Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:47]=[N:46][C:5]2[O:6][C:7]3([CH2:45][CH2:44]3)[C:8](=[O:43])[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[O:30][CH2:31][C:32]([CH3:41])([CH3:40])[C:33]([O:35]C(C)(C)C)=[O:34])=[CH:20][C:19]=4[CH3:42])=[O:17])[CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:47]=[N:46][C:5]2[O:6][C:7]3([CH2:45][CH2:44]3)[C:8](=[O:43])[N:9]([CH:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[O:30][CH2:31][C:32]([CH3:40])([CH3:41])[C:33]([OH:35])=[O:34])=[CH:20][C:19]=4[CH3:42])=[O:17])[CH2:14][CH2:15]3)[C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2ccccc2OCC(C)(C)C(=O)OC(C)(C)C)ccc1C(=O)N1CCC(N2C(=O)C3(CC3)Oc3ncc(Cl)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2OCC(C)(C)C(=O)O)ccc1C(=O)N1CCC(N2C(=O)C3(CC3)Oc3ncc(Cl)cc32)CC1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a dichloromethane solution (13 ml) of tert-butyl 3-[(4′-{[4-(7′-Chloro-2′-oxospiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazin]-1′(2′H)-yl)piperidin-1-yl]carbonyl}-3′-methylbiphenyl-2-yl)oxy]-2,2-dimethylpropanoate (642 mg) was added at room temperature trifluoroacetic acid (6.5 ml), followed by stirring overnight. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue for neutralization, and then a 10% aqueous citric acid solution was added, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 3-[(4′-{[4-(7′-chloro-2′-oxospiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazin]-1′(2′H)-yl)piperidin-1-yl]carbonyl}-3′-methylbiphenyl-2-yl)oxy]-2,2-dimethylpropanoic acid (440 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[CH:9]=2)[NH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:30]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31]1.O>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=3[F:17])[CH:9]=2)[N:4]([CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][O:30]2)[N:3]=1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]nc(Br)c2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(Br)nn2C1CCCCO1
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of 3-bromo-5-(2,6-difluoro-phenyl)-1H-indazole (30.0 g, 97.05 mmol) and p-toluene sulfonic acid (3.7 g, 19.4 mmol) in THF (776 ml) was added 3,4-dihydro-2H-pyran (18.2 ml, 194.1 mmol) at RT. The mixture was stirred at 70° C. for 8 h. The reaction mixture was cooled to RT. Water was added to the reaction mixture and extracted with EtOAc (2×200 ml). The organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure. The crude product was purified by column using (100-200 mesh) silica with 0-5% EtOAc in hexane to provide 3-bromo-5-(2,6-difluoro-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-indazole (18.5 g, 48.4% yield). MS (ESI, pos. ion) m/z: 393.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]3)[CH2:10][C:9](=[O:18])[O:8][C:5]2=[CH:6][CH:7]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>CCCCCC.O1CCCC1>[OH:18][CH:9]1[CH2:10][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[O:8]1
Reactant: O=C1NC(=O)C2(CC(=O)Oc3ccc(F)cc32)N1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1NC(=O)C2(CC(O)Oc3ccc(F)cc32)N1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a slurry of 640 mg. (0.002 mole) of 6-fluorospiro[chroman-4,4'-imidazolidine]2,2',5'-trione in 40 ml. of toluene at -78° C. was added 852 mg. (0.006 mole) of diisobutylaluminum hydride in hexane, and the reaction mixture allowed to stir at -78° C. for 30 minutes. The reaction was allowed to warm to 0° C. and was stirred for 24 hours. The reaction was recooled to -40° C., 6 ml. of dry tetrahydrofuran was added and the reaction warmed to 0° C. Additional diisobutylaluminum hydride (1.0 ml) was added in 0.2 ml. portions. The reaction mixture was added to 10% hydrochloric acid and the mixture extracted with ethyl acetate. The combined extracts were washed dried and concentrated to dryness. The residue was chromatographed to give 67 mg. of the desired compound, m.p. 247°-251° C. (dec.).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH:9]=[CH:10][CH:11]=[C:12]2[O:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:7][C:6]=1[O:21][CH3:22])([CH3:3])[CH3:2]>[C].[Pd].O1CCCC1>[CH:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][CH2:11][CH:12]2[O:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:7][C:6]=1[O:21][CH3:22])([CH3:3])[CH3:2]
Reactant: COc1cc(C=CC=C2OC(=O)NC2=O)ccc1OC(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OC(C)C
Yield: 59.8 %

Procedure:
A mixture of 5-(4-isopropoxy-3-methoxycinnamylidene)-2,4-oxazolidinedione (7.1 g), palladium-carbon (5%, 7.1 g) and tetrahydrofuran (THF) (150 ml) was subjected to catalytic hydrogenation under 1 atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-ethyl acetate (4:1), 5-[3-(4-isopropoxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione (4.3 g, 60%) was obtained as an oily product.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH3:28])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23]C(C)(C)C)=O)[CH2:17][CH2:16]1)=[O:7].C(O)(C(F)(F)F)=O.[NH:38]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@@H:39](C(O)=O)[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C@@H:39]([NH:38][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:21]([N:18]2[CH2:17][CH2:16][CH:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]3[CH:3]=[CH:4][N:5]([CH3:28])[C:6]3=[O:7])[CH2:20][CH2:19]2)=[O:23])=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: COC(CN(C)C(=O)Nc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccn(-c2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)OC(C)(C)C)CC2)c1=O
Temperature: 25 °C

Procedure:
To a 150 mL round-bottomed flask equipped with stirring was added tert-butyl 4-(2-{[(2,2-dimethoxyethyl)methylamino]carbonylamino}phenyl)-piperidinecarboxylate (Step a) (1.4 g, 3.3 mmol) and a 50% aqueous TFA soln (50 mL). The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL), stirred at 0° C. and treated with Boc-p-Cl-D-PheOH (Advanced ChemTech) (0.94 g, 3.15 mmol), HOBT (Novabiochem) (0.425 g, 3.15 mmol), TEA (Aldrich) (0.44 mL, 3.15 mmol) and EDC (Advanced ChemTech) (0.91 g, 4.7 mmol). The reaction was warmed to RT over 2 h and stirred at RT for 12 h. The reaction mixture was diluted with CH2Cl2 (60 mL) and the organic phase was washed with satd NaHCO3 (50 mL), and satd NaCl (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a pale yellow oil (0.55 g). MS (ESI, pos. ion) m/z: 539 (M+1). Calc'd for C29H35ClN4O4: 538.23.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[CH:32][C:31]=3[O:40][CH3:41])[C@H:14]2[CH3:42])[CH:10]=[CH:11][CH:12]=1>C1COCC1.Cl.CCOC(C)=O>[F:39][C:33]1[C:34]([CH:36]([CH3:38])[CH3:37])=[CH:35][C:30]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:20]=2[CH2:19][N:15]2[C@@H:14]([CH3:42])[C@@H:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[CH:2]=[O:1])[O:17][C:16]2=[O:18])=[C:31]([O:40][CH3:41])[CH:32]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cccc(C3OCCCO3)c2)[C@@H]1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cccc(C=O)c2)[C@@H]1C

Procedure:
The solution of (4S,5R)-5-[3-(1,3-dioxan-2-yl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 210) (380 mg, 0.647 mmol) in THF and 1N HCl (3:1) (4 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried and concentrated in vacuo. The crude material was purified by flash chromatography (Si) to provide 3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde. LCMS calc.=530.19; found=530.4 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 10.03 (s, 1H); 7.88 (s, 0.5H); 7.87 (s, 0.5H); 7.77-7.52 (m, 5H); 7.37 (d, J=3.5 Hz, 0.5H); 7.36 (d, J=3.4 Hz, 0.5H); 7.02 (d, J=8.4 Hz, 0.5H); 6.99 (d, J=8.4 Hz, 0.5H); 6.71 (d, J=3.5 Hz, 0.5H); 6.69 (d, J=3.4 Hz, 0.5H); 4.17 (d, J=15.8 Hz, 0.5H); 6.98 (d, J=15.8 Hz, 0.5H); 3.78 (s, 3H); 3.85-3.71 (m, 1H); 3.26-3.19 (m, 1H); 1.30-1.26 (m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H); 0.53 (d, J=6.6 Hz, 1.5H); 0.40 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1
Reactant: Cn1cc(-c2ncc(-c3ccc4cc(O)ccc4c3)o2)c2ccccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2cc(-c3cnc(-c4cn(C)c5ccccc45)o3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A mixture of 6-[2-(1-methyl-1H-indol-3-yl)-oxazol-5-yl]-naphthalen-2-ol (289 mg, 0.843 mmol), prepared in step 4 of Example 8, methyl bromoacetate (80 μL, 0.845 mmol) and cesium carbonate (852 mg, 2.61 mmol) in 50 mL of acetone was stirred under nitrogen at room temperature for 19 h (overnight). The acetone was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic layer was separated and the aqueous layer extracted two times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give methyl ({6-[2-(1-methyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (289 mg, 90%) as a tan solid, mp 187-189° C. Elemental Analysis for C25H20N2O4 Calc'd: C, 72.80; H, 4.89; N, 6.79. Found: C, 71.55; H, 4.86; N, 6.53
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](Cl)=[O:33]>>[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])=[O:33]
Reactant: O=C(Cl)c1ccco1
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Product: O=C(CCNC(=O)c1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylcarbonyl)amino]-1-oxopropyl]hydrazide (31) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared in the manner described above in Example 9, and 2-furoyl chloride in the same manner as described in Example 10 on a 1.9 mmol scale to yield 0.37 g (43%) of product.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: Cc1ccccc1C=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1C
Yield: 98.4 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2-methylcinnamic acid (2.3 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.2 g, 98%) as an oily product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(Cl)nc32)cc1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)nc32)cc1
Yield: 90.7 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(4-methylphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example T-2, 0.17 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.17 g of the title compound as a solid, mp 192-194° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][C:33]1([CH3:41])[O:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][O:34]1.[CH3:42][C:43]1[CH:48]=[C:47]([C:49]2[N:53]=[C:52]([C:54]3[S:61][C:60]([CH3:62])=[C:59]4[C:55]=3[CH2:56][C@H:57]3[C:63]([CH3:65])([CH3:64])[C@H:58]34)[O:51][N:50]=2)[CH:46]=[C:45]([CH3:66])[C:44]=1O>C1COCC1>[CH3:32][C:33]1([CH3:41])[O:38][CH2:37][CH:36]([CH2:39][O:40][C:44]2[C:45]([CH3:66])=[CH:46][C:47]([C:49]3[N:53]=[C:52]([C:54]4[S:61][C:60]([CH3:62])=[C:59]5[C:55]=4[CH2:56][C@H:57]4[C:63]([CH3:64])([CH3:65])[C@H:58]45)[O:51][N:50]=3)=[CH:48][C:43]=2[CH3:42])[CH2:35][O:34]1
Reactant: CC1(C)OCC(CO)CO1
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCC1COC(C)(C)OC1
Reaction time: 24 h
Yield: 66.6 %

Procedure:
To a solution of triphenylphosphine (161 mg, 0.615 mmol) in dry THF is added DEAD (0.097 mL, 0.615 mmol). The solution is stirred at rt for 1 h before (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (90 mg, 0.615 mmol) and 2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenol (150 mg, 0.410 mmol) is added. Stirring is continued for 24 h. The reaction mixture is purified by prep. HPLC (Waters XTerra Prep MS C18 19×50 mm 5 μm, water (0.85% NEt2)/acetonitrile) to give 3-[4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-phenyl]-5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazole (135 mg) as colourless lyophilisate; LC-MS: tR=1.29 min, [M+1]+=495.30.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][C@@H:13](Cl)[C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4C[C@@H](Cl)[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Yield: 44.1 %

Procedure:
One gram of 3β-acetoxy-16α-chloro-5-pregnen-20-one is treated analogously to Example 1 in "Dowtherm" for 6 hours at 240° C. and worked up. Recrystallization from isopropyl ether yields 400 mg of 3β-acetoxy-5,16-pregnadien-20-one (56% of theory).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[C:18]([CH3:21])[N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.C(N(CC)C(C)C)(C)C.C(Cl)Cl>C(O)CCC>[N:31]1[C:23]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[S:20][CH:19]=[C:18]([CH3:21])[N:7]3[C:8](=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH3:3])=[C:24]2[C:28]([NH:27][CH:26]=[N:25]2)=[N:29][CH:30]=1
Reactant: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCCCO
Product: Cc1csc2nc([C@H](C)Nc3ncnc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 105 °C

Procedure:
A mixture of (S)-7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (108.2 g, 357 mmol), 6-chloropurine (71.73 g, 464.1 mmol), and N,N-diisopropylethylamine (74.6 mL, 428.4 mmol) in 1-butanol (952 mL) was degassed with nitrogen bubbling for 5 minutes. The reaction mixture was heated at 105° C. under nitrogen for 15 hours, at which point HPLC indicated amine was consumed. The reaction mixture was cooled down to room temperature before being treated with water (200 mL) at room temperature. The resulting mixture was concentrated under reduced pressure to give an oily residue and the residue was treated with CH2Cl2 (1000 mL) to give a brownish clear solution. The resulting solution was washed with 2.5% aqueous sodium carbonate solution (Na2CO3, 250 mL×2) and the organic layer was concentrated under reduced pressure to afford the crude desired product as a brownish solid. The solution of the crude desired product in CH2Cl2 was absorbed onto silica gel (300 g) and the dried silica gel was loaded onto a flash column. The flash column was eluted with pure CH2Cl2 and a mixture of CH2Cl2, MeOH and aqueous NH4OH (2000:10:5) to afford pure desired product. The fractions containing pure desired product were combined and concentrated under reduced pressure. The resulting yellowish solid (90.3 g) was dissolved in a mixture of CH2Cl2 and methanol (500:50 mL). The resulting solution was treated with ethyl acetate (900 mL) and the resulting mixture was distilled until the internal solution temperature reached 68° C. The mixture was then cooled to room temperature and subsequently to 0-5° C. for 1 hour. The solids were collected by filtration, washed with cold ethyl acetate (100 mL), and dried overnight on the filter under vacuum to afford (S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (89.5 g, 59.4% yield, 99.4% ee) as a light yellowish solid. LCMS calculated for C20H17FN7OS (M+H)+ for the free base: m/z 422.1. Found: 422.0; 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.99 (br s, 1H), 7.45 (m, 1H), 7.21-7.12 (m, 3H), 6.8 (m, 1H), 6.42 (s, 1H), 5.52 (br s, 1H), 2.79 (d, J=1.3 Hz, 3H), 1.43 (d, J=7.0 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[N:10]2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.O.NN>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)=[C:4]([C:25]([F:26])([F:28])[F:27])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccc(I)cc2C(F)(F)F)n1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.7 %

Procedure:
To a solution of crude 2-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione (1.7 g, 3.42 mmol) in THF (30 ml) was added hydrazine monohydrate (0.83 ml, 17.1 mmol, Aldrich). The resulting yellow solution was stirred at ambient temperature under nitrogen for 5 h. The resulting suspension was filtered using a hydrophobic frit and the residue washed with ether (approximately 25 ml). The filterate was concentrated in vacuo and the residue loaded in dichloromethane and purified on silica 100 g using 0-100% ethyl acetate-dichloromethane+0-20% methanol (+1% Et3N). The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow solid (0.624 g); LCMS: (System 4) MH+=368, tRET=2.54 min.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=1[CH:12]=O)([O-:3])=[O:2].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[CH:19]=[CH:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:12]=[CH:19][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1[N+:1]([O-:3])=[O:2])[CH3:18]
Reactant: O=Cc1cccc(C=O)c1[N+](=O)[O-]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccc(C=CC(=O)OCC)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
The 2-nitro-1,3-benzenedialdehyde (3.4 g, 0.019 mole) is dissolved in toluene (60 ml) and carbethoxymethylene triphenylphosphorane (19.2 g, 0.06 mole) is added. The mixture is heated at 60° C. for eight hours, cooled, and concentrated at reduced pressure. Diethyl ether (100 ml) is added and the mixture is filtered. The filtrate is concentrated and purified by flash chromatography over silica (elution with 4:1 hexane:ethyl acetate) to afford, after concentration, pure 2-nitro-1,3-benzenediacrylic acid diethyl ester, mp 114°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17](F)=[CH:18][C:13]=2[NH:12][C:11](=[O:21])[CH2:10][N:9]=1.[CH3:22][OH:23].[H-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([O:23][CH3:22])=[CH:18][C:13]=2[NH:12][C:11](=[O:21])[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(F)c(F)cc2N1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=O)N2
Temperature: 100 °C

Procedure:
A mixture of 0.10 g (0.00033 mole) of 5-(2-chlorophenyl)-7,8-difluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Imm), 2 mL of methanol and 0.03 g of sodium hydride was heated at 100° C. for 40 minutes using microwave heating in a sealed reaction vessel. The mixture was then cooled. diluted with ethyl acetate and washed successively with water and then brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.103 g of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ia) as a white solid. MH+/Z=319.