Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][C:29]1[C:30]([F:58])=[C:31]([CH:55]=[CH:56][CH:57]=1)[CH2:32][N:33]1[CH2:54][CH2:53][C:36]2([O:41][CH2:40][CH2:39][N:38]([C:42]([C:44]3[N:45]=[C:46]([CH2:49][CH2:50][CH2:51][CH3:52])[S:47][CH:48]=3)=[O:43])[CH2:37]2)[CH2:35][CH2:34]1)(C(C)(C)C)(C)C>C1COCC1>[CH2:49]([C:46]1[S:47][CH:48]=[C:44]([C:42]([N:38]2[CH2:37][C:36]3([CH2:53][CH2:54][N:33]([CH2:32][C:31]4[CH:55]=[CH:56][CH:57]=[C:29]([CH2:28][CH2:27][OH:26])[C:30]=4[F:58])[CH2:34][CH2:35]3)[O:41][CH2:40][CH2:39]2)=[O:43])[N:45]=1)[CH2:50][CH2:51][CH3:52]
Reactant: CCCCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO[Si](C)(C)C(C)(C)C)c4F)CC3)C2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
TBAF (1M solution in THF, 2.0 mL) was added to a solution of (9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-butylthiazol-4-yl)methanone (example 78, step h) (0.350 g) in THF (4 mL). After 0.5 h, the solution was concentrated. Purification by silica gel chromatography eluting with 10:1 ethyl acetate; triethylamine gave the subtitled compound as a gum. Yield 0.24 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:9][CH2:10][C:11](OCC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCN(C(=O)OC(C)(C)C)C1CCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCCO)C1CCCCC1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a stirred solution of ethyl N-tert-butoxycarbonyl-3-cyclohexylamino-propanoate (2a, 2.18 9, 7.3 mmol) in tetrahydrofuran (20 mL) was added lithium aluminium hydride (1.0 M solution in tetrahydrofuran. 10 mL). The reaction mixture was stirred for 1 h, after which ethyl acetate (5 mL) was slowly added. Subsequently, aqueous citric acid (0.5 M, 50 mL) was added and the heterogeneous mixture was extracted with Et2O (2×100 mL). The organic layer was washed with aqueous sodium hydrogencarbonate (1 N, 25 mL). Drying over magnesium sulphate, concentration under reduced pressure and purification by silica gel chromatography (eluent: ethyl acetate/heptane, 3:7, v/v) provided 1.50 g (80%) of the title compound as a white foam. ESI-MS: 258.2 (M+H)+, 280.3 (M+Na)+, 202.2 (M+H—C4H8)+, 158.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.31.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:14]([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:14][C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COC(=O)/C=C/c1ccc(N)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COC(=O)/C=C/c1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a solution of methyl (2E)-3-(4-amino-3-nitrophenyl)acrylate (from Step 2, 1 eq) in ethanol (0.2 M) was added tin(II) chloride dihydrate (5.75 eq). The reaction mixture was heated to reflux for 8 h. At this time the reaction was allowed to cool to RT, concentrated and diluted with EtOAc. A saturated aqueous solution of NaHCO3 was added slowly. The mixture was stirred for 20 min; the organic layer was washed with brine, dried over Na2SO4 filtered and evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 70% EtOAc in PE) to afford the title compound (57%). 1H-NMR (400 MHz; DMSO-<d6, 300 K) δ 3.67 (s, 3H), 4.59 (s, 2H), 5.17 (s, 2H), 6.08 (d, J 15.6, 1H), 6.5 (d, J 8.0, 1H), 6.74 (d, J 7.6, 1H), 6.82 (s, 1H), 7.39 (d, J 15.6, 1H); MS (ES+) m/z 193 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Product: Cc1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 200 °C
Yield: 48.3 %

Procedure:
In a cylindrical quartz tube were placed 4-fluoro-1-methyl-2-nitro-benzene (20.0 g, 129 mmol) and N-methyl-piperazine (26 g, 258 mmol). The reaction was heated for 48 hours at 200° C. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed twice with water and the organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The final compound (14.65 g, 48% yield) was obtained as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1>C1COCC1.CC(O)C.O>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18]([C:17]1[CH:25]=[CH:26][C:14]([NH:13][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=2)=[CH:15][CH:16]=1)=[O:19])[CH3:24]
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CCN(CC)C(=O)c1ccc(N)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCN(CC)C(=O)c1ccc(Nc2ncc([N+](=O)[O-])c(NC)n2)cc1
Yield: 87.1 %

Procedure:
To a room temperature solution of 0.943 g (5 mmol) of 2-chloro-4-(methylamino)-5-nitropyrimidine in 25 mL THF is added a solution of 2.11 g (11 mmol) of 4-amino-N,N-diethylbenzamide in 100 mL of 2-propanol, and the resulting mixture is heated and stirred at reflux for 1 hour. The mixture is then diluted with water, the solid precipitate is collected, washed with water, and dried, to give 1.50 g (87%) of the title compound: mp (EtOH) 213–215° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:25][CH2:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)=[O:16])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Reactant: NCc1ccncc1
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccncc1
Yield: 46 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with pyridin-4-ylmethanamine, the title compound was obtained as a colorless solid in 46% yield: mp 275-278° C. (dichloromethane/methanol); 1H NMR (300 MHz, DMSO-d6) δ 11.59 (br s, 1H), 8.88-8.78 (m, 1H), 8.58 (t, J=8.9 Hz, 1H), 8.47-8.44 (m, 2H), 7.26-7.23 (m, 2H), 6.27-6.22 (m, 1H), 5.85-5.80 (m, 1H), 4.44-4.30 (m, 2H), 2.56 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 162.2, 161.6, 154.2, 150.6, 149.9, 148.8, 132.6, 123.2, 122.6, 104.4, 98.0, 42.2, 17.5; MS (ES+) m/z 343.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:18]([O-])=O)=[C:9]([CH:17]=1)[O:10][CH:11]([CH3:16])[C:12](OC)=[O:13]>C(O)C.[Ni]>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:18][C:12](=[O:13])[CH:11]([CH3:16])[O:10][C:9]=2[CH:17]=1
Reactant: COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2NC1=O
Yield: 81.2 %

Procedure:
Methyl 2-[5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenoxy]propionate (1.3 g) was dissolved in 10 ml of ethanol, raney nickel was added thereto as a catalyst, and a hydrogenation was then conducted. After the completion of the reaction, the reaction mixture was filtered and concentrated in vacuo, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=1/1) to prepare the title compound (0.9 g) as a colorless crystal (yield: 88%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O.[NH2:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51].[CH3:57][N:58]1[C@@H:75]2[CH2:76][C:63]3[CH:64]=[CH:65][C:66]([O:77][CH3:78])=[C:67]4[O:68][C@H:69]5[C:70]([CH2:72][CH2:73][C@@H:74]2[C@:61]5([C:62]=34)[CH2:60][CH2:59]1)=[O:71]>>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:57][N:58]1[C@@H:75]2[CH2:76][C:63]3[CH:64]=[CH:65][C:66]([O:77][CH3:78])=[C:67]4[O:68][C@H:69]5[C:70]([CH2:72][CH2:73][C@@H:74]2[C@:61]5([C:62]=34)[CH2:60][CH2:59]1)=[O:71]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN)C(=O)O

Procedure:
Lys-Lys-Ile-Hydrocodone was prepared by a similar method except the amino acid starting material was Boc-Lys(Boc)-Lys(Boc)-OSu and the conjugate starting material was Ile-Hydrocodone.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH:13]=2)[NH:8][C:7]([CH3:24])([CH3:23])[CH:6]=1)=[N+]=[N-].C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>CCOCC>[NH2:1][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH:13]=2)[NH:8][C:7]([CH3:24])([CH3:23])[CH:6]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CN=[N+]=[N-])=CC(C)(C)N2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1-c1ccc2c(c1)C(CN)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A round bottom flask equipped with a stir bar was charged with 4-azidomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline (0.565 mmol) and THF (4.2 mL). The system was placed under argon, after which PPh3 (0.621 mmol, 1.1 equiv) and water (0.621 mmol, 1.1 equiv) were added. The reaction was stirred overnight at room temperature. The crude reaction mixture was diluted with ether and filtered through diatomaceous earth until no more precipitate formed. The diatomaceous earth was washed well with ether. The organic layer was acidified with concentrated HCl affording a white fluffy precipitate which then oiled out. This layer was diluted with water and separated from the aqueous layer. The aqueous layer was then neutralized with Na2CO3 and extracted with methylene chloride. The organic extracts were combined and concentrated in vacuo to afford 122 mg of 4-aminomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].[NH2:12][C:13](N)=[O:14]>C(O)(=O)C>[Cl:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:13]([NH2:12])=[O:14]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: NC(N)=O
Solvent: CC(=O)O
Product: NC(=O)Nc1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A stirred solution of 3-amino-4-chlorobenzoic acid (34.2 g, 200 mmol) and urea (24 g, 400 mmol) in glacial acetic acid (200 mL) was heated at 100° C. for 24 h. The mixture was allowed to cool to room temperature and the resulting precipitate was separated by filtration, washed with water (2×100 mL) and diethyl ether (2×100 mL), then air dried to give 35 g of 4-chloro-3-ureido-benzoic acid as a grey solid that was carried on without further purification.
Reaction SMILES: [C:1](=[O:40])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:20][C@:14]12[CH2:13][CH2:12][C@H:11]([C:21]3[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=3)[C@@:10]1([CH3:28])[CH2:9][CH2:8][C@H:7]1[C@H:15]2[CH2:16][CH2:17][C@H:18]2[C@:6]1([CH3:29])[CH2:5][CH2:4][C@H:3]([O:2][C:1]([NH:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:40])[CH2:19]2
Reactant: NCCCC(=O)O
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@]12CC[C@H](OC(=O)NCCCC(=O)O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 53.9 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (20 mg, 0.036 mmol) in CH2Cl2 was added 4-aminobutanoic acid (37.1 mg, 0.36 mmol, 10 eq), DIEA (18.6 mg, 0.144 mmol, 4 eq) and DMAP (16.1 mg, 0.144 mmol, 4 eq). The resultant mixture was stirred at 40° C. for 16 h and then purified via preparative TLC to afford 4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yloxy)carbonylamino)butanoic acid (10 mg, 53.5%) as a white solid. LRMS (M−H+) m/z 514.4. 1H NMR (CD3OD, 400 MHz) δ 7.89 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.18 (d, J=9.6 Hz, 1H), 4.82 (m, 1H), 3.03 (m, 2H), 2.44-2.48 (m, 1H), 1.08-2.15 (m, 25H), 0.87 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][NH:11][C@@H:12]([CH3:20])[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][N:11]([C@@H:12]([CH3:20])[CH:13]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[C:40](=[O:41])[C@@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]3[C:33]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2nsnc12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nsnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
According to the procedure described in the synthesis method of Compound III-5, (S)—N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1,1-diethoxypropan-2-amine (Compound IX-8) (1.41 g, 4.78 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (2.4 g, 5.23 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=7:3) to obtain the title compound (2.38% g, 68%).
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:14]([OH:16])=O)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[CH2:23]([C:27]1[N:32]=[C:31]([N:33]([CH3:35])[CH3:34])[N:30]=[C:29]([NH:36][NH2:37])[N:28]=1)[CH2:24][CH:25]=[CH2:26].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:23]([C:27]1[N:32]=[C:31]([N:33]([CH3:35])[CH3:34])[N:30]=[C:29]([NH:36][NH:37][C:14]([C@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:12][N:3]([O:4][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:1]=[O:2])=[O:16])[N:28]=1)[CH2:24][CH:25]=[CH2:26]
Reactant: C=CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Reactant: C=CCCc1nc(NN)nc(N(C)C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)NNc1nc(CCC=C)nc(N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2R)-2-({N-formyl-N-benzoxy-amino}methyl)-7-octenoic acid (233 mg, 1.121 mmol), 4-(3-buten-1-yl)-6-(dimethylamino)-2-hydrazino-1,3,5-triazine (342 mg, 1.121 mmol), NMM (0.62 mL, 5.61 mmol) and HOAt (183 mg, 1.345 mmol) in DMF (11 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (258 mg, 1.345 mmol). After stirring at room temperature overnight, the reaction mixture was then purified by HPLC to afford the title compound as a white solid. MH+496.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:13]=[C:12]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]2=[CH:10][C:9]=1[CH:19]=[O:20].[CH:21]1([CH2:25][NH:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22]1.O>CN(C=O)C.C(OCC)(=O)C>[CH:21]1([CH2:25][N:26]([CH2:27][CH3:28])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH:19]=[O:20])[CH2:24][CH2:23][CH2:22]1
Reactant: CCNCC1CCC1
Reactant: Cc1nn(C)c2nc(Cl)c(C=O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC1CCC1)c1nc2c(cc1C=O)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
Potassium carbonate (0.83 g, 6 mmol) was added to a solution of 6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (1.04 g, 5.0 mmol) and cyclobutylmethyl-ethyl-amine (0.8 g, 7.0 mmol) in anhydrous DMF (8 mL) under nitrogen. After stirring for 0.5 h at RT, the reaction mixture was heated for 14 h at 80° C. Thereafter, the reaction was cooled to RT, water (30 mL) and ethyl acetate (30 mL) were added, and the organic layer was separated from the aqueous mixture. The organic extract was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography using silica gel (200-400 mesh) and eluted with 20-60% hexane:ethyl acetate to afford the title compound as a pale yellow liquid (1.23 g, yield: 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([CH3:32])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([O:15]C)[C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)C=O.C1C=C(Cl)C=C([C:40](OO)=[O:41])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:32][C:17]1[CH:18]=[C:19]([O:21][Si:22]([CH:26]([CH3:27])[CH3:28])([CH:23]([CH3:24])[CH3:25])[CH:29]([CH3:30])[CH3:31])[CH:20]=[C:2]([CH3:1])[C:3]=1[CH2:4][C:5]1[CH:12]=[CH:9][C:8]([O:13][CH2:14][O:41][CH3:40])=[C:7]([OH:15])[CH:6]=1
Reactant: COc1cc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc(C=O)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxy-methoxy-benzaldehyde (compound 15, step e; 0.460 g, 1.01 mmol) in dichloromethane 30 mL was add mCPBA (0.870 g, 2.52 mmol) and saturated sodium bicarbonate solution (2 mL). After stirring at rt overnight, the reaction mixture was poured into dichloromethane 50 mL and washed 3× with 10 mL of saturated aqueous sodium bicarbonate. The dichloromethane was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was combined with methanol (10 mL) and 2 mL of 1 N NaOH and stirred for 1.5 hours at room temperature. The reaction was acidified with 12 N HCl (pH<3) and poured into 50 mL ethyl acetate. The layers were separated and the organics were dried over sodium sulfate, filtered and concentrated. Flash column chromatography using silica and a step gradient of hexane/ethyl acetate [20:1], hexane/ethyl acetate [9:1] provided 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxy-phenol (0.189 g, 42%): 1H NMR (300 MHz, DMSO-d6): δ 8.95(s, 1H), 6.86(d, 1H, J=8.1 Hz), 6.56(s, 2H), 6.41(d, 1H, J=2.1 Hz), 6.34(dd, 1H, J=2.1 Hz and J=8.7 Hz), 5.05(s, 2H), 3.78(s, 2H), 3.38(s, 3H), 2.13(s, 6H), 1.11(m, 3H), 1.00(m, 18H); Uniplate silica gel, 250 microns; Mobile phase=10% ethyl acetate in hexane: Rf=0.15
Reaction SMILES: [C:1]([CH2:3][CH:4]([P:9]([CH3:14])(=[O:13])[O:10][CH2:11][CH3:12])[C:5]([F:8])([F:7])[F:6])#[N:2].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>[Pt]=O>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH2:2][CH2:1][CH2:3][CH:4]([P:9]([CH3:14])(=[O:13])[O:10][CH2:11][CH3:12])[C:5]([F:8])([F:6])[F:7]
Reactant: CCOP(C)(=O)C(CC#N)C(F)(F)F
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCOP(C)(=O)C(CCN)C(F)(F)F

Procedure:
250 mg of platinum oxide are added to a solution of 458.28 mg (2 mmol) of ethyl P-(3-cyano-1,1,1-trifluoro-prop-2-yl)-P-methyl-phosphinate dissolved in 28 ml of trifluoroacetic acid, and the resulting mixture is hydrogenated at 25° and 4 bar. The catalyst is filtered off and the filtrate is evaporated to dryness under reduced pressure. The resulting crude product is chromatographed on 70 g of Opti-Up® C12 with acetonitrile as the eluent. The product-containing fractions are combined and evaporated under reduced pressure to give ethyl P-(4-amino-1,1,1-trifluoro-but-2-yl)-P-methyl-phosphinate trifluoroacetate as an oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH2:13]2)[C:8]([C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[C:28]3=[N:29][CH:30]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:42][NH:43][CH3:44].CS(C)(=O)=O>>[CH3:42][N:43]([CH3:44])[C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH2:21][CH:22]([CH3:23])[CH3:24])(=[O:19])=[O:20])[CH2:13]2)[C:8]([C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][NH:31][C:28]3=[N:29][CH:30]=2)=[CH:7][N:6]=1
Reactant: CNC
Reactant: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(S(C)(=O)=O)ncc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Agent: CS(C)(=O)=O
Product: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(N(C)C)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
From {2-methanesulfonyl-5-[5-(2-trimethysilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-amine derived from Example 3, step 1, dimethylamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5 of Example 76 to give N*2*,N*2*-dimethyl-N*4*-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2,4-diamine. MS (ES+): 459.