Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([PH:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[NH2:20][C@H:21]([C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([P:9]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([NH:20][C@H:21]([C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[PH](=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Product: CCCCCCCCP(=O)(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
Octylphosphinic acid, phenylmethyl ester is reacted with L-phenylalanyl-L-leucine, phenylmethyl ester, hydrochloride salt according to the procedure of Example 1(c) to yield N-[N-[octyl(phenylmethoxy)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.N.[Li].[Cl-].[NH4+]>O1CCCC1.C(O)(C)(C)C>[O:2]=[C:3]1[CH2:8][CH2:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH2:4]1
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C(O)CCC1=CCC(=O)CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4.4 g of 4-methoxybenzenepropionic acid and 75 ml of tert-butanol, 50 ml of tetrahydrofuran and 300 ml of liquid ammonia there was added 0.85 g of lithium wire in 2-3 cm pieces over a 10 minute period to give a mixture which had a persistent deep blue color. After an additional 10 minutes, 13.4 g of powdered ammonium chloride was added and the ammonia was allowed to evaporate. The residue was dissolved in 300 ml of water and washed twice with 200-ml portions of ether. The aqueous mixture was acidified with concentrated hydrochloric acid and extracted thoroughly with three 200-ml portions of ether. The combined organic layers were dried over magnesium sulfate and the solvent was evaporated to give 4-oxocyclohex-1-enepropionic acid as a clear oil. 1H NMR (CDCl3) δ 2.20-2.80 (br m, 20H); 5.45 (m, 1H); 11.3 (br s, 1H).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([Cl:5])[Cl:4].[Cl:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:7][Si:8]([Cl:10])([Cl:9])[CH2:2][Si:3]([Cl:5])([Cl:4])[CH3:6]
Reactant: C[Si](Cl)(Cl)CCl
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Yield: 59.8 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.18 g (0.61 mmol) of tetrabutylphosphonium chloride, 1.00 g (6.12 mmol) of (chloromethyl)methyldichlorosilane, and 2.52 g (18.6 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 0.96 g of 1,1,1,3,3-pentachloro-1,3-disilabutane (yield; 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[C:30]([O:34][C:35]([NH:37][C:38]1[N:43]=[CH:42][C:41]([C:44](O)=[O:45])=[CH:40][N:39]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:36])[NH:37][C:38]1[N:43]=[CH:42][C:41]([C:44](=[O:45])[NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][S:21]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)(=[O:22])=[O:23])=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[CH:40][N:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)cn1
Product: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(NC(=O)c1cnc(NC(=O)OC(C)(C)C)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 7-methoxy-8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Example 22, Step 1) and 2-[(tert-butoxycarbonyl)amino]pyrimidine-5-carboxylic acid. High vacuum drying gave the title compound (227 mg, 74%): HPLC MS RT=2.57 min, MH+=645.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 1.46 (9H, s), 2.22-2.27 (2H, m), 3.15-3.18 (4H, m), 3.24-3.29 (2H, m), 3.62-3.65 (4H, m), 4.00 (3H, s), 4.20-4.27 (2H, m), 4.38 (2H, t), 4.52-4.58 (2H, m), 7.47 (1H, d), 8.03 (1H, d), 9.26 (2H, s).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:30][N:29]=[C:28]([CH3:31])[N:27]=1.N1C(C)=CC=CC=1C>ClCCl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:8]([NH:25][C:26]2[S:30][N:29]=[C:28]([CH3:31])[N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nsc(N)n1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2nc(C)ns2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (prepared as in Example 1, 102 mg, 0.40 mmol) in dichloromethane (2 mL) was treated with oxalyl chloride (218 μL of 2M solution in dichloromethane), and N,N-dimethylformamide (1 drop). Effervescence was observed. The reaction mixture was stirred for 0.5 h at 25° C., under nitrogen. The reaction mixture was concentrated, and dissolved in N,N-dimethylformamide (2 mL) and treated with 5-amino-3-methyl-1,2,4-thiadiazole (48 mg, 0.41 mmol), and 2,6-lutidine (64 mg, 0.60 mmol). The reaction mixture was stirred at 25° C., under nitrogen for 18 h. The reaction mixture was diluted with methylene chloride, washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 4 g; 0% to 35% methanol/dichloromethane) to afford ((S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-propionamide (30 mg, 22% as a white powder: LR-ES-MS m/z calculated for C16H22N4O3S [M]+ 350, observed [M+H]+ 351; 1H NMR (300 MHz, CDCl3) δ ppm 0.74-0.96 (m, 1H) 1.03-1.42 (m, 3H) 1.38-2.15 (m, 7H) 2.53 (s, 3H) 3.83 (s, 3H) 3.98 (d, J=17.8 Hz, 1H) 4.13 (d, J=17.8 Hz, 1H) 5.24 (t, J=7.7 Hz, 1H) 5.38 (s, 1H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].Cl.OO.N=O.[CH2:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O.O=[Fe].O=[Fe]O[Fe]=O.C(#N)C>[CH:18]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: C1CCCCC1
Agent: O=[Fe]
Agent: O=[Fe]O[Fe]=O
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Yield: 50 %

Procedure:
Iron (II,III) oxide (0.107 g, 0.462 mmol) is added to a mixture of 2.51 g (14.6 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 24 ml of acetonitrile, and 15 ml of cyclohexane. The reaction mixture is brought to reflux, and a solution of 0.306 g of concentrated hydrochloric acid in 2 ml of water is added. A solution of 4.49 g (66 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 70 minutes to the reaction mixture while the reaction temperature is maintained at 60-62 degrees. After approximately 65% of the peroxide is added, 0.055 g (0.238 mmol) of iron (II,III) oxide and a solution of 0.107 g of concentrated hydrochloric acid are added to the reaction mixture. The mixture is heated at reflux after the peroxide is added until GC analysis shows that the starting nitroxyl compound is no longer present. After work up and purification according to the procedure of Example 54, the yield of the title compound is 1.87 g (50% yield), GC assay 96%.
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([C:7]2=[N:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2].O.[H][H]>C(O)(=O)C>[CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([CH:7]2[NH:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2]
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Reactant: [H][H]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C1(C)C(=O)NC2c3ccccc3C(=O)N21

Procedure:
A solution of 1.2 g 3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H), 5-dione in 75 ml acetic acid and 10 ml water containing 100 mg 5% palladium on carbon is shaken in an atmosphere of hydrogen at a pressure of 10 psi and room temperature. One equivalent of hydrogen is absorbed in 75 minutes. The mixture is filtered, and the filtrate concentrated under reduced pressure. To the residue is added toluene which is then removed in vacuo. This is repeated. To the gummy residue is added a small volume of acetonitrile to give the desired 1,9b-dihydro-3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione as a crystalline solid identical to that prepared in Example 1.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[C:34](=[O:35])[C:33]2[S:32][C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[C:25]=2[CH:24]=[N:23]1)(=O)C.Cl[C:37]1[CH:38]=[C:39]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][N:56]([CH:59]4[CH2:62][O:61][CH2:60]4)[CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:40]2[N:41]([CH:43]=[CH:44][N:45]=2)[N:42]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:21][C:9]1[CH:10]=[C:11]([C:37]2[CH:38]=[C:39]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([N:53]4[CH2:58][CH2:57][N:56]([CH:59]5[CH2:62][O:61][CH2:60]5)[CH2:55][CH2:54]4)=[CH:49][N:48]=3)[C:40]3[N:41]([CH:43]=[CH:44][N:45]=3)[N:42]=2)[C:6]([CH2:5][OH:4])=[C:7]([N:22]2[C:34](=[O:35])[C:33]3[S:32][C:31]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=4[C:25]=3[CH:24]=[N:23]2)[CH:8]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nccn2n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=c1c2sc3c(c2cnn1-c1cc(F)cc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4nccn4n2)c1CO)CCCC3
Temperature: 110 °C
Yield: 8.7 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate (200 mg, 0.44 mmol), 6-chloro-N-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine 105a (155 mg, 0.44 mmol), tricyclohexylphosphine (112 mg, 0.4 mmol), Pd2(dba)3 (28 mg, 0.024 mmol), Cs2CO3 (261 mg, 0.8 mmol), and dioxane (25 mL). After three cycles of vacuum/argon flush, the reaction mixture was heated at 110° C. for 16 h. The mixture was evaporated in vacuo and the residue was extracted with ethyl acetate (10 mL×2). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 112 (26 mg, 12%). MS: [M+H]+ 680. 1H NMR (500 MHz, DMSO) δ 9.95 (s, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.67 (s, 1H), 7.45-7.53 (m, 4H), 4.54-4.57 (m, 3H), 4.45-4.47 (m, 2H), 4.33 (d, J=12.5, 2H), 3.35-3.46 (m, 1H), 3.13-3.17 (m, 4H), 2.83-2.94 (m, 4H), 2.47-2.50 (m, 4H), 1.82-1.87 (m, 4H)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2C(=O)C)(=[O:3])[CH3:2].O.S(=O)(=O)(O)[OH:35].C(O)(C)C>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:31]([OH:35])=[O:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Oc1cc(C(=O)O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2NC21
Reaction time: 0.5 h

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (29 mg) in acetone (2 ml) was added a mixture of chromium trioxide (26 mg), water (76 μl) and sulfuric acid (22 μl) in an ice-water bath. After stirring for 30 minutes in an ice-water bath, isopropyl alcohol (2 ml) was added to the reaction mixture. The resultant mixture was then poured into water (10 ml) and extracted with a mixture of chloroform and methanol (2:1, v/v) (10 ml×5). The extracts were combined and dried over magnesium sulfate, and then evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform, methanol and water (65:25:4, v/v) to afford 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylic acid (5 mg).
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.BrC1C=C(C)C(C(N2CCC(N3CCC[C@H]3CO)CC2)=O)=C(C)C=1.[F:47][C:48]([F:81])([F:80])[C:49]1[CH:50]=[C:51]([C:59]2[N:64]=[C:63]([CH3:65])[C:62]([C:66]([N:68]3[CH2:73][CH2:72][CH:71]([N:74]4[CH2:78][CH2:77][CH2:76][CH2:75]4)[CH2:70][CH2:69]3)=[O:67])=[C:61]([CH3:79])[N:60]=2)[CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1.N1CCC(N2CCC[C@H]2[CH2:93][O:94][C:95](=[O:102])[C:96]2[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=2)CC1>>[F:58][C:55]([F:56])([F:57])[C:53]1[CH:52]=[C:51]([C:59]2[N:64]=[C:63]([CH3:65])[C:62]([C:66]([N:68]3[CH2:69][CH2:70][CH:71]([N:74]4[CH2:78][CH2:77][CH2:76][C@H:75]4[CH2:93][O:94][C:95](=[O:102])[C:96]4[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=4)[CH2:72][CH2:73]3)=[O:67])=[C:61]([CH3:79])[N:60]=2)[CH:50]=[C:49]([C:48]([F:47])([F:80])[F:81])[CH:54]=1
Reactant: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Reactant: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4 B), 2-(3,5-bis-trifluoromethyl-phenyl)-4,6-dimethyl-pyrimidine-5-carboxylic acid (example 15) was converted into its acid chloride and subsequently reacted with benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 3) to give benzoic acid (S)-1-{1-[2-(3,5-bis-trifluoromethyl-phenyl)-4,6-dimethyl-pyrimidine-5-carbonyl]-piperidin-4-yl}-pyrrolidin-2-ylmethyl ester, which was subsequently saponified to give the title compound as colorless solid. MS: 531.2 (MH+).
Reaction SMILES: [NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[I-].[K+].P(=O)(O)(O)O.[K].[C:50](#[N:52])[CH3:51]>>[F:34][C:26]1[CH:25]=[C:24]([C:11]2[C:12]([CH3:22])([CH3:23])[C@H:13]3[C@:8]([CH3:35])([CH2:9][CH:10]=2)[C@@H:7]2[C@:16]([CH3:21])([C@@:17]4([CH3:20])[C@H:4]([CH2:5][CH2:6]2)[C@H:3]2[C@H:36]([C:39]([CH3:41])=[CH2:40])[CH2:37][CH2:38][C@:2]2([NH:1][CH2:51][CH2:50][N:52]2[CH2:25][CH2:26][CH2:27][C:28]2=[O:29])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: CC#N
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P(O)(O)O
Agent: [I-]
Agent: [K+]
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Reaction time: 70.25 h
Yield: 41.7 %

Procedure:
To a sealable flask containing methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate (50 mg, 0.089 mmol) was added potassium iodide (39.9 mg, 0.240 mmol) and phosphoric acid, potassium salt (83 mg, 0.392 mmol). The mixture was diluted with acetonitrile (1 mL) and the crude alkylating solution described above (1.007 mL, 0.445 mmol) was added. The mixture was flushed with N2 and the vial was sealed and heated to 120° C. After 15.5 h of heating, the mixture was cooled to rt. An additional 0.5 mL of the crude alkylating solution was added and the mixture was again heated to 120° C. After 70.25 h, the mixture was cooled to rt. The mixture was adsorbed to silica gel and was purified by flash chromatography using a 0-5% MeOH in DCM gradient and a Thomson 12 g silica gel column. The fractions containing the expected product were combined and were concentrated under reduced pressure to give methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (25 mg, 0.037 mmol, 41.7% yield) as a yellow film. LCMS: m/e 673.5 (M+H)+, 2.03 min (method 2).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[SH:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C@@H:21]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]3[OH:23])[N:19]=[CH:20][C:13]=12.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([S:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C@@H:21]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]3[OH:23])[N:19]=[CH:20][C:13]=12)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC[C@H]1O[C@@H](n2ncc3c(S)ncnc32)[C@H](O)[C@@H]1O
Reactant: BrCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](n2ncc3c(SCC=Cc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 40 °C

Procedure:
Cinnamyl bromide (3.04 g) was added to a stirred solution of 4-mercapto-1-β-D-ribofuranosylpyrazolo[3,4-d]-pyrimidine (4.0 g) and potassium carbonate (2.13 g) in N,N-dimethylformamide. The solution was heated (40° C. on an oil bath) for 2 hours. After cooling the reaction mixture was poured into water (0.6 l) and the resultant precipitate was collected and washed with water. The 4-cinnamylthio-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine so obtained was recrystallised from methanol, washed with water and dried (in vacuo at 55° C.), yield 3.2 g, m.p. 165°-166° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)=[CH:12][C:11]=1[CH3:23].O[C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH3:1][C:2]1[C:7]([CH2:8][O:9][C:25]2[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11]([CH3:23])=[CH:12][C:13]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1cccc(CO)c1C
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCOC5)cc4C)c3C)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
(S)-(2,2′,6′-Trimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 12e (75 mg, 0.24 mmol), methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (50 mg, 0.24 mmol) and triphenylphosphine (94 mg, 0.36 mmol) were dissolved in 20 mL of dichloromethane. The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (73 mg, 0.36 mmol), then warmed up to room temperature and stirred for 2 hours. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl 2-((S)-6-((2,2′,6′-trimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 12f (100 mg, yield 83.0%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][O:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH:11]1([C:10]2[O:9][N:8]=[C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[C:4]([OH:5])=[O:3])[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1c(-c2ccccc2)noc1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)noc1C1CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid ethyl ester (408 mg, 1.58 mmol) in ethanol (4 mL) was added aqueous sodium hydroxide (1 N, 3.17 mL, 3.17 mmol) and the mixture was stirred for 3 h at 80° C. The ethanol was distilled off and the residue diluted with water (5 mL) and acified with aqueous HCl (1N) to pH=1. The resulting suspension was filtered off and washed with water affording the title compound (314 mg, 86%) as a white solid. MS: m/e=230.3[M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[C@@H:19]([N:21]([CH3:30])[C:22](=[O:29])/[CH:23]=[CH:24]/[CH2:25][N:26]([CH3:28])[CH3:27])[CH3:20])=[CH:4][N:3]=1.[NH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:27][N:26]([CH3:28])[CH2:25]/[CH:24]=[CH:23]/[C:22]([N:21]([CH3:30])[C@@H:19]([CH3:20])[C:18]([NH:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:3][CH:4]=1)=[O:31])=[O:29]
Reactant: CCCNc1nc(Cl)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C
Reactant: NCCN1CCOCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCCNc1nc(NCCN2CCOCC2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To (S,E)-N-(1-((5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-4-(dimethylamino)-N-methyl-2-butenamide (L4, 30 mg), 4-(2-aminoethyl)morpholine (18 μL), tris(dibenzylideneacetone)dipalladium(0) (6.1 mg), 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene (7.7 mg) and cesium carbonate (65 mg), 1,4-dioxane (2 mL) was added at room temperature, the reaction vessel was sealed, and then the mixture was stirred at 150° C. for 30 minutes by using a microwave reaction system. The reaction mixture was cooled to room temperature, then the insoluble matter was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 95% ethyl acetate/5% methanol) to obtain oily (S,E)-4-(dimethylamino)-N-methyl-N-(1-((5-(2-((2-morpholinoethyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-2-butenamide (12-15, 2.9 mg).