Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(N(CC)CC)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@@](CCCO)(c2ccc(F)cc2)CCN1[C@H]1CCCNC1
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1O[C@@](CCCO)(c2ccc(F)cc2)CCN1[C@H]1CCCN(c2ccc(C(F)(F)F)cn2)C1
Yield: 7 %

Procedure:
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (100 mg, 0.30 mmol), 2-bromo-5-(trifluoromethyl)pyridine (67 mg, 0.36 mmol), and triethylamine (91 mg, 0.90 mmol) in acetonitrile was heated to reflux for 3 h. The reaction mixture was concentrated. The residue was purified by preparative TLC and preparative HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-1,3-oxazinan-2-one (10.09 mg, 7%). LC-MS Method 2 tR=1.34 min, m/z=482. 1H NMR (400 MHz, CDCl3): 1.28 (m, 1H), 1.64 (m, 2H), 1.76 (m, 3H), 1.92 (m, 2H), 2.18 (m, 1H), 2.27 (m, 1H), 2.77 (m, 3H), 3.21 (m, 1H), 3.52 (t, 2H), 3.83 (broad, 1H), 4.11 (d, 1H), 4.25 (d, 1H), 6.57 (d, 1H), 7.03 (t, 2H), 7.23 (m, 2H), 7.54 (d, 1H), 8.29 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)=[N:9][NH:10][CH:11]=2)=[CH:3][CH:2]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C>N1C=CC=CC=1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[C:14]([NH:18][C:28]([NH:27][C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=4)=[O:29])[CH:15]=[CH:16][CH:17]=3)=[N:9][NH:10][CH:11]=2)=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To 3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (700 mg, 3 mmol) in anhydrous pyridine (15 mL) at 0° C. 4-trifluoromethylphenylisocyanate (420 μL, 3 mmol) was added. The reaction was stirred for 2 hours at 0° C. under nitrogen atmosphere to give a mixture of monourea and bis-urea as regioisomeric mixture. Solvent was removed under reduced pressure. The residue was dissolved in methanol (15 mL) and triethylamine (1 mL, 7.8 mmol) was added and the reaction was stirred at room temperature overnight. After this time only the monourea could be detected by HPLC/MS. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL) and washed successively with water (3×50 mL). The crude was purified by silica gel column chromatography (DCM/methanol 9:1) to give the desired product as a white solid (75%).
Reaction SMILES: [BH4-].[Na+].[C:3]12([C:13](=[O:39])[CH2:14][O:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([C@H:27]5[CH2:32][CH2:31][C@H:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[NH:18][N:17]=3)[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>O1CCCC1.C(O)C>[C:3]12([CH:13]([OH:39])[CH2:14][O:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:22]=[CH:23][C:24]([C@H:27]5[CH2:28][CH2:29][C@H:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[NH:18][N:17]=3)[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(OCC(=O)C45CC6CC(CC(C6)C4)C5)n[nH]3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(OCC(O)C45CC6CC(CC(C6)C4)C5)n[nH]3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (38 mg, 0.1 mmol) was added to a solution of the product from Example 1F (25 mg, 0.05 mmol) in tetrahydrofuran (3 mL) and ethanol (3 mL) maintained at 0° C. The reaction was allowed to warm to room temperature over 30 min and then stirred at room temperature for 1 hour. After this time the reaction was quenched by addition of water (5 mL) and extracted with ethyl acetate. The organic extracts were combined and washed with water, brine, dried (MgSO4), filtered and concentrated to a brown oil which was purified via flash column (eluting with 15% ethyl acetate in hexanes) to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (m, 2H), 1.19 (t, J=7.32 Hz, 3H), 1.42-1.99 (m, 22H), 2.22 (d, J=6.71 Hz, 2H), 2.47 (m, 1H), 3.89 (dd, J1=10.38 Hz, J2=7.94 Hz, 1H), 4.02 (m, 1H), 4.06 (q, J=7.32 Hz, 2H), 4.24 (dd, J1=10.37 Hz, J2=2.74 Hz, 1H), 4.71 (s, 1H), 6.07 (s, 1H), 7.28 (d, J=8.24 Hz, 2H), 7.59 (d, J=8.24 Hz, 2H), 12.21 (br s, 1H); MS (ESI) m/z 507.4 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:26]1[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[C:28](Cl)[N:27]=1>C(#N)C>[NH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:26]2[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][N:27]=2)[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccnc(NCC2CCNCC2)n1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was prepared as follows: A 40 mL round-bottomed vial was charged with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.76 mmol, 1.1 equiv.), acetonitrile (4 mL), DiPEA (2.37 mmol, 1.5 equiv.), methyl 2,6-dichloropyrimidine-4-carboxylate (1.58 mmol, 1 equiv.), and then shaken at 85° C. for 72 h. The reaction mixture was concentrated under reduced pressure and purified on SiO2 using a Biotage and a 10-50% EtOAc/hexanes gradient to provide the desired protected amine (233 mg, 552 mg theoretical, 42%). Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was prepared using the general TFA de-protection procedure and used directly in the general displacement procedure to provide the title compound (4 mg, 73.4 mg theoretical, 5%). LC-MS m/z 456.1 (M+1).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O>>[O:31]=[C:22]1[N:21]([C:17]2[CH:16]=[C:15]([F:32])[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:19]([F:20])[CH:18]=2)[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCNCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperidinecarboxylic 1,1-dimethylethyl ester ((EXAMPLE 35, Step 7, 847 mg) and trifluoroacetic acid (12 mL) maintained at 0° C. under N2 is stirred for two hours and then concentrated under reduced pressure to remove excess trifluoroacetic acid. The residue is diluted with saturated aqueous potassium carbonate (70 mL) and methylene chloride (50 mL), and the layers are separated. The aqueous phase is extracted with methylene chloride (2×50 mL), and the combined organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, triturated with diethyl ether and recrystallized from ethyl acetate to give the title compound, NMR (CDCl3, 400 MHz) 7.08, 6.10, 4.78, 4.00, 3.74, 3.64, 3.19, 3.07, 2.72, 2.03, 1.99, 1.68 δ.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][Si](C(C)(C)C)(C)C)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:1])[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1Cl
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a slurry of methyltriphenylphosphonium bromide (0.23 g) in dry THF (5 ml) under nitrogen at −78° C., n-butyl lithium (1.6M in hexanes, 0.37 ml) was added dropwise over 2 min. The mixture was allowed to warm to 0° C., stirred for 20 min, cooled to −78° C. and a solution of 3-chloro-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzaldehyde* (0.134 g) in dry THF (5 ml) added. The reaction mixture was allowed to reach room temperature overnight and quenched with saturated aqueous ammonium chloride. The resultant mixture was extracted with diethyl ether and the combined organic extracts were concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane, followed by 5% to 25% ethyl acetate:cyclohexane) to give the title compound (0.049 g) as an oil. *Boukouvalas, J; Maltais, F; Lachance, N., Tetrahedron Lett. (1994), 35(43), 7897–900.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:19]>C1COCC1.CO>[CH3:19][O:16][C:15]([C:11]1[S:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:13][C:12]=1[CH3:14])=[O:17]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1sc(NC(=O)OC(C)(C)C)nc1C
Reaction time: 6 h

Procedure:
2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid (0.52 g) was dissolved in THF: MeOH (2:1, 10 mL) and 2 eq of TMSCHN2 (2M sln in hex) was added at RT and stirred for 6 h. All volatiles were removed in vacuum by rotavap and the residue was dried in vacuum to give 2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid methyl ester (0.52 g). This was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3) 3.83 (s, 3H), 2.65 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][CH2:11][S:12]([NH2:15])(=[O:14])=[O:13].[Cl:18][C:19]1[C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:23](Cl)[N:22]=[C:21]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[N:20]=1>CN(C)C=O>[Cl:18][C:19]1[N:20]=[C:21]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[N:22]=[C:23]([NH:15][S:12]([CH2:11][CH2:10][CH2:9][C:8]([CH3:17])([CH3:16])[CH3:7])(=[O:14])=[O:13])[C:24]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33]
Reactant: CC(C)(C)CCCS(N)(=O)=O
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)CCCC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
Caesium carbonate (2.62 g) was added to a solution of 4,4-dimethylpentane-1-sulphonic acid amide (720 mg) and 4,6-dichloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidine (Can. Pat. Appl. 2071193) (1.40 g) in dry N,N-dimethyl formamide (8 ml) and the resulting mixture stirred at 80° C. for 4 hours under nitrogen. The reaction mixture was allowed to cool and then partitioned between ethyl acetate (40 ml) and 2N aqueous hydrochloric acid (20 ml). The organic phase was separated, washed (brine 2×20 ml), dried (Na2SO4) and evaporated under reduced pressure. Column chromatography on silica eluting with a solvent gradient of dichloromethane:methanol 100:0 changing to 99:1 gave crude product which was recrystallised from ethyl acetate:pentane to give N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-4,4-dimethyl-1-pentanesulfonamide as a white solid (1.08 g).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[N:6]=[N:7][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([CH3:11])[N:10]=1)=[O:2]>C(O)(=O)C.[Pd]>[CH:1]([NH:3][NH:4][C:5]1[NH:6][N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([CH3:11])[N:10]=1)=[O:2]
Reactant: Cc1nc(NNC=O)nnc1-c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1N=C(NNC=O)NN=C1c1ccccc1
Yield: 21.6 %

Procedure:
A solution of 3-(2-formylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (2.71 g) in acetic acid (60 ml) was hydrogenated over 5% palladium on carbon (2 g) under atmospheric pressure at room temperature. After the theoretical amount of hydrogen gas was absorbed, the catalyst was filtered off, washed with methanol, and the filtrate was evaporated. The residue was dissolved in water, and the solution was washed with chloroform, neutralized with an aqueous solution of sodium carbonate, and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resultant residue was recrystallized from methanol to give colorless crystals of 3-(2-formylhydrazino)-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (0.59 g), m.p. 216°~219° C. (decomp.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[C:14](OC(=O)C)(=[O:16])[CH3:15].[OH-].[Na+]>C(Cl)Cl>[C:14]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1)(=[O:16])[CH3:15]
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)NC1CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
3-Amino-1-benzylpyrrolidine [8.3 g, prepared by a method of G. C. Helsley et al., J. Med. Chem., 11, 1034 (1968)] was dissolved in methylene chloride (40 ml) and thereto acetic anhydride (5.3 g) was added dropwise with stirring under cooling with ice-water and the mixture was stirred for 1.5 hours. After addition of 2N sodium hydroxide (40 ml), the mixture was extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to give 3-acetylamino-1benzylpyrrolidine (9.0 g) as oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](O)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C(=O)(O)[O-].[Na+]>[CH3:9][C:4]1[N:3]=[C:2]2[N:1]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:7]2=[CH:6][CH:5]=1
Reactant: Cc1ccc(O)c(N)n1
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc2oc(-c3ccccc3)nc2n1

Procedure:
A mixture of 1.25 g. of 2-amino-3-hydroxy-6-methylpyridine, 6 g. of polyphosphoric acid and 2.0 g. benzoic acid was heated at 190°-200° C. for 10 minutes. The cooled mixture was diluted with water and basified with solid sodium bicarbonate. The resulting precipitate was collected and recrystallized from ether to give 5-methyl-2-phenyloxazolo[4,5-b]pyridine, m.p. 148°-149° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH:42]=[N:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH:45]([CH3:46])[CH3:47])[CH:42]=[N:41][N:40]=5)=[O:57])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CC(C)C)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CC(C)C)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.7 g) was dissolved in dichloromethane (50 ml). The solution was cooled to −78° C., and a solution of 3-chloroperbenzoic acid (0.39 g) in dichloromethane (5 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (extraction solvent: ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-((4-isobutyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 33) (0.57 g) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Yield: 67.9 %

Procedure:
To a solution of 4-carbamoylpiperidine-1-carboxylic acid tert-butyl ester (5.6 g) in a mixture of tetrahydrofuran (110 ml) and carbon tetrachloride (90 ml) was added triphenylphosphine (24.4 g), and the mixture was stirred under reflux for 1.5 hours. After completion of the reaction, the reaction mixture was filtrated and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) and dried under reduced pressure to give the title compound (3.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CS(O[C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]1)(=O)=O>CN(C=O)C>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([C@H:35]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34]3)[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:18]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc([N+](=O)[O-])cc3)c3c(N)ncnc32)C1
Reaction time: 6 h
Yield: 51.8 %

Procedure:
Synthesis of(S)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate. A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.62 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 6 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford (S)-tert-butyl 3-(4-amino-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.43 g, 52% yield). ESI-MS m/z [M+H]+ found 426.7, calculated 426.2.
Reaction SMILES: [OH:1][C:2]([CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:8][CH:7]=1)=[O:3].[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C>[CH2:40]([O:3][C:2]([CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:8][CH:7]=1)=[O:1])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)OCCCCCCCCCCCCCCCC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 250-mL round-bottom flask were added 2-methyl-acrylic acid 6-[4-(2-hydroxycarbonyl-vinyl)-phenoxy]-hexyl ester (4.98 g, 15.0 mmol), 1-hexadecanol (4.00 g, 16.5 mmol) and DMAP (92 mg, 0.75 mmol) as solids and a stirbar. The flask was purged with N2, followed by the addition of CH2Cl2 (35 mL). The suspension was stirred at room temperature for 20 min to give a white slurry. The flask was cooled in an ice bath and DCC (3.25 g, 15.75 mmol) was introduced. The mixture quickly became a light yellow solution, which was then removed from the ice bath and stirred at room temperature. After 20 h, the resulting white slurry was loaded on a SiO2 column (˜100 g) for quick purification. The product was eluted off with 10% EtOAc in hexanes. The fractions with the desired product were combined, concentrated and then dried in vacuo to a white solid (7.17 g, 86%) of Addition Monomer 7.
Reaction SMILES: II.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:29]([NH:32][NH:33][C:34](=O)[CH2:35][N:36]1[C:40]([CH2:41][CH3:42])=[C:39]([O:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)[C:38]([CH2:52][CH3:53])=[N:37]1)(=[O:31])[CH3:30]>ClCCl>[CH2:52]([C:38]1[C:39]([O:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[CH:48][CH:49]=2)=[C:40]([CH2:41][CH3:42])[N:36]([CH2:35][C:34]2[O:31][C:29]([CH3:30])=[N:32][N:33]=2)[N:37]=1)[CH3:53]
Reactant: CCc1nn(CC(=O)NNC(C)=O)c(CC)c1Oc1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nn(Cc2nnc(C)o2)c(CC)c1Oc1ccc(C#N)cc1
Reaction time: 0.17 h
Yield: 49 %

Procedure:
Iodine (243 mg, 0.95 mmol) was added portionwise to a solution of triphenylphosphine (250 mg, 0.95 mmol) in dichloromethane (10 ml). The reaction mixture was then stirred for 10 minutes, after which time triethylamine (194 mg, 1.9 mmol) was added, followed by the acetylacetohydrazide of step (b) above (170 mg, 0.48 mmol). The reaction mixture was then stirred at room temperature for 12 hours after which time it was evaporated to dryness and purified by flash chromatography on silica gel eluting with ethyl acetate:pentane (1:1, by volume) to provide the title compound (80 mg, 49%) as 4:1 mixture product:triphenylphosphine oxide.