Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.CO.[NH3:26]>>[CH3:22][N:21]([CH3:23])[CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:12]2[C:11]3[C:10]4[CH2:9][CH2:8][CH2:7][C:6]=4[S:5][C:4]=3[N:3]=[C:2]([NH2:26])[N:13]=2)[CH2:16][CH2:17]1
Reactant: N
Reactant: CN(C)C1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Solvent: CO
Product: CN(C)C1CCC(Nc2nc(N)nc3sc4c(c23)CCC4)CC1
Temperature: 140 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A 20-mL sealed tube containing a solution of 4-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (80 mg, 0.23 mmol, 1.00 equiv) in 10 mL of saturated methanol-NH3 solution. The resulting solution was stirred overnight at 140° C. in an oil bath and concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 12 min); UV detection at 254 nm. This resulted 12-N-[4-(dimethylamino)cyclohexyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene-10,12-diamine (13 mg, 17%) was obtained as a brown solid. MS (ES, m/z) 332 [M+H]+; 1H NMR (300 MHz, CDCl3): δ 4.61 (s, 3H), 3.87-3.97 (m, 1H), 2.80-2.83 (m, 4H), 2.35-2.45 (m, 2H), 2.24 (s, 6H), 2.01-2.18 (m, 3H), 1.86 (s, 3H), 1.29-1.41 (dd, 2H), 1.14-1.18 (t, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([N:11]=[C:12]=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:14][C:15]1[NH:19][N:18]=[C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[N+:31]([O-:33])=[O:32])[CH:16]=1.Cl>CN(C=O)C>[C:7]([NH:11][C:12]([N:19]1[C:15]([CH3:14])=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[N+:31]([O-:33])=[O:32])=[N:18]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])nn1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.8 %

Procedure:
Potassium carbonate (0.83 g, 6.0 mmol) and tert-butyl isocyanate (0.59 g, 6.0 mmol) were added to a solution of 5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole (1.15 g, 4.0 mmol) in DMF (10 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of N-tert-butyl-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)-pyrazole-1-carboxamide (0.80 g, yield: 51.8%). mp: 104-106° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.41 (s, 9H), 2.61 (s, 3H), 5.82 (s, 1H), 6.65-6.90 (br s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.82 (dd, J=2.1 and 8.7 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][C@@H:16]([N:19]([CH3:21])[CH3:20])[C@@H:15]([F:22])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1>>[F:22][C@@H:15]1[C@H:16]([N:19]([CH3:21])[CH3:20])[CH2:17][CH2:18][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=[C:2]([N:31]2[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=[C:30]2[CH3:29])[N:10]=3)[CH2:14]1
Reactant: CN(C)[C@@H]1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)C[C@@H]1F
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@@H](N(C)C)[C@@H](F)C3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, (3S,4R)-1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-fluoro-N,N-dimethylpiperidin-4-amine and 2-methyl-1H-benzo[d]imidazole were reacted to give 181. LCMS m/z: 508.3 (MH+)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[C:21]([CH3:28])[C:19]=2[N:20]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:25]([C:23]3[CH:22]=[C:21]([CH3:28])[C:19]4[N:20]=[C:16]([C:3]5[CH:4]=[C:5]([C:8]6[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=6)[CH:6]=[CH:7][C:2]=5[OH:1])[NH:17][C:18]=4[CH:24]=3)=[O:27])=[CH:42][CH:43]=2)[CH2:32][CH2:31]1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3c(C)cc(C(=O)O)cc3[nH]2)c1
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccc(O)c(-c2nc3c(C)cc(C(=O)Nc4ccc(CCN5CCN(C)CC5)cc4)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of the crude of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-7-methyl-3H-benzoimidazole-5-carboxylic acid (estimated 0.4 mmol), 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine (88 mg, 0.4 mmol) and HATU (167 mg, 0.44 mmol) in DMF (5 mL) was added DIEA (0.5 mL, 371 mg, 2.87 mmol). The reaction mixture was stirred at room temperature for 2 h and heated at 60° C. for 15 h, and then evaporated to dry under reduced pressure. The residue was diluted with DMSO (1.5 mL), filtered and then purified with using HPLC (TFA/H2O/CH3CN) to afford the title compound (34.5 mg, 11% from two steps from 3,4-diamino-5-methyl-benzoic acid). 1H NMR (MeOH-d4) δ 2.77 (s, 3H), 2.90 (s, 3H), 2.97-3.43 (12H), 3.97 (s, 3H), 7.09 (m, 1H), 7.22 (d, J=9 Hz, 1H), 7.31 (d, J=9 Hz, 2H), 7.70 (d, J=9 Hz, 2H), 7.82-7.84 (2H), 7.91 (s, 1H), 8.17 (m, 1H), 8.20 (s, 1H), 8.31 (s, 1H). ESI-MS m/z 577.5 (MH+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[S:6][C:5]([N:7]3[CH2:15][CH:14]4[CH2:16][N:10]5[CH2:11][CH:12]([CH2:17][CH:8]3[CH2:9]5)[CH2:13]4)=[N:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)cc1

Procedure:
The title compound was prepared from the product of Example 105A and 4-fluorophenylboronic acid according to General Method C: LC-MS Method D (ESI+) m/z 330.0 (M+H)+, retention time 1.51 minutes.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1>C(O)(=O)C>[OH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: N#Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 79.1 %

Procedure:
A mixture of nitric acid (1.16 g, 12 mmol) and glacial acetic acid (1 mL) was heated to 40° C. To this mixture was added rapidly a solution of 4-hydroxybenzonitrile (1 g, 8.4 mmol) in glacial acetic acid (4 mL) until the flask temperature rose to 50° C. Then the solution was added at a rate such that the temperature was maintained at 50-60° C. When addition was complete the mixture was stirred for another 20 min at 55° C., and then poured into ice-water (24 mL). The mixture was filtered and the solid was washed with water to give 4-hydroxy-3-nitrobenzonitrile 1.09 g (79%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].C(O)(=O)[CH:11]([CH2:13][C:14](O)=O)[OH:12]>S(=O)(=O)(O)O>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]2[C:7]([CH:14]=[CH:13][C:11](=[O:12])[O:9]2)=[CH:6][CH:5]=1
Reactant: Cc1c(O)cccc1O
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(O)ccc2ccc(=O)oc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 20.64 %

Procedure:
2-methyl resorcinol (0.161 mmol, 20.024 g) and malic acid (0.165 mmol, 22.129 g) were dissolved in concentrated sulfuric acid. The reaction mixture was stirred at 80° C. for 24 h. The resulting solution was then poured over crushed ice, and the precipitate was collected by vacuum filtration. The precipitate was then washed with 5% NaHCO3 and again collected by vacuum filtration yielding an orange-yellow solid in a 20.64% yield.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:43][C@@H:42]2[C@:29]([CH3:46])([CH2:30][CH:31]=[C:32]3[C@H:41]2[CH2:40][CH2:39][C:38]2[C@:33]3([CH3:45])[CH:34]=[CH:35][C:36](=[O:44])[CH:37]=2)[C@H:3]1[C:4](=[O:28])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=C(N3CCCC3)N=[C:14]([N:23]3[CH2:27][CH2:26]CC3)[N:13]=2)[CH2:8][CH2:7]1.CS(O)(=O)=O.[CH3:52][C@@H:53]1C[C@@H]2[C@](C)(CC=C3[C@H]2CCC2[C@]3(C)C=CC(=O)C=2)[C@H]1C(=O)CN1CCN(C2C=C(N3CCCC3)N=C(N3CCCC3)N=2)CC1.CS(O)(=O)=O.CS(O)(=O)=O.C[C@@H]1C[C@@H]2[C@](C)(CC=C3[C@H]2CCC2[C@]3(C)C=CC(=O)C=2)[C@H]1C(=O)CN1CCN(C2C=C(N3CCCC3)N=C(N3CCCC3)N=2)CC1.Cl>>[CH2:27]([NH:23][C:14]1[N:13]=[C:12]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4](=[O:28])[C@@H:3]3[C@:29]4([CH3:46])[C@H:42]([C@H:41]5[C:32](=[CH:31][CH2:30]4)[C@:33]4([CH3:45])[C:38](=[CH:37][C:36](=[O:44])[CH:35]=[CH:34]4)[CH2:39][CH2:40]5)[CH2:43][C@H:2]3[CH3:1])[CH2:11][CH2:10]2)[CH:17]=[CH:53][CH:52]=1)[CH3:26]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Agent: CS(=O)(=O)O
Agent: Cl
Product: CCNc1cccc(N2CCN(CC(=O)[C@H]3[C@H](C)C[C@H]4[C@@H]5CCC6=CC(=O)C=C[C@]6(C)C5=CC[C@@]43C)CC2)n1

Procedure:
The preferred amino substituted steroid (XI) is 16α-methyl-21-[4[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione. More preferred is 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna -1,4,9(11)-triene-3,20-dione monomethanesulfonate, 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione bismethanesulfonate and 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-trient-3,20 -dione hydrochloride. Most preferred is 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[OH:21][C@@H:22]([CH3:40])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([O:38][CH3:39])[CH:31]=2)[CH2:26][CH2:25]1>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([CH:27]4[CH2:28][CH2:29][N:24]([CH2:23][C@@H:22]([OH:21])[CH3:40])[CH2:25][CH2:26]4)=[CH:31][C:32]=3[O:38][CH3:39])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(C2CCN(C[C@H](C)O)CC2)ccc1C=O
Product: COc1cc(C2CCN(C[C@H](C)O)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 70 %

Procedure:
In a similar fashion as for the synthesis of III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-[1-((S)-2-hydroxypropyl)-piperidin-4-yl]-2-methoxy-benzaldehyde were reacted to produce the title compound (70%). 1H NMR (d-chloroform): 10.81 (br s, 1H), 8.33 (d, J=9 Hz, 1H), 8.01 (s, 1H), 7.03 (d, J=9 Hz, 1H), 6.94 (s, 1H), 6.42 (s, 1H), 6.35 (m, 2H), 5.55 (d, J=8 Hz, 1H), 5.27 (br s, 1H), 5.20 (t, J=9 Hz, 1H), 4.07 (s, 3H), 3.89 (m, 1H), 3.58 (m, 1H), 3.18 (m, 2H), 2.97 (d, J=11 Hz, 1H), 2.92 (s, 1H), 2.87 (d, J=11 Hz, 1H), 2.61 (m, 1H), 2.49-2.24 (m, 4H), 2.08 (t, J=11 Hz, 1H), 1.94-1.71 (m, 5H), 1.18 (d, J=7 Hz, 3H). MS: 551.2 (M+H). HPLC retention time: 1.84 minutes (G Method).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][CH:12]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
The product from Example 164a (0.7 g, 2.4 mmol) was added to ethanol (30 mL) and sodium borohydride (115 g, 3.11 mmol) was added portion wise. The reaction was stirred for 1 h and then the excess sodium borohydride was destroyed by drop wise addition of acetic acid. The reaction was poured onto ice/water and extracted with ethyl acetate. The organic phase washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (0.634 g, 90%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C>CO.[Rh]>[C:1]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCc1ccccc1
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCC1CCCCC1
Reaction time: 20 h

Procedure:
N-BOC-2-phenylethylamine (3.1 g) and 5% rhodium on alumina (1.1 g) are combined in methanol (40 ml) containing acetic acid (1.0 ml). The mixture is shaken under hydrogen at 50 psi for about 20 hours. The mixture is filtered, evaporated in vacuo, and the residue taken up into ethyl acetate. The organic solution is washed with water, 5% sodium bicarbonate solution, water, brine, dried over sodium sulfate, filtered, and evaporated in vacuo to give N-BOC-2-cyclohexylethylamine.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH3:8][Si:9]([O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15])([CH3:11])[CH3:10]>>[CH3:11][Si:9]([O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[NH:15][C:1](=[O:5])[C:2]([CH3:4])=[O:3])([CH3:8])[CH3:10]
Reactant: CC(=O)C(=O)Cl
Reactant: CC(C)C[C@H](N)C(=O)O[Si](C)(C)C
Agent: Cl
Product: CC(=O)C(=O)N[C@@H](CC(C)C)C(=O)O[Si](C)(C)C

Procedure:
A method of synthesizing pyruvyl-leucine according to the invention comprises the steps of reacting sodium pyruvate with oxalyl chloride to yield pyruvyl chloride, then reacting the pyruvyl chloride with a suspension of leucine trimethylsilyl ester hydrochloride to yield a pyruvyl-leucine trimethylsilyl ester and then subjecting the pyruvyl leucine trimethylsilyl ester to hydrolysis to yield pyruvyl-leucine. The pyruvyl-leucine synthesized via the route set forth above serves as a pyruvyl-amino acid pyruvate precursor.
Reaction SMILES: ON1[C:6](=[O:7])[C:5](N2C(=O)CCC2=O)=[C:4]([CH2:15][C:16]2(NC(=O)CCCCC)CCCC[C:17]2([NH:30]C(=O)CCCCC)NC(=O)CCCCC)C1=O.CN(C)C=[O:50]>>[NH2:30][CH2:17][CH2:16][CH2:15][CH2:4][CH2:5][C:6]([OH:7])=[O:50]
Reactant: CCCCCC(=O)NC1(CC2=C(N3C(=O)CCC3=O)C(=O)N(O)C2=O)CCCCC1(NC(=O)CCCCC)NC(=O)CCCCC
Reactant: CN(C)C=O
Product: NCCCCCC(=O)O

Procedure:
An N-hydroxysuccinimidyltricaproamidocyclohexylmethylmaleimide, a compound having the structure of FIG. 14 of the attached drawings where Z has the structure of FIG. 3, Z' has the structure of FIG. 11, n is 3, and C6H10 is 1,4-cyclohexyl, was then produced from a solution of 100 mg N-hydroxysuceinimidyldicaproamidocyclohexylmethylmaleimide in 2 ml dry dimethylformamide, 23.4 mg 6-aminocaproic acid and 40.5 mg dicyelohexylearbodiimide. A nitrogen atmosphere was established in a flask above the N-hydroxysuccinimidyldicaproamidocyclohexylmethylmaleimide solution, and the 6-aminocaproie acid was added to the flask. The reaction mixture was then stirred under nitrogen at room temperature of about 22° for 16 hours, after which time the dieyclohexylcarbodiimide was added to the flask. Stirring at room temperature was continued for an additional 6 hours, after which time dicyclohexylurea which had precipitated was removed from the reaction mixture by filtration, and the dimethylformamide was evaporated under reduced pressure from the filtrate. A tacky solid which remained was purified by flash chromatography on silica gel (10v/v methanol in chloroform), yielding 60 mg of the N-hydroxysuccinimidyltricaproamidocyclohexylmethylmaleimide, a white solid which has the indicated formula.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[CH:19][N:18]=[CH:17][C:13]=3[CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>O.C(O)(=O)C>[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[CH:19][N:18]=[CH:17][C:13]=3[C:14](=[N:1][OH:3])[C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1Cc2cnccc2Nc2ncccc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1c(=NO)c2cnccc2[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of sodium nitrite (0.259 g, 3.75 mmol) in water (1.0 mL) was added dropwise to a solution of 6,11-dihydro-5H-dipyrido[2,3-b:3′,4′-f]azepin-5-one (0.330 g, 1.56 mmol, Intermediate D-6) dissolved in acetic acid (6.0 mL). The mixture was stirred at room temperature for 90 minutes at which time a precipitate had formed. The yellow mixture was reduced to about half original volume in vacuo, and then diluted with 20 mL water and stirred for 30 minutes. A thick precipitate formed which was collected by suction filtration, washed with water and then dried in a vacuum oven at 50° C. overnight. The desired product was obtained as a yellow powder (224 mg, 60%). (2 peaks, ˜2:1 ratio of oxime isomers). 1H NMR (DMSO-d6, ˜2:1 mixture of oxime isomers): δ 12.55 & 12.32 (bs, 1H), 11.41 & 11.18 (bs, 1H), 8.67 (m, 2H), 8.54-8.25 (m, 2H), 7.56 (m, 1H), 7.27 (m, 1H). LC/MS: 241 (M+H)+
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][CH:34]2[C:38]3=[N:39][CH:40]=[CH:41][CH:42]=[C:37]3[CH2:36][CH:35]2[CH2:43][CH3:44])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][CH:34]2[C:38]3=[N:39][CH:40]=[CH:41][CH:42]=[C:37]3[CH2:36][CH:35]2[CH2:43][CH3:44])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1cnc(CC)c(NC2c3ncccc3CC2CC)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2c3ncccc3CC2CC)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.37, 7.78, 7.31, 5.42-5.25, 3.28, 2.75-2.48, 1.96, 1.62, 1.34, 1.05; HRMS (FAB) calcd for C18H23BrN4+H 375.1185, found 375.1193.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C@@H:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1.[CH3:18][Al](C)C.C1(C)C=CC=CC=1>ClCCl>[OH:1][C:2]1([CH3:18])[N:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C@@H:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1
Reactant: C[Al](C)C
Reactant: C=CCOC(=O)N1C(=O)CC[C@@H]1C(=O)OCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCOC(=O)N1[C@@H](C(=O)OCC)CCC1(C)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-allyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (9.1 g, 38 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0° C. before trimethylaluminum −2 M in toluene (94 mL, 190 mmol) was added and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with a minimal amount of ammonium chloride (saturated, aqueous) to form a white solid, which was filtered off to give the crude product. After purification by chromatography, the title compound was obtained. MS (ES+): 258 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[N:6][C:7]=1[I:8].[C:11](Cl)(Cl)=[S:12]>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][C:11](=[S:12])[NH:9][C:5]2=[N:6][C:7]=1[I:8]
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(Cl)c(I)nc1N
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: S=c1[nH]c2cc(Cl)c(I)nc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMAP (15.4 g, 126 mmol) was added to a THF (200 mL) solution of 5-chloro-6-iodopyridine-2,3-diamine (17 g, 63.1 mmol). Thiophosgene (4.9 mL, 63.1 mmol) was then added drop-wise via addition funnel under nitrogen and allowed to stir at rt for 1 h. The mixture was then partitioned between ethyl acetate (500 mL) and 2N HCl (100 mL). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated to give the desired product as a white powder, which was used in the next step without further purification. LC-MS: calculated for C6H3ClN3S 311.5, observed m/e: 311.91 (M+H)+ (Rt 1.69/5 min).
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>O1CCCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:17]2[CH2:18][CH2:19][N:14]([C:3]3[C:4](=[O:13])[C:5]4[C:10]([C:11](=[O:12])[C:2]=3[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:15][CH2:16]2)=[O:29])=[CH:23][CH:22]=1
Reactant: CC1=C(N2CCNCC2)C(=O)c2ccccc2C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC1=C(N2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of 150 mg of 3-methyl-2piperazinyl-1,4-naphthoquinone in 50 ml of tetrahydrofuran was treated with a solution of 100 mg of 4-chlorophenylisocyanate in 10 ml of tetrahydrofuran. This mixture was stirred 1/2 hour, then evaporated in vacuo and the residue taken up in dichloromethane and filtered. The filtrate was evaporated and the residue recrystallized from dichloromethane/hexane, giving 200 mg of the desired product, mp 190°-192° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C@H:39]([OH:41])[CH3:40]>>[OH:41][C@H:39]([CH3:40])[CH2:38][NH:37][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:29][CH:30]=1
Reactant: C[C@@H](O)CN
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: C[C@@H](O)CNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 86.4 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 48 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.