Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH:7]([CH3:16])[CH2:6][C:5]2=[O:17].Cl[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].[OH-].[K+]>ClCCl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:22]([O:21][C:19]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([C:12]([F:14])([F:13])[F:15])[CH:10]=2)[C:5](=[O:17])[CH2:6][CH:7]1[CH3:16])=[O:20])([CH3:24])[CH3:23]
Reactant: CC(C)OC(=O)Cl
Reactant: CC1CC(=O)c2cc(F)c(C(F)(F)F)cc2N1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)N1c2cc(C(F)(F)F)c(F)cc2C(=O)CC1C
Reaction time: 8 h

Procedure:
6-Fluoro-2-methyl-4-oxo-7-trifluoromethyl-3,4-dihydro-2H-quinoline (1.01 g, 4.08 mmol) was dissolved in 10 mL of dichloromethane and 5 mL of pyridine, and stirred as isopropyl chloroformate (48 mL of a 1 molar solution in toluene, 48 mmol) was added slowly via syringe. After stirring overnight, 100 ml of a 1M aqueous potassium hydroxide solution was added and the aqueous phase was extracted with ethyl acetate (3×75 mL), the combined organics were washed with 1M HCl (2×50 mL), 100 mL each of a saturated sodium bicarbonate solution and brine, before being dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford 1.1 g of an oil, which was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexanes to afford 940 mg (69%) of the title compound as an oil. 1H NMR (CDCl3) δ 1.24 (d, 3H), 1.34 (d, 3H), 1.38 (d, 3H), 2.65 (dd, 1H), 3.05 (dd, 1H), 5.1-5.3 (m, 2H),
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:6]=1)([CH3:3])[CH3:2].[NH2:28][C:29]1[C:30]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=2)=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=1>>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:28][C:29]2[C:30]([C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=3)=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:10])=[C:7]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH2:16]2)[CH:6]=1)([CH3:3])[CH3:2]
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)Sc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Product: CC(C)Sc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 28 %

Procedure:
Using a procedure analogous to Example 1-G, 4-iso-propylthio-2-(1-t-butoxycarbonylpiperidin-4-yloxy)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a glass (350 mg, 28%).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([OH:25])[CH:23]=4)[NH:18][N:17]=3)[NH:13]2)=[CH:9][CH:8]=1)[CH3:2].[N+](C1C=C[C:34]([O:37][P:38]([CH3:50])(=O)[O:39]C2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.N12CCCN=C1CCCCC2.CO>ClCCl>[CH3:34][O:37][P:38]([CH3:50])(=[O:39])[O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:26][CH3:27])[CH:15]=2
Reactant: CCN(CC)CCOc1ccc2cc(-c3n[nH]c4ccc(O)cc34)[nH]c2c1
Reactant: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc2cc(-c3n[nH]c4ccc(OP(C)(=O)OC)cc34)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
The compound methylphosphonic acid 3-[6-(2-diethylamino-ethoxy)-1H-indol-2-yl]-1H-indazol-5-yl ester methyl ester is prepared as follows: 100 mg of 3-[6-(2-diethylaminoethoxy)-1H-indol-2-yl]-1H-indazol-5-ol in solution in 4 ml of dichloromethane with 93 mg of methylphosphonic acid bis-(4-nitrophenyl)ester (prepared according to procedure E) are stirred at ambient temperature. A solution of 41 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 1 ml of dichloromethane is added dropwise. The solution is stirred overnight at ambient temperature. 41 μl of DBU, followed by 115 μl of methanol, are then added. This operation is repeated after stirring for 4 h 15 min. After stirring for another hour at ambient temperature, the solvent is evaporated off and the crude is purified by flash chromatography on a cartridge of 25 g of silica, eluent: dichloromethane/methanol, 90/10 to 60/40 in steps. The fractions obtained are concentrated and purified by preparative LC/MS to isolate 30 mg of methylphosphonic acid 3-[6-(2-diethylaminoethoxy)-1H-indol-2-yl]-1H-indazol-5-yl ester methyl ester in the form of a colorless oil.
Reaction SMILES: [CH2:1]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:27]([CH3:32])([CH3:31])[C:28](Br)=[O:29].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[CH2:20]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]3[C:28](=[O:29])[CH:27]([CH3:32])[CH2:31][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C(=O)C(C)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A 2000 mL round flask was charged with 9,9-dihexyl-9H-fluorene (79 g, 236.2 mmol) and 2-bromo-2-methylpropanoyl bromide (54.3 g, 236.2 mmol), and then dissolved with 600 mL of carbon disulfide inputted thereto. Then, the reactor was cooled with ice water. Under nitrogen atmosphere, aluminum trichloride (78.7 g, 590.4 mmol) was slowly added thereto in ten lots over 2 hours. The mixture was stirred at room temperature for 8 hours, and then the reaction was terminated by addition of 500 mL of distilled water, followed by washing 3 times with 500 mL of distilled water. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials and drying, to thereby obtain 89.0 g of 9,9-dihexyl-2-methyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (yield: 93.6%) as highly viscous oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][C@@H:22]4[CH2:26][CH2:27][CH2:28][C@@H:21]34)[N:17]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]3)[C:4]=2[C:5]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=2)=[N:6][C:7]=1[C:8]#[N:9].[F-].[Cs+].[CH3:39][NH:40][CH3:41].CS(C)=O>C1COCC1.CCOC(C)=O>[Cl:16][C:14]1[CH:15]=[C:10]([C:5]2[C:4]3[N:17]([CH2:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]4)[C:18]([N:20]4[CH2:25][CH2:24][O:23][C@@H:22]5[CH2:26][CH2:27][CH2:28][C@@H:21]45)=[N:19][C:3]=3[C:2]([N:40]([CH3:41])[CH3:39])=[C:7]([C:8]#[N:9])[N:6]=2)[CH:11]=[N:12][CH:13]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CNC
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CN(C)c1c(C#N)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Temperature: 100 °C

Procedure:
A dry vial, under an atmosphere of nitrogen, was charged with 7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 11.2, step 1; 50 mg, 0.095 mmol), CsF (101 mg, 0.666 mmol), dimethylamine (0.476 mL of a 2M solution in THF, 0.952 mmol) and DMSO (1 mL). The vial was sealed and heated to 100° C. for 8 hours. The reaction was cooled to room temperature, diluted with EtOAc (25 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column with 0 to 100% EtOAc/hexanes to afford 4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C29H36ClN7O [M+H]+=534. found=534.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:21]([OH:23])=O)[C:6](=[O:20])[N:7]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(Cl)(=O)C(Cl)=O.[C:30]1(=[O:37])[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH2:31]1.C(N(CC)CC)C.CC(C)(O)C#N>C(Cl)(Cl)Cl.CN(C)C=O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:21]([C:31]1[C:32](=[O:36])[CH2:33][CH2:34][CH2:35][C:30]=1[OH:37])=[O:23])[C:6](=[O:20])[N:7]2[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2c(=O)c(C(=O)O)nc3c(F)cccc32)cc1
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=O)c(C(=O)C3=C(O)CCCC3=O)nc3c(F)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
11.1 g (35 mmol) of 5-fluoro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid was dissolved in chloroform (300 mL), and to this solution, N,N-dimethylformamide (0.5 mL) and 6.7 g (53 mmol) of oxalyl chloride were added sequentially. The mixture was stirred for one hour at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in chloroform (100 mL), and this solution was added dropwise at 0° C. over 5 minutes to a solution prepared by dissolving 4.4 g (39 mmol) of 1,3-cyclohexanedione and 4.3 g (43 mmol) of triethylamine in chloroform (200 mL). The reaction solution was returned to room temperature and stirred for 3 hours, and then 1.5 g (18 mmol) of acetone cyanohydrin and 4.3 g (43 mmol) of triethylamine were added thereto. The mixture was stirred for 12 hours at room temperature. The reaction solution was washed with 10% hydrochloric acid and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was washed with methanol, to obtain 13.6 g (yield: 94%) of 5-fluoro-3-(2-hydroxy-6-oxo-1-cyclohexenecarbonyl)-1-(4-methoxyphenyl)-quinoxalin-2(1H)-one as a pale orange-colored powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:18][C@@H:19]([OH:43])[C@@H:20]([N:28](CC3C=CC=CC=3)CC3C=CC=CC=3)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:44][S:45]([OH:48])(=[O:47])=[O:46].O>CO.[OH-].[OH-].[Pd+2]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:18][C@@H:19]([OH:43])[C@@H:20]([NH2:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:11])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:44][S:45]([OH:48])(=[O:47])=[O:46]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: CS(=O)(=O)O
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reaction time: 18 h
Yield: 87.1 %

Procedure:
Crude 1-[N-[(1,3-benzodioxol-5-yl)sulfonyl]-N-(2-methylpropyl)amino]-3(S)-[bis(phenylmethyl)amino]-4-phenyl-2(R)-butanol (6.2 g, 0.010 moles) was dissolved in methanol (40 mL). Methanesulfonic acid (0.969 g, 0.010 moles) and water (5 mL) were then added to the solution. The mixture was placed in a 500 mL Parr hydrogenation bottle containing 20% Pd(OH)2 on carbon (255 mg, 50% water content). The bottle was placed in the hydrogenator and purged 5 times with nitrogen and 5 times with hydrogen. The reaction was allowed to proceed at 35° C. with 63 PSI hydrogen pressure for 18 hours. Additional catalyst (125 mg) was added and, after purging, the hydrogenation continued for and additional 20 hours. The mixture was filtered through celite which was washed with methanol (2×10 mL). Approximately one third of the methanol was removed under reduced pressure. The remaining methanol was removed by aziotropic distillation with toluene at 80 torr. Toluene was added in 15, 10, 10 and 10 mL portions. The product crystallized from the mixture and was filtered and washed twice with 10 mL portions of toluene. The solid was dried at room temperature at 1 torr for 6 hours to yield the amine salt (4.5 g, 84%). HPLC/MS (electrospray) was consistent with the desired product (m/z 421 [M+H]+).
Reaction SMILES: C(C1C=CC(CN)=CC=1)(C)(C)C.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[C:28]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]=[C:40]=[O:41])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].[NH2:42][CH2:43][C:44]1[CH:49]=[C:48]([CH:50]=[CH2:51])[C:47]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:46]([Cl:57])[CH:45]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([CH2:38][NH:39][C:40](=[O:41])[NH:42][CH2:43][C:44]2[CH:49]=[C:48]([CH:50]=[CH2:51])[C:47]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:46]([Cl:57])[CH:45]=2)=[CH:36][CH:37]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: C=Cc1cc(CN)cc(Cl)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)c1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(Cl)c1NS(C)(=O)=O
Reaction time: 5 h
Yield: 17.66 %

Procedure:
4-tert-butylbenzylamine (1.5 eq, 71.10 μl, 0.44 mmol), BOC2O (1.5 eq, 0.44 mmol, 101.19 μl), and DMAP (0.2 eq, 0.06 mmol, 7.08 mg) were added in methylene chloride. The reaction mixture was stirred for 5 hr. After confirming the synthesis of the 1-tert-butyl-4-isocyanatomethylbenzene with TLC, N-(4-Aminomethyl-2-chloro-6-vinylphenyl)methanesulfonamide (1 eq, 0.29 mmol, 108.6 mg) and TEA (2 eq, 0.58 mmol, 80.84 μl) were added into the reaction mixture. The reaction mixture was stirred for 12 hr and purified with similar procedure to step 7 of example 8 to gave a title compound (23.0 mg, 17.66%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC1(c2ccccc2)CCNCC1
Yield: 110.8 %

Procedure:
To a cooled suspension of 10% Pd-C (0.5 g) in 10 mL methanol was added a solution of 1-benzyl-4-methyl-4-phenylpiperidine (4.5 g, 17.0 mmol) in 40 mL of methanol and the resulting suspension was hydrogenated in a Parr bomb under 250 psi of hydrogen for two days. The suspension was filtered through a pad of celite and the solvent was removed from the filtrate to obtain 4-methyl-4-phenylpiperidine as a yellow solid (3.3 g, 99% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12](=[O:38])[CH2:13][C:14]([NH:16][CH2:17][C:18]2[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]3[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]3=[N:22][C:23]=2[CH2:24][CH3:25])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)=[O:40].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>CCOC(C)=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:11][CH2:10][C:4]3[CH:3]=[C:2]([C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([CH:39]=[O:40])[CH:46]=4)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=3)=[O:38])[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(OC)c(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(OC)c(-c2cccc(C=O)c2)c1
Yield: 63 %

Procedure:
A mixture of N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (0.800 g, 1.362 mmol), (3-formylphenyl)boronic acid (0.225 g, 1.5 mmol), tetrakis (triphenylphosphine) palladium (0) (0.058 g, 0.05 mmol), sodium carbonate (0.371 g, 3.5 mmol), and 1,4-dioxane (12 ml) and water (4 ml), with stirring under N2, was microwaved at 140° C. for 30 minutes. The reaction mixture was diluted with EtOAc and water and the organic layer taken off. It was washed with saturated NaCl, dried over Na2SO4, and evaporated resulting in a viscous taffy. The viscous taffy was purified on a Chromatotron Plate Silica Gel (1000μ) eluting with CH2Cl2— MeOH (97:3) to afford N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}propanediamide (526 mg, 91%) as a viscous, nearly colorless, taffy. LC-MS m/z 613.4 (M+H)+, 0.81 min (ret time).
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CN1CCOCC1.[N-:27]=[N+:28]=[N-:29].[Na+]>C1COCC1.O.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:13])[NH:14][CH2:15][CH2:16][C:17]([N:27]=[N+:28]=[N-:29])=[O:19])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCC(=O)N=[N+]=[N-]
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
Add ethyl chloroformate (2.52 g, 23.25 mmol) dropwise to a solution of 3-tert-butoxycarbonylamino-propionic acid (4 g, 21.14 mmol) and 4-methyl morpholine (2.35 g, 23.25 mmol) in THF (60 mL) at −20° C. After 40 min, warm the suspension to −5° C. and add dropwise a solution of sodium azide (3.44 g, 52.85 mmol) in water (10 mL). After 10 min, dilute the mixture with ethyl acetate (60 mL) and wash with water, saturated aqueous sodium chloride, dry over MgSO4. After filtration, remove the organic solvent to afford the product as clear oil (4.3 g, 95%). 1H NMR (DMSO-d6) δ 6.91 (broad s, 1H), 3.18 (q, J=6.4 Hz, 2H), 2.51-2.48 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH:1]1([O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[ClH:25].CCOC(C)=O>CCOC(C)=O>[ClH:25].[ClH:25].[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:9]=[CH:10][N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(OC3CCC3)ncn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1nc(OC2CCC2)cc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-(6-cyclobutoxypyrimidin-4-yl)piperazine-1-carboxylate (687 mg, 2.06 mmol) and 4 M HCl-EtOAc (30 ml) were stirred at rt for 2 h. Then EtOAc was added, and the solvent was removed in vacuo. The residue was suspended in EtOAc, and the white precipitate was collected by filtration to give 525 mg (quant) of the title compound as a white solid. The compound was used for the next step without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:44][C:45]([CH3:50])([CH3:49])[C:46](Cl)=[O:47]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:44][C:45]([CH3:50])([CH3:49])[C:46]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)=[O:47]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)C(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise trimethylacetyl chloride (0.12 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.384 g oil. Crystallization as the oxalate salt from 2-propanol provided 0.297 g colorless crystals. Mp 194° C. Mass spectrum, m+ =413. Anal (C25H37N5O6) theory C, 59.63; H, 7.41; N, 13.91; found C, 59.47; H, 7.62; N, 13.63.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[C:10]([C:12]1[CH:41]=[CH:40][C:15]([O:16][CH2:17][C@@H:18](O)[CH2:19][N:20]2[CH2:27][CH:26]3[O:28][CH:22]([CH2:23][N:24]([CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:25]3)[CH2:21]2)=[CH:14][CH:13]=1)#[N:11]>ClCCl>[C:10]([C:12]1[CH:41]=[CH:40][C:15]([O:16][CH2:17][CH:18]([F:7])[CH2:19][N:20]2[CH2:27][CH:26]3[O:28][CH:22]([CH2:23][N:24]([CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:25]3)[CH2:21]2)=[CH:14][CH:13]=1)#[N:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN1CC2CN(CC(F)COc3ccc(C#N)cc3)CC(C1)O2
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of DAST (0.73 g, 0.0043 mol) in dichloromethane (10 mL) was added tert-butyl (2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)carbamate (1.50 g, 0.0033 mol; see Preparation R above), in (10 mL) of dichloromethane, dropwise under a nitrogen atmosphere at −65° C. The reaction mixture was slowly brought to RT and stirred at this temperature for 2 h (monitored by HPLC). The reaction mixture was quenched with NaHCO3 (aq.) and extracted with dichloromethane. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel, using methanol-dichloromethane as the eluent, to yield 0.40 g of the title compound as a brownish, gummy solid.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:13][C:14]1[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=1>>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][N:22]2[C:9](=[O:11])[C:5]3[S:6][CH:7]=[CH:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:18]=1
Reactant: COC(=O)c1sccc1N=C=S
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3ccsc3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 3-isothiocyanatothiophene-2-carboxylate (0.107 g. 0.53 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.075 g, 0.53 mmol) as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C)=[O:22])[C@H:16]([CH3:25])[CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O[Li].O>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[C@H:16]([CH3:25])[CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CN1CCN(C2(c3ccc(Cl)cc3)CCCCC2)C[C@H]1C
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(C2(c3ccc(Cl)cc3)CCCCC2)CCN1CC(=O)O
Reaction time: 4 h

Procedure:
To a solution of (R)-methyl 2-(4-(1-(4-chlorophenyl)cyclohexyl)-2-methyl-piperazin-1-yl)acetate (0.5 g, 1.37 mmol) in THF (10 mL) and methanol (1 mL) at 0° C. was added a solution of LiOH.H2O (0.16 g, 3.81 mmol) in water (1 mL). The reaction mixture was stirred for 4 h. Methanol and THF were distilled under reduced pressure and the residue was washed with ethyl acetate. The pH of the aqueous layer was adjusted to 7 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product which was purified by silica gel (100-200 mesh) column chromatography eluting with 5-7% methanol in chloroform to afford pure (R)-2-(4-(1-(4-chlorophenyl)cyclohexyl)-2-methylpiperazin-1-yl)acetic acid.