Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]O)=[O:8])=[CH:5][CH:4]=[C:3]([F:11])[CH:2]=1.CI.[H-].[Na+].CN(C)[CH:18]=[O:19]>>[CH3:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([F:11])=[CH:2][C:1]=1[O:19][CH3:18])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(CO)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1cc(F)ccc1C(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 13.9 g. of 2-hydroxy-4-fluoroacetophenone and 75 ml. of dried dimethylformamide were added 30 ml. of methyl iodide. The solution was cooled to 0° C. and 4.1 g. of a 50% oil dispersion of sodium hydride were carefully added. After stirring for 1 hour at 0° C., the reaction was extracted with ethyl acetate. The organic extract was washed three times with 200 ml. each of 1N hydrochloric acid. The ethyl acetate solution was then dried and removed in vacuo. This reaction and a subsequent identical reaction provided a total of 28 g. of 2-methoxy-4-fluoroacetophenone as an oil which was used in the subsequent step without further purification.
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.ClCC(=O)C.C(O)C>[Pt](=O)=O.CO>[CH3:2][C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: O=[Pt]=O
Agent: CC(=O)CCl
Solvent: CO
Solvent: CCO
Product: Cc1cn2c(n1)CNCC2

Procedure:
2-Methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 1-chloro-2-propanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:33]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:33][CH2:11][C:10]([C:3]1[CH:4]=[C:5]([F:9])[C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc(F)c(C)cc1F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(C(=O)CBr)cc1F
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a chloroform (3.5 mL) solution of 1-(2,5-difluoro-4-methylphenyl)ethanone (0.23 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (0.27 mL) and trimethylsilyl trifluoromethanesulfonate (0.32 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (0.27 g) was added thereto, and the resultant was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, and the resultant was stirred for 15 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=99/1→95/5) to obtain the title compound (0.31 g) as a white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.S(=O)(=O)(O)O>>[CH2:7]([O:6][CH2:5][CH:4]=[O:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(COCc1ccccc1)OCC
Agent: O=S(=O)(O)O
Product: O=CCOCc1ccccc1

Procedure:
In accordance with Scheme IV, benzyloxyacetaldehyde diethyl acetal is hydrolyzed with dilute sulfuric acid giving benzyloxyacetaldehyde, which is then reacted with allyl magnesium bromide to give 1-phenylmethoxy-4-penten-2-ol. This alcohol, is brominated with bromine in carbon tetrachloride or dichloromethane at -20° C. to 0° C. to give 4,5-dibromo-1-(phenylmethoxy)-2-pentanol. This dibromo alcohol, in aqueous methanol, is cyclized with calcium hydroxide in the presence of calcium bromide, to give a racemic mixture of trans and cis-4-bromo-2[(phenylmethoxy)methyl]tetrahydrofuran, IX and X respectively, which is separated by flash column chromatography using silica gel. The trans bromide, IX, is reacted with potassium thioacetate, in a dipolar aprotic solvent, to give cis-[5-[(phenylmethoxy)methyl]-3-tetrahydrofuranyl]ethanethioate, XI. The thioacetate, XI, is reacted with iodotrimethylsilane to give cis-[5-(hydroxymethyl)-3-tetrahydrofuranyl]ethanethioate, XIII. In the same manner, the cis bromide, X, is converted to the trans-[5-(hydroxymethyl)-3-tetrahydrofuranyl]ethanethioate, XIV.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:30])[NH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:31]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: O=c1[nH]n(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12

Procedure:
6-Chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (Intermediate 3B; 194 mg, 0.471 mmol), K2CO3 (132 mg, 0.955 mmol), and iodomethane (0.044 mL, 0.707 mmol) were stirred in DMF (5 mL) at room temperature for 2 h. Water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated in MeOH to give 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. For C26H20ClN3O [M+1]+ 426. found 426.
Reaction SMILES: [C:1]([C:3]1[S:7][N:6]=[C:5]([Cl:8])[C:4]=1[Cl:9])#[N:2].[F:10][S:11]([O:14][CH3:15])(=[O:13])=[O:12]>>[F:10][S:11]([O-:14])(=[O:13])=[O:12].[C:1]([C:3]1[S:7][N+:6]([CH3:15])=[C:5]([Cl:8])[C:4]=1[Cl:9])#[N:2]
Reactant: COS(=O)(=O)F
Reactant: N#Cc1snc(Cl)c1Cl
Product: C[n+]1sc(C#N)c(Cl)c1Cl
Product: O=S(=O)([O-])F
Yield: 77 %

Procedure:
5-Cyano-3,4-dichloroisothiazole (3.6 g, 0.02 mol) and 4 ml of methyl fluorosulfonate were heated at 80°-100° for 11/2 hrs under a nitrogen atmosphere. The resulting solid was washed with ether and benzene to yield 4.5 g (77%) of 5-cyano-3,4-dichloro-2-methyl isothiazolium fluorosulfonate, mp 163-174 (d). Spectral data (NMR and IR) were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([CH:8]1[C:31](=O)[N:30]([CH3:33])[CH:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[O:27][CH:26]([CH3:39])[CH2:25][N:24]([CH3:40])[CH:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:22](=[O:45])[O:21][CH:20]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:19](=O)[N:18]([CH3:54])[CH:17]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:16](=[O:59])[O:15][CH:14]([CH3:60])[CH2:13][N:12]([CH3:61])[CH:11]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:10](=[O:66])[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1CCCCC1.C(OCC)(=O)C>C1COCC1>[CH2:46]([CH:20]1[CH2:19][N:18]([CH3:54])[CH:17]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:16](=[O:59])[O:15][CH:14]([CH3:60])[CH2:13][N:12]([CH3:61])[CH:11]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:10](=[O:66])[O:9][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31][N:30]([CH3:33])[CH:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[O:27][CH:26]([CH3:39])[CH2:25][N:24]([CH3:40])[CH:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:22](=[O:45])[O:21]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)CC1C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN1C
Agent: B
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CC1C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)CN(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)CN1C

Procedure:
By the method of Example 1, 2.99 g (3.25 mmol) of 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone (1-b) (for example from Ex. 1) in 20 ml of THF were reacted with 9.75 ml (9.75 mmol) of a 1M solution of borane. Column chromatography (silica gel, Ø=4.5 cm, l=25 cm; cyclohexane:ethyl acetate 50:1 to 5:1) gave 0.72 g of tetrareduction product 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,12,18,24-tetraon (2) (cf. Ex. 2), 0.22 g of trireduction product (1-c) and 0.91 g of unreacted starting material.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:12])[C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]([F:65])=[C:51]([C@@:53]2([CH3:64])[N:58]=[C:57]([NH2:59])[C@:56]([F:61])([CH3:60])[CH2:55][C:54]2([F:63])[F:62])[CH:52]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:59][C:57]1[C@:56]([F:61])([CH3:60])[CH2:55][C:54]([F:63])([F:62])[C@:53]([C:51]2[CH:52]=[C:47]([NH:46][C:9](=[O:11])[C:6]3[C:5]([CH3:12])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:48]=[CH:49][C:50]=2[F:65])([CH3:64])[N:58]=1
Reactant: C[C@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: Cc1cc(C#N)cnc1C(=O)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
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)[C@@](C)(F)CC2(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
5-Cyano-3-methylpicolinic acid (232 mg, 1.432 mmol) (Prepared as described in Badiger, Sangamesh et al. PCT Int. Appl., 2012095469) was placed in a round bottom flask and dissolved in DMF (7 mL). HATU (669 mg, 1.760 mmol) was added and the reaction was stirred at room temperature for 5 min, N,N-diisopropylethylamine (0.7 mL, 4.1 mmol) was added. The reaction mixture was cooled to 0° C. and added dropwise to a solution of (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethyl-3,4,5,6-tetrahydropyridin-2-amine (470 mg, 1.63 mmol) in DMF (7 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min then at 30 min at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water. The phases were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified using a RediSep Automated flash system on 80 g silica gel (eluent: ethyl acetate/heptane). The product was further purified by the following procedure: The product was dissolved in ethyl acetate (50 mL) and washed with a solution of saturated aqueous NaHCO3/water (1/1). The organic phase was washed total of 15 times (using 10 mL each time). The organic phase was dried over MgSO4, filtered, and evaporated to give N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide (153 mg, 26% yield).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17](=[S:19])[NH2:18])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:21][C:22](=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:19][CH:21]=[C:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:18]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(C)(C)n1ncc(C(N)=S)c1-c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Yield: 97.7 %

Procedure:
A solution of the compound (2.90 g, 10.46 mmol) obtained in step 4 and ethyl 4-chloroacetoacetate (1.554 mL, 11.50 mmol) in ethanol (30 mL) was stirred at 80° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate and hexane to give ethyl 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetate (3.96 g, 10.22 mmol, 98%) as a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])/[C:9](=[N:15]/[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)/[CH2:8][CH2:7][CH2:6]2.[CH3:26]N(C=O)C>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:9]3[C:8](=[CH:26][N:16]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=4)[N:15]=3)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)/C(=N/Nc1ccc([N+](=O)[O-])cc1)CCC2
Reactant: CN(C)C=O
Product: COc1cc2c(cc1OC)-c1nn(-c3ccc([N+](=O)[O-])cc3)cc1CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Phosphorous oxytrichloride (0.2 mL) was added, over a period of 0.5 h, to a magnetically solution of (E)-1-[6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-ylidene]-2-(4-nitro-phenyl)hydrazine (56 mg, 0.16 mmol) in DMF (5 mL) maintained at 0° C. under a nitrogen atmosphere. The ensuing mixture was allowed to warm to 18° C. and left stirring at this temperature for 1 h then heated to 65° C. and stirred at this temperature for a further 16 h. The hot reaction mixture was poured onto crushed ice and the crystals so-formed were collected by filtration. Recrystallisation (ethyl acetate/hexane) of this material then afforded the title compound (31 mg, 54%) as orange crystals, m.p. 150° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[CH2:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)[CH2:22][C:23]#[CH:24].Cl>CN(C=O)C>[CH2:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17])[CH2:22][C:23]#[CH:24]
Reactant: C#CCCOCCCCCCBr
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Reaction time: 1 h
Yield: 86.2 %

Procedure:
(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (10 g) in DMF (100 ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 2.33 g) in DMF (50 ml) with stirring under nitrogen and maintaining the internal temperature at 0°. Stirring was continued at 0–5° for 1 h. The mixture was recooled to 0° and a solution of 6-bromohexyl but-3-ynyl ether (14.7 g) in DMF (50 ml) was added over 1 min. The mixture was then stirred at 20–30° for 2 h. 2M HCl (9 ml) was added and the mixture was partitioned between water and diethyl ether. The aqueous layer was extracted with more diethyl ether and the combined organic layers were washed twice with brine. After drying (MgSO4) the solution was concentrated and loaded onto a column of silica gel (600 g) set up in diethyl ether: petroleum ether (bp 40–60°) (1:2). The column was eluted successively with this mixture, then (1:1) and then diethyl ether to give the title compound (13.88 g) LCMS RT=3.45 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[O:14])[CH2:6][CH2:5][C:4]=2[N:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:21]1([N:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:7]3[CH2:6][CH2:5][C:4]4[N:3]=[C:2]([N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH:11]=[CH:10][C:9]=4[CH2:8]3)[CH2:16][CH2:17]2)[CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: O=C(CN1CCc2nc(Cl)ccc2C1)N1CCN(C2CCC2)CC1
Product: O=C(CN1CCc2nc(N3CCCC3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 170 °C

Procedure:
A mixture of 2-chloro-6-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-1,6-naphthyridine (80 mg, 0.23 mmol) and pyrrolidine (2.5 mL) is heated by microwave (300 w) at 170° C. for 2 hr. Solvent is removed and the residue is partitioned between saturated NaHCO3 solution (10 mL) and DCM (10 mL). The layers are separated and the aqueous layer is extracted with DCM (10 ml). The combined extracts are dried and evaporated. The residue is purified by PTLC to give the title compound as a light yellow oil. MS (M+1): 384.3; 1H NMR (5, CDCl3): 7.07 (d, 1H), 6.16 (d, 1H), 3.62-3.69 (m, 4H), 3.53 (s, 2H), 3.40-3.44 (m, 4H), 3.34 (s, 2H), 2.78-2.90 (m, 4H), 2.61-2.72 (m, 1H), 2.27 (q, 4H), 1.63-2.04 (m, 10H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[C:32]1[N:36]2[CH2:37][C:38]3[C:43]([C:35]2=[N:34][N:33]=1)=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3.O[CH:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.C(O)(C(F)(F)F)=O>[C:55]([O:54][C:52]([N:49]1[CH2:50][CH2:51][CH:46]([O:44][C:41]2[CH:42]=[C:43]3[C:38]([CH2:37][N:36]4[C:32]([C:22]5[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:24][O:25][C:21]=5[CH3:20])=[N:33][N:34]=[C:35]43)=[CH:39][CH:40]=2)[CH2:47][CH2:48]1)=[O:53])([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(O)cc1-2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.9 %

Procedure:
Under nitrogen atmosphere, triphenylphosphine bound resin (1.22 g, 1.36 mmol, 1.12 mmol/g) was swelled in dichloromethane for 30 minutes. 3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ol (0.3 g, 0.91 mmol) (prepared as in Example 3, Step (a)), 4-hydroxy-boc-piperidine (0.27 g, 1.36 mmol, 1.5 eq.) and diethyl azodicarboxylate (0.21 ml, 1.36 mmol, 1.5 eq.) were added and the reaction was stirred at room temperature overnight. The resin was filtered off and washed with dichloromethane, methanol and ether. The combined organics were concentrated in vacuo. The residue was purified by alumina chromatography, eluting with dichloromethane 2% methanol/dichloromethane (0.5% methanol gradient), and was used without further purification in the next step. b) 3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(piperidin-4-yloxy)-5H-[1,2,4]triazolo[3,4-α]isoindole 4-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindol-8-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (466 mg, 0.91 mmol) was dissolved in TFA (5 ml) and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated K2CO3 (aq). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by alumina chromatography, eluting with dichloromethane→5% methanol/dichloromethane (in 1% methanol gradient), to afford the title compound as a white solid (4 mg, 1% over 2 steps). 1H NMR (400 MHz, d4 MeOH) δ 7.53–7.43 (6H, m), 7.32 (1H, d, J=8.5 Hz), 7.08 (1H, dd, J=8.5, 2.4 Hz), 4.63–4.60 (1H, m), 4.24 (2H, s), 3.16–3.11 (2H, m), 2.85–2.79 (2H, m), 2.64 (3H, s), 2.09–2.05 (2H, m), 1.78–1.72 (2H, m). m/z (ES+) 414 (M+H)+.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[CH2:5]([O:12][CH2:13][C@@H:14]([OH:28])[CH2:15][CH2:16][C@H:17]([OH:27])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I([O-])(=O)(=O)=[O:30].[Na+].O>ClC(Cl)(Cl)Cl>[CH2:20]([O:19][CH2:18][C@@H:17]1[CH2:16][CH2:15][C@@H:14]([CH2:13][O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:28][S:1](=[O:2])(=[O:30])[O:27]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O[C@@H](CC[C@H](O)COCc1ccccc1)COCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=S1(=O)O[C@H](COCc2ccccc2)CC[C@@H](COCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.43 g (12 mmol) of thionyl chloride were slowly added to 3.30 g (10 mmol) of the diol 5 in 70 ml of dry tetrachloromethane under an argon atmosphere, and the mixture was then refluxed for 90 minutes. After removal of the solvent in a rotary evaporator, the residue was taken up in a mixture of tetrachloromethane (40 ml), acetonitrile (40 ml) and water (60 ml) and, at 0° C., 15 mg (72 μmol) of RuCl3*3H2O and 4.28 g (20 mmol) of sodium periodate were added. The mixture was then left to stir at room temperature for one hour, and then 50 ml of water were added to the suspension. Subsequent extraction with diethyl ether (3×75 ml) and washing of the organic phase with saturated NaCl solution (100 ml), followed by drying (Na2SO4), resulted in a residue which on column chromatography (n-hexane:AcOEt=2:1, Rf=0.20) afforded compound 7 in a yield of 3.37 g (86%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH2:31][C:30]#[CH:29])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C#CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
To a solution of 200 mg (0.59 mmol) of 3-[4-chloro-2-fluoro-5-(hydroxy)phenyl]-1-methyl-6- (trifluoromethyl)-2,4 (1H,3H) -pyrimidinedione in 3 mL of acetonitrile was added 162 mg of potassium carbonate (1.18 mmol) and 131 mL (1.18 mmol) of an 80% solution of propargyl bromide in toluene. It was warmed under reflux for 2 h. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give colorless oil which was flash chromatographed over silica gel, eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 204 mg of title compound as a white foam: 1H-NMR (CDCl3, 200 MHz) ppm 7.35 (d, 1H), 7.0 (d, 1H), 6.4 (s, 1H), 4.78 (d, 2H), 3.58 (s, 3H), 2.6 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][OH:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][OH:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCSCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNCCSCCO)ccc1Cl
Yield: 50.9 %

Procedure:
Prepared according to the method described in Example 2 from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.800 g, Example 1b), 2-(2-aminoethylthio)ethanol (0.584 g) and sodium triacetoxyborohydride (0.715 g) in 1,2-dichloroethane (15 ml). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a white powder (0.536 g).