Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:38])[C:32]([OH:37])([CH3:36])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:38])[C:32]([OH:37])([CH3:36])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: CCOC(=O)C(C)(O)C(=O)O
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CCOC(=O)C(C)(O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-hydroxy-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. White solid (>98%). MS: m/e=503(M+H+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16](C1C=CC(OC)=C2C=1C=CN2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Reactant: Brc1ccc2cn[nH]c2c1
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2cn[nH]c2c1

Procedure:
3-(1H-Indazol-6-yl)-3-phenyl-acrylic acid ethyl ester CCXXVII was prepared from 6-bromo-1H-indazole using the procedure described for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][CH2:34][C@H:33]([C:36]#[N:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@@H:30]2[CH2:31][CH2:32][C@H:33]([C:36]#[N:37])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: N#C[C@H]1CC[C@@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@@H](C#N)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (40 mg, 0.4 mmol) and triethyloxonium tetrafluoroborate (89 mg, 0.47 mmol) in tetrahydrofuran (0.4 mL) became a solution after stirring for 15 min. After another 45 min, this solution was added to a mixture of cis-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexanecarbonitrile (32 mg, 0.12 mmol) in ethanol (0.74 mL) and heated at reflux overnight. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.1 mg, 2.9%). LCMS calculated for C17H19N4OS (M+H)+: m/z=327.1. Found: 327.0.
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:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13]([OH:15])=[O:14])[O:12][C:7]=2[CH:6]=1.S(Cl)(Cl)=O.[CH:33]1C=CC=CC=1>>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13]([O:15][CH3:33])=[O:14])[O:12][C:7]=2[CH:6]=1
Reactant: CN1C(=O)C(C)(C(=O)O)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(C)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(2-Chloro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylic acid (Compound 23) (0.4 g) was dissolved in benzene (10 ml), and thionyl chloride (2 ml) was added thereto, followed by heating under reflux for 3 hours. The solvent was then evaporated under a reduced pressure, methanol (5 ml) was added thereto, and the mixture was stirred at room temperature for one hour. The solvent was then evaporated under a reduced pressure, and the residue was purified by use of silica gel chromatography (eluant: n-hexane/ethyl acetate= 3/1) to give 0.2 g of the title compound (colorless crystals).
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].C[N-]C.[Ti+4:13].[CH3:14][Si:15]([CH2:18][Li])([CH3:17])[CH3:16]>CCCCC>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].[CH3:14][Si:15]([CH2:18][Ti+3:13])([CH3:17])[CH3:16]
Reactant: [Ti+4]
Reactant: [Li]C[Si](C)(C)C
Agent: C[N-]C
Solvent: CCCCC
Product: C[Si](C)(C)C[Ti+3]
Reaction time: 1 h
Yield: 17.4 %

Procedure:
To a stirred solution of 4.20 g of titanium tetrakis(dimethylamide) in about 10 ml of pentane was added a solution of 1.77 g of trimethylsilylmethyllithium in pentane. Lithium dimethylamide precipitated immediately. The mixture was stirred for 1 hour and filtered, pentane was removed from the filtrate by rotary evaporation, and the residual pale-yellow oil was distilled through a short still-head under reduced pressure, to give 0.87 g of trimethylsilylmethyltitanium tris(dimethylamide), bp 55° C. (50 μ). Nmr in C6D6 : δ (NMe) 3.07, δ (SiMe) 0.22, δ (CH2) 0.35 ppm downfield from tetramethylsilane.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[CH2:16][C:17]([C:19]1[C:20]([CH:33]([CH3:35])[CH3:34])=[C:21]([O:28][S:29](=[O:32])(=[O:31])[NH2:30])[C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=1)=[O:18])[CH3:3].[CH:36](C1C=CC=C(C(C)C)C=1OS(N=C=O)(=O)=O)([CH3:38])[CH3:37].C(C1C=C(C(C)C)C=C(C(C)C)C=1OS(N=C=O)(=O)=O)(C)C>>[CH3:3][CH:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:7]=[C:6]([CH:13]([CH3:14])[CH3:15])[C:5]=1[CH2:16][C:17]([C:19]1[C:20]([CH:33]([CH3:35])[CH3:34])=[C:21]([O:28][S:29](=[O:31])(=[O:32])[NH2:30])[C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][C:24]=1[CH:36]([CH3:38])[CH3:37])=[O:18])[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1OS(=O)(=O)N=C=O
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1
Agent: CC(C)c1cc(C(C)C)c(OS(=O)(=O)N=C=O)c(C(C)C)c1
Product: CC(C)c1cc(C(C)C)c(CC(=O)c2c(C(C)C)cc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1

Procedure:
This compound was prepared in the same manner as the title compound of Example 5, except that 2,6-diisopropylphenoxy sulfonyl isocyanate was replaced with 2,4,6-triisopropylphenoxy sulfonyl isocyanate, mp 178°-180° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH:6]([C:8]1[C:9](=[O:21])[N:10]([CH3:20])[C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[NH2:7].C(N(CC)CC)C>O1CCOCC1>[CH3:20][N:10]1[C:11]2[C:16](=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[N:17]=[C:8]([NH:6][NH:7][C:1](=[O:4])[CH2:2][CH3:3])[C:9]1=[O:21]
Reactant: CCC(=O)Cl
Reactant: COc1ccc2c(c1)nc(NN)c(=O)n2C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC(=O)NNc1nc2cc(OC)ccc2n(C)c1=O

Procedure:
Propionyl chloride (2.63 g., 28.4 mmol) is added dropwise to a solution of 3-hydrazino-1-methyl-6-methoxy-1H-quinoxalin-2-one (4.5 g., 23.7 mmol) and triethylamine (2.87 g., 28.4 mmol) in 250 ml. of dioxane and stirred at room temperature for four days. The dioxane is then removed under vacuum and the residue washed with water, filtered, and dried at 80° C. under high vacuum. The material is then recrystallized from ethanol, filtered and dried at 80° under high vacuum overnight to yield purified product.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH2:17][CH:18]([OH:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:12]([CH3:25])[CH:11]=1.N1C=CN=C1>ClCCl.CCOC(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH3:25])[C:13]([CH2:17][CH:18]([O:24][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:14]([CH3:16])[CH:15]=1
Reactant: COC(=O)CC(O)Cc1c(C)cc(Br)cc1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CC(Cc1c(C)cc(Br)cc1C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
TBS-Cl (1291 mg, 4.28 mmol) was added to a solution of 2A (860 mg, 2.86 mmol) and imidazole (389 mg, 5.71 mmol) in dichloromethane (20 mL) and stirred overnight at rt. The reaction was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% ethyl acetate in hexane over 15 min using a 40 g silica gel cartridge) to yield 2B (830 mg, 1.998 mmol, 70.0% yield) as a clear oil. 1H NMR (500 MHz, chloroform-d) δ ppm 7.15 (2H, s), 4.28-4.36 (1H, m), 3.68 (3H, s), 2.82 (2H, ddd, J=53.09, 13.89, 7.02 Hz), 2.53 (2H, ddd, J=57.43, 15.06, 6.19 Hz), 2.33 (6H, s), 0.80 (9H, s), −0.10 (3H, s), −0.32 (3H, s).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:40])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:22]=1[CH2:37][CH2:38][CH3:39])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:40])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:37][CH2:38][CH3:39])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 59.1 %

Procedure:
A mixture of 3.0 g of 1-[2,4-dihydroxy-3-propylphenyl)ethanone, 6.65 g of [4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]acetic acid ethyl ester and 4.3 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 24 hours. The reaction mixture was concentrated in vacuo to a red oil which was purified by high pressure liquid chromatography using 25% ethyl acetate-hexane to yield 4.95 g (59%) of [4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy] acetic acid ethyl ester as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH2:3][CH2:2]1.C1COCC1.C1C(=O)N([O:26][C:27]([O:29][CH2:30][CH:31]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)=O)C(=O)C1>C([O-])(O)=O.[Na+]>[CH:42]1[C:43]2[CH:31]([CH2:30][O:29][C:27]([N:1]3[CH2:6][CH2:5][CH:4](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH2:3][CH2:2]3)=[O:26])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]=2[CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)/C=C/C=C/C1CCNCC1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)/C=C/C=C/C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The above solid (24) was taken up in saturated NaHCO3 (50 mL)/THF (50 mL). To this was added Fmoc-Osu (3.0 g, 9.0 mmol) at room temperature. The suspension became clear within 30 min. After stirring at room temperature overnight, the solution was concentrated to remove organic solvent, the resulting white suspension was acidified with 1 N HCl (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried (MgSO4) and concentrated to give a white solid (25) (3.63 g, >100%). 1H NMR (500 MHz, CDCL3) δ 7.77 (d, J=7.5 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.34 (dd, J=15.0, 11.0 Hz, 1H), 7.32 (t, J=7.5 Hz, 2H), 6.21 (dd J=15.0, 11.0 Hz, 1H), 6.09 (dd, J=15.0, 7.0 Hz, 1H), 5.85 (d, J=15.5 Hz, 1H), 4.45 (br s, 2H), 4.18 (m, 3H), 2.83 (br s, 2H), 2.31 (m, 1H), 1.72 (m, 2H), 1.26 (m, 2H); MS (ES+) m/z 404.81 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[C:24]([CH3:26])([CH3:25])[CH2:23][C:22](=O)[CH2:21][C:20]3([CH3:29])[CH3:28])[N:8]=2)[CH2:3][CH2:2]1.C(OCC)(=O)C.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Pt]>[O:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:8]=[C:9]([N:19]3[C:20]([CH3:29])([CH3:28])[CH2:21][CH:22]([NH:40][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:23][C:24]3([CH3:26])[CH3:25])[N:10]=2)[CH2:18][CH2:17]1
Reactant: CCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCNC1CC(C)(C)N(c2nc(N3CCOCC3)nc(N3CCOCC3)n2)C(C)(C)C1

Procedure:
12 g of 2,4-bis-morpholino-6-(4-oxo-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 21) are hydrogenated in 120 ml of methanol and 60 ml of ethyl acetate at 40° and a pressure of 80 bar with 5% platinum on charcoal as the catalyst in the presence of 6 g of butylamine and 0.25 g of p-toluenesulfonic acid until the reaction has ended. The reaction mixture is filtered and evaporated. After dissolving the residue in methylene chloride and washing with water, the organic phase is dried over Na2SO4 and evaporated. The residue is dissolved in toluene/acetone and purified chromatographically on an SiO2 column. The oily product crystallizes after a few days and melts at 82°-87°.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:16])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: COc1cc(F)c(C(=O)O)cc1Br
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(F)c(C(=O)Cl)cc1Br
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, 5-bromo-2-fluoro-4-methoxybenzoic acid (10.0 g) was suspended in DMF/toluene solution (50 mL) (DMF concentration: 300 ppm). To the suspension was added dropwise thionyl chloride (5.73 g) at 70° C. After stirring at 70° C. for 2 hr, the completion of the reaction was confirmed by HPLC. Toluene and excess thionyl chloride were evaporated under reduced pressure. To the concentrated residue was added toluene (30 mL), and the mixture was concentrated again under reduced pressure. To the obtained acid chloride (5-bromo-2-fluoro-4-methoxybenzoic acid chloride) was added toluene (30 mL), and the mixture was directly used in the next step.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][C:11]=1[CH2:10][CH2:9]3.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)(=O)C>[C:27]([O:20][C:13]1[CH:14]=[CH:15][C:16]2[C@@H:17]3[C@H:8]([C@H:5]4[C@@:3]([CH2:19][CH2:18]3)([CH3:4])[C:2](=[CH2:1])[CH2:7][CH2:6]4)[CH2:9][CH2:10][C:11]=2[CH:12]=1)(=[O:29])[CH3:28]
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(OC(C)=O)ccc4[C@H]3CC[C@]12C

Procedure:
A solution of 17-methylenestra-1,3,5(10)-trien-3-ol (10, 5.84 g, 21.8 mmol) in anh. pyridine (32 mL, 0.40 mol) and acetic anhydride (9.7 mL, 0.10 mol) was stirred 24, after which ethyl acetate (250 mL) was added. See FIG. 17. The mixture was washed with three 100 mL portions of 1 N hydrochloric acid+100 mL of saturated sodium bicarbonate+100 mL of saturated copper sulfate+100 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol gave lustrous white platelets (5.84 g, 18.8 mmol), m.p. 77-79° C.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[CH:18][CH:17]=1)[CH3:2].CO.[H][H]>[Pd].C(O)(=O)C>[CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1nc(C(F)(F)F)nc2c1ncn2-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1nc(C(F)(F)F)nc2c1ncn2-c1ccc(O)cc1
Reaction time: 5 h
Yield: 68.1 %

Procedure:
A mixture of 6-ethyl-9-(4-benzyloxyphenyl)-2-trifluoromethylpurine (0.1 mmol), palladium on active carbon (0.001 mol, methanol (50 mL) and acetic acid (3 mL) was shaken under 30 psi hydrogen. After 5 hours, the reaction mixture was filtered through celite and the filtrate was concentrated under vacuum. The resulting residue was dissolved in 30 mL of ethyl acetate and washed with 5% aqueous sodium bicarbonate (1×30 mL). Concentration and Chromatography (5% methanol in dichloromethane) gave 6-ethyl-9-(4-hydroxyphenyl)-2-trifluoromethylpurine (21 mg, 93%). 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.45 (d, J=7.2 Hz, 2H), 6.96 (d, J=7.2 Hz, 2H), 3.29 (q, J=7.5 Hz, 2 H), 3.11 (s, 1H), 1.41 (t, J=7.5 Hz, 3H). [ESMS m/z (309.4 (M+H)+)]
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:23]([Si:26](Cl)([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24].O>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:17][Si:26]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[N:11][NH:12][C:13]=2[CH:14]([CH3:15])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(I)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1[nH]nc(O[Si](C(C)C)(C(C)C)C(C)C)c1Cc1ccc(I)cc1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 1,2-dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-pyrazol-3-one (5 g) and imidazole (1.19 g) in N,N-dimethylformamide (20 mL) was added triisopropylsilyl chloride (3.1 g) at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropylsilyloxy-1H-pyrazole (7.27 g). To a solution of obtained 4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropylsilyloxy-1H-pyrazole (3 g) in N,N-dimethylformamide (10 mL) was added sodium hydride (55%, 0.33 g) under ice-cooling, and the mixture was stirred for 20 minutes. To the reaction mixture were added a solution of 1-benzoyloxy-3-chloropropane (3.0 g) in N,N-dimethylformamide (10 mL) and potassium iodide (0.25 g) at the same temperature, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1-10/1) to give 1-(3-benzoyloxypropyl)-4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropylsilyloxy-1H-pyrazole (2.55 g). This material was dissolved in tetrahydrofuran (3 mL). To the solution was added 4 mol/L hydrochloric acid (1,4-dioxane solution, 10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was poured into water. The organic layer was separated, and the organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added a mixed solvent of n-hexane and ethyl acetate (20/1) (10 mL), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, and washed with a mixed solvent of n-hexane and ethyl acetate (20/1) and dried under reduced pressure to give the title compound (0.85 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19].[NH2:22][CH2:23][CH:24]([NH:51][C:52](=[O:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:25](=[O:50])[NH:26][CH:27]([C:36](=[O:49])[N:37]([CH2:41][CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[CH:38]([CH3:40])[CH3:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH:27]([NH:26][C:25]([CH:24]([NH:51][C:52](=[O:61])[O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:23][NH:22][S:18]([C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[Cl:10])(=[O:20])=[O:19])=[O:50])[C:36](=[O:49])[N:37]([CH2:41][CH:42]([O:43][CH2:44][CH3:45])[O:46][CH2:47][CH3:48])[CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=1
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CN)NC(=O)OCc1ccccc1)C(C)C)OCC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1)C(C)C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
1.94 ml (11.09 mmol) of DIEA and 1.5 g (6.1 mmol) of 2,4-dichlorophenylsulfonyl chloride are added to a solution of 3.2 g (5.54 mmol) of benzyl (2-amino-1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate in 75 ml of DCM. The solution is stirred at room temperature overnight. The solution is then concentrated in vacuo, and the residue is purified by column chromatography on 100 g of SiO2 (eluent DCM followed by 20% EtOAc/DCM). 2.78 g of the desired product are obtained as a colorless foam. MW=784.19 (calculated, monoisotopic); measured value (M+Na)+=807.24
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1)=O.[BH4-].[Na+]>C1COCC1.CO>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:23][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Reaction time: 1 h

Procedure:
The product from step (vii) (55 mg) was combined with methyl (4-formylphenyl)acetate (0.0329 g) and stirred in THF (15 mL) for 16 h. Sodium borohydride (0.015 g) was added followed by MeOH (3 drops) and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with MeOH and purified via RPHPLC to give the title compound. Yield 17 mg.