Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH2:12]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])[CH3:13].C(O)(=O)C>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH:20]2[CH2:21][CH2:22][CH2:23][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:18][CH2:19]2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCOC(=O)N1CCCC(=O)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C2CCCN(C(=O)OCC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Ethyl isonipecotate (2.54 g, 2.50 mL, 16.2 mmol) and 4-oxoazepane-1-carboxylic acid ethyl ester (3.00 g, 16.2 mmol) were dissolved in DCM (100 mL) at rt and titanium isopropoxide (5.07 g, 5.40 mL, 17.8 mmol) was added. The reaction mixture was stirred at rt for 1 h. STAB (13.7 g, 32.4 mmol) and acetic acid (0.5 mL) were added and the reaction mixture was stirred at rt overnight under nitrogen. The reaction mixture was quenched with the addition of water (5 mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was washed with sat. NaHCO3 sol., sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 Å, 50 mL per min, gradient 2% to 4% MeOH in DCM]) to give ethyl 4-[4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (2.56 g, 48%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[C:12]([C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][N:15]=3)[S:11][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1S
Reactant: CC(C)(C)OC(=O)CCc1ccnc(C#N)c1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccc(F)cc3s2)c1
Yield: 55.5 %

Procedure:
4-Fluorothiosalicylic acid (1.9 g, 11.3 mmol) and tert-butyl 3-(2-cyano-4-pyridyl)propanoate (1.3 g, 5.6 mmol) were dissolved in pyridine (20 ml), and the mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.2 g, 54%) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](O)=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[NH:3]1.S(Cl)([Cl:22])=O>>[Cl:22][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[C:2](=[O:1])[NH:3][C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[S:6][C:7]=2[CH:12]=1)=[O:14]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(c1)Sc1ccccc1NC2=O

Procedure:
Heat a solution of 5 gm. of 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-3-carboxylic acid and 40 ml of thionyl chloride under reflux for 20 minutes. Evaporate the reaction mixture under vacuum to dryness. Repeat the evaporation with two 30 ml portions of carbon tetrachloride. Crystallize the residue from diisopropyl ether to obtain the title product.
Reaction SMILES: [CH2:1]([C:8]1[C:9](I)=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:24](=[O:28])[CH:25]([CH3:27])[CH3:26].C(OCC)(=O)C>O1CCCC1>[CH2:1]([C:8]1[C:9]([CH:24]([OH:28])[CH:25]([CH3:27])[CH3:26])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: Ic1nc2ccccc2cc1Cc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(O)c1nc2ccccc2cc1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-benzyl-2-iodoquinoline 11 (1 eq., 1.45 g) in dry tetrahydrofuran (20 ml) at −78° C., was added isopropyl magnesium chloride (3 eq., 6.3 ml). The color of the solution was changed from green to orange in 1 h. Isobutyraldehyde 12 (3 eq., 1.15 ml) was added and the reaction mixture was allowed to warm up to room temperature and stirred for another hour. Ethyl acetate was added. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography to yield 150 mg of 1-(3-benzylquinolin-2-yl)-2-methylpropan-1-ol 13.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:56][C:57]([O:60][C:61]([NH:63][C:64]([N:73]1[CH2:78][CH2:77][CH:76]([C:79](O)=[O:80])[CH2:75][CH2:74]1)=[N:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[O:62])([CH3:59])[CH3:58].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:72][C:69]([O:68][C:66]([NH:65][C:64]([N:73]1[CH2:78][CH2:77][CH:76]([C:79]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:80])[CH2:75][CH2:74]1)=[N:63][C:61]([O:60][C:57]([CH3:56])([CH3:58])[CH3:59])=[O:62])=[O:67])([CH3:70])[CH3:71]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To a solution of the compound prepared in Example 6 (0.2 g, 0.7 mmol) in N,N-dimethylformamide (2 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.10 g, 0.26 mmol) at 0° C. After stirring for 20 minutes, the compound prepared in Example 7 (0.12 g, 0.26 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.8 mmol) were added and the reaction stirred at room temperature for 2 h. The reaction was quenched by adding ice cold water and the resulting precipitate was collected by filtration, dried and the crude product purified by flash chromatography to afford the title compound (0.11 g, 61%) as a white solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[Cl:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[N:13]=[CH:12][N:11]=1.O>CN(C)C=O>[CH3:6][O:5][C:1](=[O:4])[CH2:2][O:3][C:14]1[C:15]([N+:16]([O-:18])=[O:17])=[C:10]([Cl:9])[N:11]=[CH:12][N:13]=1
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ncnc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.5 %

Procedure:
In a 50 ml flask at low temperature, methyl glycolate (0.22 ml, 2.8 mmol) and sodium hydride (114 mg, 2.8 mmol) were dissolved in N,N-dimethyl formamide (7 ml) and then stirred for 10 minutes. 4,6-dichloro-5-nitro-pyrimidine (500 mg, 2.6 mmol) dissolved in N,N-dimethyl formamide (6.5 ml) was added thereto dropwise and then stirred at the same temperature for additional 10 minutes, and then the temperature was raised to room temperature and stirred for additional 10 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography eluting with a solvent of dichloromethane to obtain yellow liquid (280 mg, 44%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][C@H:15]1[CH2:20][NH:19][C@H:18]([CH3:21])[CH2:17][NH:16]1.O>CN(C=O)C>[CH3:14][C@H:15]1[CH2:20][NH:19][C@H:18]([CH3:21])[CH2:17][N:16]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1
Temperature: 80 °C

Procedure:
A 1 g portion of 4-fluoro-2-trifluoromethylbenzonitrile and 2.4 g of trans-2,5-dimethylpiperazine were dissolved in 30 ml of DMF and heated at 80° C. for a whole day and night. The reaction solution was mixed with water, extracted with ethyl acetate and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography, and 1.3 g of the title compound was obtained from chloroform-methanol (10:1, v/v) eluate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:28]5[C@H:35]([CH3:36])[CH2:34][C@@H:33]([O:37]C(=O)C6C=CC([N+]([O-])=O)=CC=6)[C:29]=5[N:30]=[CH:31][N:32]=4)=[CH:23][CH:22]=3)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>C(Cl)Cl>[OH:55][C:49]([C:51]([F:54])([F:53])[F:52])=[O:50].[OH:55][C:49]([C:51]([F:54])([F:53])[F:52])=[O:50].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[C:28]5[C@H:35]([CH3:36])[CH2:34][C@@H:33]([OH:37])[C:29]=5[N:30]=[CH:31][N:32]=4)=[CH:25][CH:26]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(-c3ccc(C4(c5ccc(Cl)cc5)CCN(C(=O)OC(C)(C)C)CC4)cc3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C4(c5ccc(Cl)cc5)CCNCC4)cc3)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
tert-Butyl 4-(4-chlorophenyl)-4-(4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperidine-1-carboxylate (36 mg, 0.069 mmol) was dissolved in DCM (3 mL) and cooled to 0° C. Then TFA (1.5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 1 hour, concentrated under reduced pressure, dissolved in DMF (1 mL) and purified by reverse phase HPLC (0-100% AcCN/H2O) to give (5R,7R)-4-(4-(4-(4-chlorophenyl)piperidin-4-yl)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol di-TFA salt (9 mg, 31% yield). 1H NMR (DMSO-d6, 400 MHz) δ 9.09 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.42 (q, J=4.8 Hz, 4H), 5.64 (d, J=6.0 Hz, 1H), 5.06 (q, J=6.8 Hz, 1H), 3.85 (br s, 1H), 3.05 (br s, 3H), 2.89 (m, 2H), 2.61 (br s, 3H), 2.11 (m, 2H), 1.16 (t, J=6.4 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H). LCMS: M+1 420.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[Mg].[CH2:11]([S:18]C1C=CC(C#N)=CC=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C.O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH3:8])[C:11]([C:12]1[CH:13]=[CH:14][C:15]([CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:16][CH:17]=1)=[S:18]
Reactant: N#Cc1ccc(SCc2ccccc2)cc1
Reactant: Cc1ccc(Br)cc1F
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=S)c2ccc(Cc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A solution of 95 g (500 mmol) of 4-bromo-2-fluorotoluene in 200 ml of anhydrous ethyl ether is added dropwise to a suspension of 12.2 g (500 mmol) of magnesium turnings covered with anhydrous ethyl ether. When the addition has ended, the mixture is stirred for 30 minutes at room temperature and a solution of 50 g of 4-(benzylthio)benzonitrile in 200 ml of anhydrous tetrahydrofuran is then added dropwise. The ethyl ether is distilled and the mixture is refluxed for 6 hours. After cooling, the mixture is run dropwise into 600 ml of 6N hydrochloric acid solution and the resulting solution is refluxed for 6 hours. After the addition of isopropyl ether, the crystals formed are filtered off and washed with ethanol and then with ethyl ether to give 55.4 g of 3-fluoro-4-methyl-4'-benzylthiobenzophenone in the form of crystals melting at 122° C.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[CH2:37][CH2:38][O:39]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:22][C:5]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:39][CH2:38][CH2:37][C:26]2[N:27]=[C:28]([C:30]3([CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[O:29][C:25]=2[CH3:24])=[CH:9][CH:8]=1)[C:4]([OH:23])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1C
Product: Cc1ccccc1OC(C)(Cc1ccc(OCCc2nc(C3(C)CCCCC3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxy-propionic acid ethyl ester and Toluene-4-sulfonic acid 2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethyl ester. 1H NMR (400 MHz, CDCl3): δ 7.14-7.11 (m, 3H), 7.08-7.04 (m, 1H), 6.91 (t, 1H, J=7.82 Hz), 6.81 (d, 1H, J=8.60 Hz), 6.76 (d, 2H, J=8.60 Hz), 4.10 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.18 (d, 1H, J=14.08 Hz), 2.93 (t, 2H, J=6.26 Hz), 2.27 (s, 3H), 2.17 (s, 3H), 2.13-2.06 (m, 2H), 1.54-1.48 (m, 8H), 1.40-1.34 (m, 3H), 1.27 (s, 3H). MS [EI+] 492 (M+H)+, [EI−] 490 (M−H)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C@@H:26]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:31]=1)[CH2:27]O)[CH2:19]2.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C@@H:26]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:31]=1)[CH2:27][N:46]1[C:42](=[O:52])[C:43]3[C:44](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:45]1=[O:47])[CH2:19]2
Reactant: C[Si](C)(C)C#Cc1cccc(C[C@@H](CO)N2Cc3cc(Br)ccc3C2=O)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccc(C[C@@H](CN2C(=O)c3ccccc3C2=O)N2Cc3cc(Br)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of diisopropyl azodicarboxylate (0.35 mL, 1.8 mmol) in tetrahydrofuran (2.9 mL) was added 5-bromo-2-((1S)-2-hydroxy-1-{3-[(trimethylsilyl)ethynyl]benzyl}ethyl)-isoindolin-1-one (0.58 g, 1.3 mmol), phthalimide (0.21 g, 1.4 mmol), and triphenylphosphine (0.35 g, 1.3 mmol). The mixture was stirred at room temperature for 4 h. Direct purification by combi-flash chromatography eluting with 0-60% EtOAc in hexanes afforded the desired product. LC-MS found: 571.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:23](O)[CH2:24][CH2:25]CC>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH2:7][CH2:23][CH2:24][CH3:25])=[O:4]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Reactant: CCCCCO
Agent: [Ti+4]
Agent: CC[O-]
Product: CCCCCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 25 °C

Procedure:
A solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (2.89 g) in 1-pentanol (61 ml) was treated at 0° C. under a nitrogen atmosphere with titanium (IV) ethoxide (0.80 ml). The solution was warmed to room temperature and then slowly heated for 2.5 hours keeping the temperature between 60°-80° C. The excess 1-pentanol was removed by distillation under high vacuum. The residue was washed successively with 50 ml of saturated aqueous NH4Cl solution, two 100 ml portions of saturated aqueous NaHCO3 solution and 50 ml of brine. The organic phase was dried (Na2SO4), filtered and concentrated to afford an oil which was purified by chromatography using preparative HPLC (silica gel, 5% methanol in ethyl acetate). The appropriate fractions were combined and concentrated under vacuum to yield 2.2 g of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, n-pentyl ester as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[CH:17][CH:16]=1>>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[CH:19][CH:20]=2)[N:4]=1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: N#CCCCc1ccc(O)cc1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCCC#N)cc1

Procedure:
According to the method described for Reference Example 45, 4-chloromethyl-2-(furan-2-yl)-5-methyloxazole was allowed to react with 4-(4hydroxyphenyl)butyronitrile to give 4-[4-[2-(furan-2yl)-5-methyl-4-oxazolylmethoxy]phenyl]butyronitrile as an oily product. NMR(δ ppm in CDCl3): 1.85-2.05(2H,m), 2.31(2H,t,J=7Hz), 2.42(3H,s), 2.72(2H,t,J=7.5Hz), 4.97(2H,s), 6.52(1H,dd,J=3.5&2Hz), 6.9-7.0(3H,m), 7.10(2H,d,J=9Hz), 7.53(1H,dd,J=2&1Hz).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][C@@H:14]1[CH2:19][NH:18][CH2:17][C@H:16]([N:20]2[CH:28]=[N:27][C:26]3[C:25](=[O:29])[NH:24][C:23]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:22][C:21]2=3)[O:15]1.C(N(CC)CC)C.[C:48](Cl)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>ClCCl>[OH:12][CH2:13][C@@H:14]1[CH2:19][N:18]([C:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:17][C@H:16]([N:20]2[CH:28]=[N:27][C:26]3[C:25](=[O:29])[NH:24][C:23]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:22][C:21]2=3)[O:15]1
Reactant: O=C(COc1ccccc1)Nc1nc2c(ncn2[C@H]2CNC[C@@H](CO)O2)c(=O)[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COc1ccccc1)Nc1nc2c(ncn2[C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Yield: 82 %

Procedure:
In 30 mL of dichloromethane was suspended 2.0 g of N9-{(2R,6S)-6-(hydroxymethyl)morpholin-2-yl}-N2-(phenoxyacetyl)guanine p-toluenesulfonate (REFERENCE EXAMPLE 1), and 13.9 g of triethylamine and 18.3 g of trityl chloride were added to the suspension under ice cooling. The mixture was stirred at room temperature for an hour. The reaction solution was washed with saturated sodium bicarbonate aqueous solution and then with, water, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. To the residue was added 40 mL of 0.2 M sodium citrate buffer (pH 3)/methanol (1:4 (v/v)), and the mixture was stirred. Subsequently, 40 mL of water was added and the suspension mixture was stirred for an hour under ice cooling. The precipitates were taken out by filtration, washed with cold methanol and dried to give 1.84 g of the objective compound (yield: 82.0%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9].[H-].[Na+].[Br:23][C:24]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].O>CN(C)C=O>[Br:23][C:24]1[CH:31]=[C:30]([O:10][CH:7]([C:6]2[S:5][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)=[N:3][C:2]=2[CH3:1])[CH2:8][CH3:9])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Oc1ccc(C#N)c(Br)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C

Procedure:
500 mg 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol were dissolved in 5 ml dimethylformamide. 108 mg sodium hydride were added and the mixture stirred at room temperature. After thirty minutes commercially available 2-bromo-4-fluorobenzonitrile were added and the reaction mixture stirred at room temperature for one hour. Then 5 ml water were added and the mixture extracted three times with portions of 30 ml ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by reversed phase HPLC to obtain 375 mg 2-Bromo-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].I[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]>[I:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)N(c1ccccc1)c1ccc(-c2ccc(I)cc2)cc1
Yield: 64.9 %

Procedure:
20.3 g (0.15 mol) of acetanilide, 73.1 g (0.18 mol) of 4,4'-diiodobiphenyl, 22.1 g (0.16 mol) of anhydrous potassium carbonate, 2.16 g (0.034 mol) of copper powder, and 35 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 190° C. to 205° C. for 10 hours. The reaction product was then extracted with 200 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 6/1 mixture of toluene and ethyl acetate) to obtain 40.2 g (yield: 64.8%) of N-(4'-iodo-4-biphenylyl)acetanilide. The melting point of the product was from 135.0° C. to 136.0° C.
Reaction SMILES: [NH3:1].[CH2:2]([NH:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[CH2:2]([NH:9][C:10]1[CH:15]=[C:14]([NH2:1])[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Ammonia (49 mmol) is purged in THF for 1 h at −70° C., benzyl-(5-fluoro-2-nitro-phenyl)-amine E-1.1″ (6.000 g; 24 mmol) is added to the reaction mixture. The reaction mixture is stirred in a steel bomb vessel at 90° C. for 16 h. The reaction is then cooled to 0° C., diluted with water and extracted with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered and concentrated under reduced pressure. The residue is used in the next step without further purification (yield: 84%; 5.000 g; 20.554 mmol).