2:16])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: Cc1cc(C)nc(N)c1
Agent: CN(C)CCN(C)C
Agent: C[Si]1(C)CC[Si](C)(C)N1CCCBr
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(CCCCN)nc(-n2c(C)ccc2C)c1
Temperature: -20 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
1 g (5 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyridine (prepared from the 6-amino-2,4-lutidine according to J. Chem. Soc., Perkin Trans., 1984, 12, 2801) is dissolved, under an argon atmosphere, in 10 ml of anhydrous ethyl ether and 1.132 ml (7.5 mmol) of N,N,N,N-tetramethylethylenediamine (TMEDA). The reaction mixture is cooled down to −20° C. and 2.4 ml (6 mmol) of a 2.5 M solution of BuLi in hexane is added dropwise. After 5 hours at −20° C., the reaction mixture is cooled down to −45° C. and 1.68 g (6 mmol) of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane is added and the temperature is allowed to return to ambient temperature overnight. 50 ml of a saturated solution of ammonium chloride is added and the mixture is agitated for 2 hours at 25° C. The organic phase is decanted and washed successively with 40 ml of water and 40 ml of salt water, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue obtained is purified on a silica column (eluent=dichloromethane with 5% ethanol) in order to produce a yellow oil with a yield of 62%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[C:4]([F:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:13])[C:9]([NH:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)Cc1ccc(Br)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)C(Br)c1ccc(Br)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-N-methylacetamide (2.479 mmol) in carbon tetrachloride (5 mL) was degassed with a stream of nitrogen for five minutes, at which point the solution was treated with N-bromosuccinimide (2.73 mmol) and azobisisobutyronitrile (0.248 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred at 80° C. overnight. After stirring overnight, the reaction was cooled to room temperature. The reaction mixture was degassed again with a stream of nitrogen for three minutes and was treated with N-bromosuccinimide (0.56 mmol) and azobisisobutyronitrile (0.124 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred at 80° C. for two days. The reaction was then allowed to cool and was concentrated to dryness in vacuo. Purification of the residue by silica gel chromatography (0-50% ethyl acetate/hexanes) afforded the title compound as a white solid (296 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 2.65 (d, J=4.55 Hz, 3 H) 5.81 (s, 1 H) 7.49 (dd, J=8.59, 1.77 Hz, 1 H) 7.61 (dd, J=9.98, 1.89 Hz, 1 H) 7.72 (t, J=8.21 Hz, 1 H) 8.49 (br. s., 1 H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[CH:27]=[C:26]([NH:28]N)[CH:25]=[CH:24][N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:25]=[CH:24][N:23]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1ccnc(Cl)c1
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccnc(Cl)c1
Yield: 9 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2-chloro-4-hydrazinopyridine according to the method described for Example 1 in 9% yield. MS: M=350.1 (M+H)+