Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C(F)(F)F)cn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-5-(trifluoromethyl)pyridine following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.86, m/z=503 (M+1); 1H NMR (CDCl3) 8.87 (s, 1H), 7.93 (dd, 1H), 7.72 (t, 3H), 7.18 (m, 2H), 6.98 (m, 4H), 5.67 (m, 1H), 3.52 (t, 1H), 2.89 (m, 1H), 1.49 (d, 3H).
Reaction SMILES: [Na].O.C([O:5][C:6]([C:8]1[N:9]=[C:10]2[CH:17]=[N:16][N:15]([CH2:18][CH3:19])[C:11]2=[N:12][C:13]=1[OH:14])=[O:7])C.[OH-].[Na+]>>[CH2:18]([N:15]1[C:11]2=[N:12][C:13]([OH:14])=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[C:10]2[CH:17]=[N:16]1)[CH3:19]
Reactant: CCOC(=O)c1nc2cnn(CC)c2nc1O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CCn1ncc2nc(C(=O)O)c(O)nc21
Reaction time: 16 h

Procedure:
57 g. of sodium salt of 1-ethyl-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid ethyl ester hydrate (2:1), prepared according to Example 1b, and 400 ml. of aqueous sodium hydroxide are heated to 60° with stirring for 16 hours. Then the solution is filtered and the filtrate is acidified with concentrated hydrochloric acid. The precipitated 1-ethyl-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid is filtered off, washed with water and dried at 70°, yield 31.4 g. (71%). A sample recrystallized from acetonitrile melts at 194°-195°.
Reaction SMILES: SN=[C:3]=[O:4].[C:5]([O-:18])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCC.C([O-])(=[O:31])CCCCCCCCCCC.C([Sn+2]CCCC)CCC>>[C:3]([OH:4])(=[O:31])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:18])=[O:17]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: O=C=NS
Agent: CCCC[Sn+2]CCCC
Product: O=C(O)CCCCCCCC(=O)O
Temperature: 100 °C

Procedure:
About 50 grams of the mercaptoisocyanate solution prepared in Example 1 along with 0.01 g of dibutyltin dilaurate should be added to about 40 grams of the above prepared polyester and heated for about 3 hours at 100° C. to form a polyester having reactive mercapto groups.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[CH2:12][C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33]1([C:39]#[CH:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.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:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[C:40]#[C:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:12][C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)C[C@@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(C#Cc4ccccc4)ncnc32)C[C@@H]1O
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A solution of (1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(6-chloro-9H-purin-9-yl)cyclopentanol (0.1 g, 0.26 mmol), Pd(PPh3)2Cl2 (0.006 g, 0.0089 mmol), CuI (0.004 g, 0.02 mmol) and triethylamine (0.145 mL, 1.04 mmol) in DMF (5 mL) was heated at 70° C. under argon for 1 h. Phenylacetylene (0.057 mL, 0.52 mmol) was added, the reaction mixture was stirred for 3 h, and the reaction was concentrated. The residue was dissolved in DCM and washed with saturated aq NaHCO3 and saturated aq EDTA.Na2 acid. The organic layer was dried (Na2SO4), concentrated and purified by flash chromatography (0 to 50% EtOAc/DCM) to afford the title compound (0.096 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:35][CH2:36][CH3:37])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]([NH:33][CH3:34])=[O:32])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27].[OH-].[Li+].CO.C1COCC1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH2:35][CH2:36][CH3:37])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]([NH:33][CH3:34])=[O:32])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 34 (70 mg, 0.14 mmol) and excess 1.0M lithium hydroxide solution were added to about 2 ml of methanol and about 1 ml of THF. The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate and washed with water. Chromatography of the reaction mixture on silica gel with 90% ethyl acetate/10% methanol/trace amount of acetic acid as eluant gave the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].I[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: FC(F)(F)c1ccc(CCI)cc1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1cccc(NCCc2ccc(C(F)(F)F)cc2)c1
Reaction time: 72 h
Yield: 43.3 %

Procedure:
To a solution of 2-(3-Amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.25 g, 1.11 mmol) in acetonitrile (5 ml), Na2CO3 (0.131 g, 1.24 mmol) and 1-(2-Iodo-ethyl)-4-trifluoromethyl-Benzene (0.372 g, 1.24 mmol) were added. The reaction mixture was stirred at r. t for 3 days, solvent was removed under reduced pressure and extracted in Ethyl acetate (75 ml) and washed with brine (2×10 ml) dried over Na2SO4. After evaporation, the residue was purified by flash chromatography (1:5 ethyl acetate:hexanes) to give 2-Methyl-2-{3-[2-(4-trifluoromethyl-phenyl)-ethylamino]-phenoxy}-propionic acid ethyl ester (0.19 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]1([C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH2:31]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:29]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:15]([Cl:16])=[CH:14][C:5]=2[N:6]=[C:7]1[CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (521 mg) in DMF (5 mL) was added potassium carbonate powder (802 mg) and 2-phenyl benzyl bromide (1.43 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-40% EtOAc/hexanes), followed by recrystallization with Et2O/hexanes to yield the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([CH:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=2[O:22][CH2:23][CH3:24])[OH:9])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[CH:13]=[C:12]([CH:19]([CH3:20])[CH3:21])[C:11]=2[O:22][CH2:23][CH3:24])=[O:9])[CH:7]=1
Reactant: CCOc1c(C(C)C)cc(C(C)C)cc1C(O)c1cc(Br)ccc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1c(C(=O)c2cc(Br)ccc2F)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
(5-Bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanol (1.88 g, 4.6 mmol) was dissolved in dichloromethane (5 ml) and added to a suspension of pyridinium chlorochromate (1.1 g, 5.1 mmol) in dichloromethane (20 ml). After stirring at ambient temperature under and atmosphere of nitrogen for 4 h the reaction was diluted with ether (50 mL) and filtered through a plug of florosil. The remaining solvent was evaporated to yield (5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanone as yellow crystals (1.75 g, 94%). 1H NMR (250 MHz, CDCl3): δ 7.81 (dd, 1H, J=3.1, J=6.9), 7.62 (m, 1H), 7.33 (d, 1H, J=2.5), 7.28 (d, 1H, J=2.5), 7.02 (dd, 1H, J=11.2, J=9.4), 3.67 (q, 2H, J=6.9), 3.34 (m, 1H), 2.95 (m, 1H), 1.31 (s, 3H), 1.28 (s, 6H), 1.25 (s, 3H), 1.02 (t, 3H, J=6.9). MS [EI+] 407, 409 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[CH:27]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][CH:24]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH:39][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][C@@H:24]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(COc2ccccc2)OCC1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](COc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
Add triethylamine (0.009 mL, 0.066 mmol) and acetic anhydride (0.004 mL, 0.044 mmol) to a solution of (2R,5R)-(5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-phenoxymethyl-morpholine-4-carboxylic acid tert-butyl ester (0.021 g, 0.044 mmol) in tetrahydrofuran (0.44 mL) and stir at room temperature for 1 hour. Concentrate and purify (silica gel chromatography, eluting with 50:50 to 60:40 ethyl acetate:hexanes) to give the title compound as a white foam (0.010 g, 45.5%).
Reaction SMILES: [OH:1][C@@:2]1([CH:15]=[CH2:16])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[C@H:3]1[CH3:14].FC(F)(F)C(O)=O>>[CH3:14][C@H:3]1[C@@:2]([CH:15]=[CH2:16])([OH:1])[CH2:6][CH2:5][NH:4]1
Reactant: C=C[C@]1(O)CCN(C(=O)OC(C)(C)C)[C@H]1C
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@]1(O)CCN[C@H]1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 306.2 %

Procedure:
To tert-butyl (2S,3R)-3-hydroxy-2-methyl-3-vinylpyrrolidine-1-carboxylate (684 mg, 2.85 mmol) was added trifluoroacetic acid (3.0 ml). The mixture was stirred at room temperature for 15 min, and concentrated under reduced pressure to give (2S,3R)-2-methyl-3-vinylpyrrolidin-3-ol (yield: 1.11 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:55])[CH3:54].Br[C:67]1[CH:72]=[CH:71][C:70]([O:73][C:74]([F:77])([F:76])[F:75])=[CH:69][CH:68]=1>C(OC(=O)C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][N:63]([C:67]2[CH:68]=[CH:69][C:70]([O:73][C:74]([F:75])([F:76])[F:77])=[CH:71][CH:72]=2)[CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 100 °C
Yield: 12.6 %

Procedure:
To a mixture of cesium carbonate (1.88 g, 5.7 mmol), palladium(II) acetate (46.1 mg, 0.205 mmol), rac-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (192 mg, 0.31 mmol), tert-Butyl-1-piperazine carboxylate (928 mg, 4.93 mmol) and 1-Bromo-4-(trifluoromethoxy)benzene (1 g, 4.11 mmol) was added degazed toluene (10 ml). The mixture was heated to 100° C. for 4 hours. The mixture was cool to room temperature, diluted with ethylacetate, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over silica gel: eluent: heptane/ethylacetate 0-10% over 20 minutes to provide the title compound (180 mg, 13%) as a yellow solid, MS (m/e): 347.4 (M+H, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH:25][OH:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:25]([CH:17]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O-:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ONC1CCCCCCC1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: [O-][N+](=Cc1ccc(OCc2ccccc2)cc1)C1CCCCCCC1
Yield: 47.1 %

Procedure:
A solution of 4-benzyloxybenzaldehyde (12.7 g, 0.060 mol), N-cyclooctylhydroxylamine (10.0 g, 0.070 mol) and a catalytic amount of HCl in methanol (300mL) was refluxed for 56 hours with molecular sieves in a soxhlet for water removal. The reaction mixture was concentrated and dry flash columned on silica with hexanes/ethyl acetate to give the title compound as a pale yellow powder, (9.53 g, 47.0% yield), m.p. 107.5° C. (Rf=0.46 on a silica gel plate using hexanes:EtOAc, 1:1, v:v, as an eluant). The N-cyclooctylhydroxylamine precursor was obtained by sodium cyanoborohydride reduction of cyclooctanone oxime in acetic acid/tetrahydrofuran.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)C(=O)N(C2C=CC(SC3C=CC=CC=3)=CC=2)N=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[Cl:37][CH2:38][Cl:39]>>[CH3:2][CH2:11][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:37][CH2:38][Cl:39]
Reactant: O=c1c2ccccc2c(Br)nn1-c1ccc(Sc2ccccc2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCC
Yield: 31 %

Procedure:
4-Bromo-2-(4-phenylsulfanyl-phenyl)-2H-phthalazin-1-one (0.095 g, 0.23 mmol) and MCPBA (0.052 g, 0.23 mmol) were stirred at room temperature in dichloromethane (1 ml) for 1 h. The tide compound was obtained after evaporation of the solvent in vacuum and subsequent purification of the raw product by chromatography over silica gel with heptane:dichloromethane (1:1 until 0:1) (0.031 g, 31% yield). 1H-NMR: (400 MHz, CDCl3) 8.49 (1H, d), 7.80–7.99 (5H, m), 7.76 (2H, d), 7.69 (2H, d), 7.48 (3H, m); MS (ESI+)=427.22 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][SH:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][S:28][CH2:30][C:31](=[O:32])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CS)cc3)cc2)CC1
Reactant: O=C(CBr)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CSCC(=O)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-mercaptomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-1-phenyl-ethanone.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:21])[N:4]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH:10]=O)[N:7]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][C:27]([C@:30]23[CH2:35][C@H:34]2[CH2:33][NH:32][CH2:31]3)=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]1[C:3](=[O:21])[N:4]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH2:10][N:32]2[CH2:33][C@H:34]3[C@:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:37])[F:36])=[CH:29][CH:28]=4)([CH2:35]3)[CH2:31]2)[N:7]=1
Reactant: Cc1nn(CCC=O)c(=O)n(C(=O)c2ccccc2)c1=O
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Product: Cc1nn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.1 %

Procedure:
3-[6-methyl-3,5-dioxo-4-(phenylcarbonyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl]propanal, Titanium (IV) isopropoxide (0.110 mL, 0.376 mmol) and (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (for reference preparation procedure see WO2005/080382, 62.6 mg, 0.276 mmol) were dissolved in 1,2-Dichloroethane (DCE) (9 mL) and the mixture was stirred at room temperature for 20 minutes. Afterwards the solution was cooled down to 0° C. and NaBH(AcO)3 (80 mg, 0.376 mmol) was added. The mixture was stirred at rt overnight. The day after it was quenched with water and diluted with DCM. The mixture was filtered and extracted; organic phase was washed with water and NaHCO3 saturated solution and solvent was eliminated under reduced pressure. Crude product was purified by flash chromatography (DCM to DCM/MeOH/NH3 9:1:0.1) affording the title compound 6-methyl-4-(phenylcarbonyl)-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (102 mg, 0.143 mmol, 57.1% yield). 6-methyl-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione formed during the reaction was recovered (25 mg, 0.063 mmol).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.CS(O[CH2:12][C:13]1([CH3:30])[CH2:17][C:16](=[O:18])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[CH2:14]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C=O)C.O>[CH3:29][O:28][C:21]1[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=1[CH2:19][N:15]1[CH2:14][C:13]([CH2:30][N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)([CH3:12])[CH2:17][C:16]1=[O:18]
Reactant: COc1ccc(CN2CC(C)(COS(C)(=O)=O)CC2=O)c(OC)c1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC(C)(Cn3cc(I)cn3)CC2=O)c(OC)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 4-iodo-1H-pyrazole (270 mg, 1.4 mmol), [1-(2,4-dimethoxybenzyl)-3-methyl-5-oxopyrrolidin-3-yl]methyl methanesulfonate (500 mg, 1.4 mmol), cesium carbonate (910 mg, 2.8 mmol), and potassium iodide (10 mg, 0.05 mmol) in DMF (80 mL) was stirred at 80° C. for 12 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give 1-(2,4-Dimethoxybenzyl)-4-[(4-iodo-1H-pyrazol-1-yl)methyl]-4-methylpyrrolidin-2-one. MS ESI calc'd. for C18H231 N3O3 [M+H]+ 456. found 456. 1H NMR (400 MHz, MeOD): δ 7.49 (s, 1H), 7.44 (s, 1H), 7.05 (d, J=8 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 6.49-6.47 (m, 1H), 4.30 (d, J=4 Hz, 2H), 4.06 (d, J=2 Hz, 2H), 3.78 (s, 6H), 3.33-3.29 (m, 1H), 2.91 (d, J=6.4 Hz, 1H), 2.54 (d, J=16.8 Hz, 1H), 2.17 (d, J=16.8 Hz, 1H), 1.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][C:53]1=[O:58]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([NH:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][C:53]1=[O:58])=[O:7]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Reactant: NC1CCCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A, 400 mg, 1.5 mmol) was dissolved in 10 mL dimethylformamide. N,N-Diisopropyl ethyl amine (505 mg, 3.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (571 mg, 1.5 mmol) were added. After 5 minutes of stirring at room temperature 2-amino-cyclohexanone (CAS 6946-05-0) (247 mg, 1.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate 1:0→0:1) yielded 2-methoxy-6-methylsulfanyl-N-(2-oxo-cyclohexyl)-4-trifluoromethyl-benzamide as a white foam (370 mg, 68%), MS: m/e=362.2 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]2OCCO2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[O:33]1[CH2:37][C:36](=[O:38])[NH:35][C:34]1=[O:39].N1CCCCC1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[C:37]2[O:33][C:34](=[O:39])[NH:35][C:36]2=[O:38])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: COc1cc(CCCCCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C1COC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1cc(CCCCCC=C2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 16 h

Procedure:
A mixture of 2-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl]-1,3-dioxolan (3.6 g), 2,4-oxazolidinedione (1.7 g), piperidine (0.72 g) and acetic acid (50 ml) was stirred for 16 hours under reflux. The reaction mixture was concentrated under reduced pressure, which was dissolved in ethyl acetate. The solution was successively washed with a saturated aqueous solution of sodium hydrogencarbonate, water, 1N HCl and water, followed by drying (MgSO4). The ethyl acetate layer was concentrated under reduced pressure, which was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (50:1), was obtained 5-[6-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]hexylidene]-2,4-oxazolidinedione as an oily product. The oily product was dissolved in tetrahydrofuran (THF) (80 ml), to which was added palladium-carbon (5%, 1.0 g). The mixture 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-methanol (50:1), was obtained 5-[6-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]hexyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-isopropyl ether to give colorless prisms, m.p.113-117° C.