Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]=[CH:6][C@@H:7]([CH3:29])[C@@H:8]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:11][OH:12])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[CH:5]=[CH:6][C@@H:7]([CH3:29])[C@@H:8]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15])[CH:11]=[O:12])[CH3:2]
Reactant: CCOC(=O)C=C[C@@H](C)[C@H](C[C@@H](CO)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)C=C[C@@H](C)[C@H](C[C@@H](C=O)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h

Procedure:
The alcohol 59 (3.86 g, 8.34 mmol) in CH2Cl2 (20 mL) was treated with Dess-Martin periodinane (5.3 g, 12.5 mmol). After 1 h, the mixture was quenched with saturated NaHCO3 (50 mL). The aqueous layer was extracted with ethyl ether (20 mL×2) and the combined extracts were dried over anhydrous MgSO4. Filtration and concentration followed by short flash column chromatography (hexane/EtOAc 4:1) to remove the residue from Dess-Martin reagent provided the aldehyde as a colorless oil: 1H NMR (300 MHz, CDCl3) (s, 1H), 7.02. dd, J=15.9, 6.6 Hz, 1H), 5.77 (dd, J=15.9, 1.4 Hz, 1H), 4.15 (dq, J=1.0, 7.2 Hz, 2H), 4.07 (ddd, J=6.4, 4.8, 1.4 Hz, 1H), 3.84 (ddd, J=8.6, 6.8, 4.4 Hz, 1H), 2.52 (m, 1H), 1.66 (m, 2H), 1.25 (t, J=7.1 Hz, 3H), 0.99 (d, J=6.9 Hz, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H), 0.03 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH:3]([CH2:5][CH3:6])[CH3:4].C(N(CC)CC)C.[CH:17]12[CH2:23][CH:20]([CH:21]=[CH:22]1)[CH:19]1[C:24]([O:26][C:27](=O)[CH:18]21)=[O:25]>C1(C)C=CC=CC=1>[C:7]([CH:2]([N:1]1[C:24](=[O:25])[CH:19]2[CH:18]([CH:17]3[CH2:23][CH:20]2[CH:21]=[CH:22]3)[C:27]1=[O:26])[CH:3]([CH3:4])[CH2:5][CH3:6])([OH:9])=[O:8]
Reactant: CCC(C)C(N)C(=O)O
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(C)C(C(=O)O)N1C(=O)C2C3C=CC(C3)C2C1=O
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a suspension of (dl)-isoleucine (2.03 g, 15.5 mmol) in toluene (40 mL) was added triethylamine (2.4 mL, 17.2 mmol). The mixture was heated to reflux temperature and bicyclo[2.2.1]hept-5-en-2,3-dicarboxylic anhydride (2.53 g, 15.5 mmol) was added. The reaction mixture was kept at reflux temperature and allowed to react for 4 hrs. After cooling to room temperature, the solvent was evaporated and the residue dissolved in H2O. The aqueous solution was washed with EtOAc, acidified with conc. HCl until pH=1, and extracted with EtOAc. The organic phase was washed with 5% HCl and brine and dried over Na2SO4. Removal of the solvent gave a white solid (3.72 g) which was recrystallized from EtOAc/hexane to yield the pure product as colorless crystals: mp=109° C.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][Si:10]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23])([CH3:12])[CH3:11].CI>C1COCC1>[CH3:11][Si:10]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([CH3:2])[C:22]([O:24][CH3:25])=[O:23])([CH3:12])[CH3:9]
Reactant: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 M LDA solution (1.24 mL, 2.48 mmol) was added to solution of methyl 2-(2-((trimethylsilyl)ethynyl)phenyl)acetate (I10) (0.306 g, 1.24 mmol) in THF (10 mL) at −78° C. and the mixture stirred for 30 minutes. Methyl iodide was then added (0.155 mL, 2.48 mmol) and the reaction mixture slowly warmed to room temperature over 1.5 hours. The reaction mixture was then left to stir at room temperature for 18 hours before quenching with a saturated solution of NH4Cl (20 mL). EtOAc (20 mL) was then added and the layers separated. The aqueous layer was further extracted with EtOAc (2×20 mL). The solvent was removed in vacuo to give a brown oil which was purified by column chromatography on silica gel (0-5% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I50) (0.297 g, 92%) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ7.49-7.44 (m, 1H), 7.33-7.24 (m, peaks obscured by CDCl3), 7.21-7.17 (m, 1H), 4.25 (q, J=7.2 Hz, 1H), 3.67 (s, 3H), 1.51 (d, J=7.2 Hz, 3H), 0.26 (s, 9H).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CC(N=[C:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:39]1)C1C=CC(CCC2C=CC=CC=2)=CC=1>>[ClH:1].[CH3:2][CH:3]([N:19]=[C:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:39]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(N=C1CCCCCN1)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1ccccc1OCCc1ccccc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccccc1OCCc1ccccc1

Procedure:
Substituting this amine for the α-methyl-p-phenethylbenzylamine of Example 7 results in the formation of hexahydro-2-[α-methyl-o-(2-phenylethoxy)benzylimino]-azepine hydrochloride, having a M.P. of 189°-90° C. (dec.).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:39][O:38][C:17]3=[CH:18][C:19]4[CH2:20][C@@H:21]([C:35](O)=[O:36])[N:22]([C@H:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:27][CH3:28])[CH2:23][C:24]=4[CH:25]=[C:16]3[O:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.C[O:43][C:44](=[O:62])[C@@H:45]([NH2:61])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[C:54]=2[CH3:60])=[CH:49][CH:48]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.C(Cl)CCl>[CH3:59][C:55]1[C:54]([CH3:60])=[C:53]([C:50]2[CH:51]=[CH:52][C:47]([CH2:46][C@H:45]([NH:61][C:35]([C@@H:21]3[CH2:20][C:19]4[CH:18]=[C:17]5[O:38][CH2:39][C@H:14]([C:11]6[CH:10]=[CH:9][C:8]([O:1][C:2]7[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=7)=[CH:13][CH:12]=6)[O:15][C:16]5=[CH:25][C:24]=4[CH2:23][N:22]3[C@H:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:27][CH3:28])=[O:36])[C:44]([OH:43])=[O:62])=[CH:48][CH:49]=2)[CH:58]=[CH:57][N:56]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(Oc2ccccc2)cc1)O3
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1ccc(Oc2ccccc2)cc1)O3
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.7 %

Procedure:
(3S,8S)-3-(4-Phenoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (10 mg), (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (8 mg), EDC (5 mg), and HOBt (3 mg) were suspended in 5 mL DCM and NMM (0.009 mL) added. The reaction mixture was stirred at room temperature for 6 hours and directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (9 mg). LCMS (m/z): 775.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2>C(O)C>[CH2:5]([N:6]([CH3:7])[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2)[CH3:4]
Reactant: O=C1NCc2cc(F)ccc21
Solvent: CCO
Product: CCN(C)c1ccc2c(c1)CNC2=O
Temperature: 165 °C
Yield: 59 %

Procedure:
A 500-mL high-pressure bomb reactor was charged with 106b (539 mg, 3.57 mmol), ethanol (30 mL) and excess N,N-ethylmethylamine (50 mL). The mixture was heated at 165° C. for 36 h. After this time, the mixture was concentrated and the resulting residue was purified by flash column chromatography (silica, 98:2 ethyl acetate/triethyl-amine) to afford 106c in 59% yield (397 mg) as a yellow solid: mp 127-129° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.42 (dd, J=7.0, 2.5 Hz, 1H), 6.77-6.75 (m, 2H), 4.23 (s, 2H), 3.46 (q, J=7.0 Hz, 2H), 2.94 (s, 3H), 1.06 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 191.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Li]CCCC.[C:18](=[O:20])=[O:19]>CCOCC>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 500 mL three-neck flask fitted with magnetic stirrer, nitrogen lines and a 125 mL addition funnel was charged with 200 mL of dry ether (newly opened can) and 6-bromo-2-naphthol (15.6 g, 70 mmol). The atmosphere was replaced with nitrogen and a solution of 15 mL of 10M n-BuLi in 100 mL of ether (150 mmol) was added via the addition funnel over a 30 minute period. The solution became pale yellow with a precipitate. After stirring for 20 minutes more, dry ice was added until the solution became quite cold (<-25° C.) and green in color. The solution was warmed to room temperature and quenched by the addition of 200 mL of water. The two-phase system was transferred to a separatory funnel, the layers separated and the ether solution extracted with 100 mL of saturated NaHCO3 solution. The combined aqueous layers were washed with 100 mL of ether and neutralized by careful addition of 12N HCl. The pale blue solid was filtered and dried in the air to give 10.3 g (76%): mp 238°-241° C. (dec.); lit. mp 240°-241° C.; reference: S. V. Sunthankar and H. Gilman, J. Org. Chem., 16, 8 (1951). * ##STR24##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].CC([O-])(C)C.[K+]>CS(C)=O.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:22][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCCSc1ccc(Cl)nc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCSc1ccc(Oc2ccc(Cl)c(Cl)c2)nc1C#N

Procedure:
6-Chloro-3-propylthio-2-pyridinecarbonitrile (12.8 g) was mixed with 10.6 g of 3,4-dichlorophenol in the presence of 7.3 g of t-BuOK in DMSO (10 ml) and THF (100 ml). The desired, 6-(3,4-dichlorophenoxy)-3-propylthio-2-pyridinecarbonitrile was recovered, m.p. 67°-69° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[C:32]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C1(C)OCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(CN1C(=O)c2cccc(OC(C)=O)c2C1=O)C(C)=O
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
Ethyl 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (102.4 mg, 0.34 mmol) was dissolved in dichloromethane, and pyridine (55 μl, 0.682 mmol) and acetyl chloride (49 μl, 0.68 mmol) were then slowly added dropwise to the obtained solution at 0° C. The resulting mixture was then stirred at the same temperature for 10 minutes. After the reaction was completed, the reaction mixture was washed with water and then the aqueous layer was extracted with dichloromethane. The combined organic layer was dried with anhydrous sulfate and distilled under a reduced pressure. The desired product (64 mg, 54%) was obtained by performing column chromatography (eluent: n-hexane/ethyl acetate=3/1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:23]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:22](I)[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][CH:37]([CH3:42])[CH:38]([OH:41])[C:39]#[CH:40]>C1COCC1.CCN(CC)CC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27])[N:30]([S:31]([CH3:34])(=[O:33])=[O:32])[C:39]([CH:38]([OH:41])[CH:37]([CH3:42])[CH3:36])=[CH:40]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1cc(I)c(NS(C)(=O)=O)cc1S(C)(=O)=O)(c1ccccc1)c1ccccc1
Reactant: C#CC(O)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C(O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1S(C)(=O)=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
PdCl2(PPh3)2 (277 mg, 0.38 mmol) and CuI (73 mg, 0.38 mmol) were added to a solution of N-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylsulfonyl)phenyl)methanesulfonamide (2.45 g, 3.8 mmol) in THF (20 mL) and Et3N (10 mL). The mixture was purged with nitrogen for 10 mins followed by addition of 4-methylpent-1-yn-3-ol (745 mg, 7.6 mmol) and stirred at 65° C. for 8 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with 1N HCl (50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel eluting with EtOAc/hexanes (3/7) to provide 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-ol (2.1 g, 90% yield). LC-MS m/z 614 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 7.90 (s, 1H), 7.71-7.67 (s, 4H), 7.46-7.35 (m, 6H), 6.77 (s, 1H), 5.21 (d, J=3.2 Hz, 2H), 6.94 (t, J=6.8 Hz, 1H), 3.22 (s, 3H), 2.90 (s, 3H), 2.61 (d, J=6.8 Hz, 1H), 2.37-2.32 (m, 1H), 1.12 (s, 9H), 1.05 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 147.25, 135.54, 135.28, 135.00, 133.66, 133.00, 132.89, 129.96, 127.85, 121.68, 115.96, 108.69, 72.30, 62.98, 44.33, 41.59, 32.88, 26.89, 20.23, 19.30, 17.61.
Reaction SMILES: [OH-].[K+].CN(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[N+:17](=[CH2:19])=[N-].CCOCC.[CH3:25][C:26]1([CH3:49])[CH2:39][N:38]2[C:29](=[N:30][C:31]3[C:36]([C:37]2=[O:40])=[CH:35][CH:34]=[C:33]([CH:41]=[CH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45]N=2)[CH:32]=3)[CH2:28][CH2:27]1.[N+](=C)=[N-]>O.C(O)C.CCOCC.C(Cl)Cl>[CH3:49][C:26]1([CH3:25])[CH2:39][N:38]2[C:29](=[N:30][C:31]3[C:36]([C:37]2=[O:40])=[CH:35][CH:34]=[C:33]([CH:41]2[CH2:42][CH:43]2[C:48]2[CH:47]=[CH:46][CH:45]=[CH:19][N:17]=2)[CH:32]=3)[CH2:28][CH2:27]1
Reactant: C=[N+]=[N-]
Reactant: CC1(C)CCc2nc3cc(C=Cc4ccccn4)ccc3c(=O)n2C1
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCc2nc3cc(C4CC4c4ccccn4)ccc3c(=O)n2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of KOH (119 equiv) in H2O and ethanol heated to 65° C. was added N-methyl-N-nitroso-p-toluenesul-fonamide (3 equiv) in ether. The diazomethane ether solution was distillated and collected at −78° C. Then, a solution of vinyl-containing material (e.g., 8,8-dimethyl-3-(2-(pyridin-2-yl)vinyl)-8,9-dihydro-6H-pyrido[2,1-b]-quinazolin-11(7H)-one, 1 equiv) and Rh(OAc)2(0.1 equiv) in CH2Cl2 was added to the ethereal diazomethane solution and stirred overnight at room temperature. The mixture was quenched with 10% acetic acid in ethyl acetate, diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography (EtOAc:n-hexane=1:3) to give the cyclopropanated product (e.g., 8,8-dimethyl-3-(2-(pyridin-2-yl)cyclopropyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([I:16])=[CH:9][N:8]=1)C>C(O)C>[I:16][C:10]1[CH:9]=[N:8][C:7]2[NH:6][CH2:5][C:4](=[O:3])[NH:13][C:12]=2[CH:11]=1
Reactant: CCOC(=O)CNc1ncc(I)cc1[N+](=O)[O-]
Solvent: CCO
Product: O=C1CNc2ncc(I)cc2N1

Procedure:
(5-Iodo-3-nitro-pyridin-2-ylamino)-acetic acid ethyl ester (17 g) was dissolved in ethanol. SnCl22H2O was added and the reaction mixture was heated to 80° C. for two (2) hours. The resulting precipitate was filtered and washed with ethanol to give the title compound as a rust colored solid (59-77% yield). M.p. 81° C., LCMS: m/z=275.91 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.94 (s, 2H), 6.94 (bs, 1H), 7.12 (d, J=1.8 Hz, 1H), 7.74 (s, J=1.8 Hz, 1H), 10.40 (bs, 1H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=O)[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:4]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:7]1[N:8]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1
Reactant: O=c1nc(-c2cccc(C(F)(F)F)c2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(Cl)n2)c1

Procedure:
The title compound was prepared from 6-trifluoromethyl-4-(3-trifluoromethylphenyl)-1H-pyrimidin-2-one (7.85 g, 25.5 mmol) and phosphoroxychloride (85 mL) according to the general procedure I. Obtained as a yellow solid (5.33 g, 64%). MS (EI) 326.1 [(M)+]; mp 65° C.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[C@H:12]([OH:21])[CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:22])[CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[S:24]([O:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[C@H:12]([O:21][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:22][S:24]([CH3:23])(=[O:26])=[O:25])[CH:3]=1)([CH3:23])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1C[C@@H](O)C2=O
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4c(cc(OS(C)(=O)=O)cc4OS(C)(=O)=O)CC[C@@H]3[C@@H]1C[C@@H](OS(C)(=O)=O)C2=O
Temperature: 0 °C

Procedure:
A solution of 400 mg. of 1,3,16α-trihydroxy-8α-estra-1,3,5(10)-trien-17-one in 5 ml. of pyridine is combined at 0° C. with 1.5 ml. of methanesulfonic acid chloride and agitated for 3 days at 0°-10° C. The mixture is thereafter introduced inyo ice water (acidified with HCl), filtered off, and the residue is dissolved in methylene chloride. After chromatography on SiO2, 250 mg. of 1,3,16α-tris(mesyloxy)-8α-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [C:1]([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16]([OH:18])[C@H:15]([N:19]2[C:23]3[N:24]=[C:25]([NH2:29])[NH:26][C:27](=[O:28])[C:22]=3[S:21][C:20]2=[O:30])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:32](=[S:40])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16]([O:18][C:32]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:40])[C@H:15]([N:19]2[C:23]3[N:24]=[C:25]([NH2:29])[NH:26][C:27](=[O:28])[C:22]=3[S:21][C:20]2=[O:30])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](OC(=S)Oc2ccccc2)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Yield: 33.4 %

Procedure:
To a solution of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl benzoate (compound 26d, 4.32 g, 10.0 mmol) in DCM (60 mL) was added DMAP (2.44 g, 20 mmol) and O-phenyl chloromethanethioate (1.6 mL, 12.0 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:10 to 1:1 EtOAc in petroleum ether) to afford 1.9 g of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-phenoxycarbothioyloxy-tetrahydrofuran-2-yl]propyl benzoate (compound 26e). MS obsd. (ESI+) [(M+H)+]: 569.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=1>>[Cl:10][C:11]1[N:12]=[C:13]([Cl:18])[CH:14]=[C:15]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[N:16]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Clc1cc(Cl)nc(Cl)n1
Product: Clc1cccc(Cc2cc(Cl)nc(Cl)n2)c1
Yield: 26 %

Procedure:
The title compound was prepared in analogous manner as described in example 2a) from 3-chloro-benzylbromide and 2,4,6-trichloropyrimidine. It was obtained as a pale-yellow oil in 26% yield.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: OB(O)c1cncnc1
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide (Stage 182.1) and pyrimidin-5-ylboronic acid to afford a light yellow foam. HPLC (Condition 4) tR=5.23 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=464.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87 (t, J=6.84 Hz, 3H) 3.14 (m, J=7.00 Hz, 2H) 3.32-3.54 (m, 4H) 4.61 (t, J=5.28 Hz, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.84 (d, J=1.00 Hz, 2H) 8.10 (dd, J=2.35, 1.17 Hz, 1H) 8.77 (dd, J=2.35, 1.17 Hz, 1H) 9.01 (d, J=0.78 Hz, 2H) 9.19 (d, J=1.17 Hz, 1H) 10.26 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>C(O)(=O)C>[CH3:1][C:2]1[N:15]([C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[Cl:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc2ccsc2c(=O)o1
Reactant: Nc1ccccc1Cl
Solvent: CC(=O)O
Product: Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl
Yield: 51.3 %

Procedure:
2-Methyl-thieno[3,2-d][1,3]oxazin-4-one (1.67 g, 10 mmol) and o-chloroaniline (2.1 mL, 20 mmol) were combined in acetic acid (20 mL) and refluxed for 4.5 hours. The reaction was partitioned between ethyl acetate and water. The two phase mixture was treated with sodium bicarbonate until the aqueous layer was basic and the phases were then separated. The aqueous phase was extracted with ethyl acetate and the combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to leave a brown oil. This residue was purified by flash chromatography on silica gel (30×150 mm). Elution with 10% and 20% ethyl acetate/hexane gave 1.42 g (51%) of 2-methyl-3-(2-chlorophenyl)-3H-thieno[3,2-d]pyrimidin-4-one was isolated as a brown oil which solidified on standing.