Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[CH2:50]([O:57][C:58]([NH:60][C@@H:61]([C:65]([CH3:68])([CH3:67])[CH3:66])[C:62](O)=[O:63])=[O:59])[CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:50]([O:57][C:58]([NH:60][C@@H:61]([C:65]([CH3:68])([CH3:67])[CH3:66])[C:62]([N:30]1[CH2:31][C@:27]([O:26][CH3:25])([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:63])=[O:59])[CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56]
Reactant: C=CCCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Yield: 74.2 %

Procedure:
HATU (248 mg, 0.652 mmol) was added to a solution of (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (200 mg, 0.593 mmol), (S)-2-((hept-6-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (201 mg, 0.741 mmol) and DIEA (0.311 mL, 1.778 mmol) in DCM (8 mL) and stirred at r.t. 60 hours. The reaction was evaporated and purified on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-methyl 1-((S)-2-((hept-6-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (260 mg, 0.440 mmol, 74% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96-1.00 (m, 1H) 1.06-1.10 (m, 1H) 1.11-1.19 (m, 7H) 1.30-1.47 (m, 4H) 1.55-1.64 (m, 2H) 1.99-2.10 (m, 2H) 2.49-2.55 (m, 1H) 2.89 (d, J=13.05 Hz, 1H) 2.93-3.04 (m, 3H) 3.73-3.80 (m, 3H) 3.92-4.10 (m, 3H) 4.11-4.20 (m, 1H) 4.31-4.41 (m, 1H) 4.87-5.05 (m, 3H) 5.23 (dd, J=10.92, 1.13 Hz, 1H) 5.38-5.42 (m, 1H) 5.68-5.75 (m, 1H) 5.75-5.86 (m, 1H) 6.62-6.76 (m, 1H) 7.28-7.43 (m, 7H) 7.63-7.69 (m, 1H). LCMS: r.t.=2.25 min., [M+H]+=591 Phenomenex Luna S10 (3×50 mm); Solvent A=95% water—5% methanol—10 mM ammonium acetate, Solvent B=5% water—95% methanol—10 mM ammonium acetate; gradient=0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 ml/min; inj. vol.=10 ul; wavelength=220 nm.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([OH:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([O:21][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:11]([O-:13])=[O:12])[CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCl
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(OCCOc2ccccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1-(2-Chloro-ethoxy)-2-nitro-benzene (116 g) and 5-methyl-2-nitro-phenol (88 g) were dissolved in 500 ml DMF and was stirred for 4 h at 90-110° C. after careful addition of 160 g potassium carbonate. The reaction mixture was poured in a mixture of crushed ice and water (8 l) which was vigorously stirred. The residue was filtered off, washed several times with water and dried. The crude product was suspended in methanol and the pale yellow residue was again filtered off, washed with methanol and dried. Yield: 150-165 g.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[CH3:2].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C@@H:18]([NH:17][C:8]([C:6]1[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:10])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:40])([F:39])[F:41]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To a solution of 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (283 mg, 1.2 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (461 mg, 1.2 mmol)[prepared according to Preparation 6] and diisopropylethylamine (1.043 ml, 5.99 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (615 mg, 1.317 mmol) in one portion. The solution was stirred at 25° C. over 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (486 mg, 0.86 mmol, 71.6% yield) as a clear oil: LCMS (ES) m/e 567 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:28][C@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([OH:29])[CH2:6]1)=[N+:2]=[N-:3].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.O>[CH3:37][S:38]([O:29][C@@H:7]1[CH2:6][C@@H:5]([CH2:4][N:1]=[N+:2]=[N-:3])[O:28][C@@H:8]1[CH2:9][O:10][Si:11]([C:24]([CH3:25])([CH3:26])[CH3:27])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:40])=[O:39]
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CN=[N+]=[N-])C[C@H]1O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CN=[N+]=[N-])C[C@H]1OS(C)(=O)=O)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a 0° C. solution, under argon, of 3.78 g of product from Example 276 in 20 ml of dry methylene chloride is added, dropwise, 1.02 g of triethylamine and 1.16 g methanesulfonylchloride. The reaction mixture is stirred for 3 hours, diluted with water, extracted with diethyl ether, concentrated in vacuo, and purified by chromatography (silica gel: 0-50% ethyl acetate/hexane) to give 4.30 g of the desired product.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])(=[O:5])[CH3:4]>C1COCC1>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5]
Reactant: CC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Reactant: BrBr
Solvent: C1CCOC1
Product: Cc1c(C(=O)CBr)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 40.7 %

Procedure:
Bromine (34 μl, 0.66 mmol) in THF (5 ml) was added to a solution of 5-acetyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (320 mg, 0.63 mmol) in TBF (10 ml). After 2 h, the yellow colour had disappeared. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was separated, evaporated, and the residue was chromatographed on silica using ethyl acetate/heptane (1/1, 2/1, 4/1) as eluent. Fractions containing the product were combined and evaporated to give the title compound (150 mg, 41%).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[N:5][N:4]2[CH2:8][CH2:9][CH2:10][C:3]=12.[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:2]2[C:6]([CH3:7])=[N:5][N:4]3[CH2:8][CH2:9][CH2:10][C:3]=23)[CH:15]=1
Reactant: Cc1nn2c(c1Br)CCC2
Reactant: COC(=O)c1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C#N)c(-c2c(C)nn3c2CCC3)c1
Temperature: 95 °C
Yield: 49.8 %

Procedure:
In a pressure sealed flask a suspension of 3-bromo-2-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (1.01 g, 5.0 mmol), 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.8 g, 6.25 mmol), and K3PO4 (2.65 g, 12.5 mmol) in dioxane (50 mL) was degassed by bubbling N2 for 30 m at room temperature. After the addition of tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) the reaction flask was sealed and the contents heated to 95° C. for 5 h. After cooling the reaction mixture was diluted several fold with EtOAc, and washed with dilute aqueous NaHCO3 followed by brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified over normal phase silica starting with 100% DCM for 5 m and then increasing to 10% MeOH in DCM over 25 m to give the desired product as a yellow solid (0.70 g, 2.49 mmol). MS m/z 282.5 (M+H)+.
Reaction SMILES: [I-:1].[Cl:2][C:3]1[C:16]2[C:7](=[S+:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(Cl)(Cl)Cl.CO>[I-:1].[C:25]([O:24][C:22]([N:29]1[CH2:30][CH2:31][N:32]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:15]=[C:16]2[C:7]([CH:6]=[C:5]([N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])[CH:4]=[C:3]2[Cl:2])=[S+:8]3)[CH2:33][CH2:34]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCNCC
Reactant: Clc1cccc2[s+]c3ccccc3nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(CC)c1cc(Cl)c2nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3[s+]c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 1.8 %

Procedure:
1-Chlorophenothiazin-5-ium Iodide (350 mg, 0.473 mmol) was dissolved in CHCl3 (5 mL) and diethylamine (0.1 mL, 1.04 mmol) was added. The resulting mixture was allowed to stir at RT for 24 h. The solvent was removed and the crude material was used without purification. The crude material was dissolved in MeOH (5 mL) and 1-Boc-piperazine (177 mg, 0.95 mmol) was added as a solution in MeOH (2 mL) and thje mixture was stirred for 24 h. The solvent was evaporated and a portion of the material was purified by prep TLC to give 5.2 mg of a product.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])=[CH:6][C:5]=1[F:21])=[N+:2]=[N-:3].Cl.[NH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+].[CH2:31]1[CH2:35]OC[CH2:32]1.CO>>[F:21][C:5]1[CH:6]=[C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:8]=[CH:9][C:4]=1[N:1]1[CH:32]=[C:31]([CH:35]=[N:23][OH:24])[N:3]=[N:2]1
Reactant: NO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N=[N+]=[N-])c(F)c2)C(=O)O1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cc(C=NO)nn3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 150 mg(0.40 mmol) of the compound of Example 17 in 10 mL of 1:1 THF-methanol was treated with 66 mg(0.96 mmol) of hydroxylamine hydrochloride and 66 mg(0.48 mmol) of potassium carbonate, followed by stirring at ambient temperature for 8 h, and then warming at reflux for 2 h. The mixture was concentrated in vacuo, and the residue was subjected to radial chromatography on a 2 mm chromatotron plate, eluting with 5%(v/v) methanol in dichloromethane. These procedures afforded 30 mg(20%) of the title compound as a white solid. Mass Spectrum (EI): m/z 376, 332, 318, 287, 274, 245, 220, 202, 187, 175, 163, 149, 139, 35 82, 56.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:12][C:13]1[N:14]([C:24]2[N:25]=[CH:26][N:27]=[C:28]([NH2:31])[C:29]=2[N:30]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17].C(O)C>N1C(C)=CC=CC=1C.C(OC(=O)C)C.C(O)C>[OH:11][CH:9]([CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][S:12][C:13]1[N:14]([C:24]2[N:25]=[CH:26][N:27]=[C:28]([NH2:31])[C:29]=2[N:30]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: Nc1ncnc2c1nc(S)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: CCO
Product: Nc1ncnc2c1nc(SCC(O)COc1ccccc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
A mixture of 1-phenoxy-2,3-epoxypropane (7.3 g, 48.6 mmoles), 8-mercaptoadenosine (11.5 g, 38.4 mmoles), 2,6 lutidine (about 20 drops) and ethanol (300 ml) is heated at reflux temperature for 1 hour, then it is concentrated to a small volume and ethyl ether is added to precipitate the compound of the title as a raw product. The precipitate is recovered by filtration, washed with ether and dried, dissolved in boiling ethanol, added to an equal amount (by weight) of silica gel and concentrated to dryness. The obtained residue is charged on a silica gel (120 g) column prepared in ethyl acetate and developed with an ethylacetate/ethanol 9/1 mixture. Fractions, containing only the end product, are combined and crystallized from dichloroethane/ethanol 9/1 yielding 6.5 g of the compound of the title. M.p. 100°-110° C. Fusion endotherm at 105° C. in DSC and [α]D30 -48.23° (c=1, CH3OH).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:18]1[CH2:20][CH2:19]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CO>C(Cl)Cl>[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([CH:27]3[O:28][CH2:29][CH2:30][NH:25][CH2:26]3)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:18]1[CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1)C1CNCCO1
Reaction time: 1 h

Procedure:
1-(2-Chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole hydrochloride (140 mg) is added at room temperature to a solution which has been prepared by adding morpholine (298 mg, a 30% methanol solution) to methylene chloride (10 ml) . After the reaction mixture is stirred for one hour at the same temperature, it is washed with water, dried and concentrated under reduced pressure. The residue is recrystallized using ether and thus, 1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholino-carbonylbenzimidazole (20 mg) is obtained. (Colorless crystal). 1H-NMR (CDCl3,): 1.04-1.12 (2H, m), 1.25-1.32 (2H, m), 1.82-1.96 (1H, m), 3.68 (8H, bs), 5.56 (2H, s), 6.55 (1H, dd, J=1, 8 Hz), 7.13 (1H, dt, J=1, 8 Hz), 7.22-7.29 (2H, m), 7.30 (1H, d, J=1 Hz), 7.46 (1H, dd, J=1, 8 Hz), 7.77 (1H, d, J=8 Hz).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][N:18]([CH3:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[O:15]1)=[O:13])[CH3:10].Cl>ClCCl>[C:1]([C:22]1[CH:23]=[CH:24][C:16]2[O:15][CH:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:19][N:18]([CH3:20])[C:17]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CN(C)c2ccccc2O1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C1CN(C)c2cc(C(C)=O)ccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6 mmol (0.1 ml) of acetyl chloride and 4 mmol (545 mg) of aluminum chloride are added to a solution of 1.6 mmol (355 mg) of 2-ethoxycarbonyl-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (described in J. Heterocyclic Chem., 1985, 22, 177) in 18 ml of dichloromethane at -10° C. The reaction mixture is stirred at room temperature for 1 hour before being hydrolysed by a cooled aqueous solution of 2 M hydrochloric acid. The mixture is extracted with dichloromethane and the organic phase is washed with a saturated solution of NaHCO3, dried over magnesium sulphate, concentrated and purified by chromatography on silica gel using a petroleum ether/ethyl acetate mixture (7/3) as eluant to yield the expected product.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH2:22][C@H:21]1[C:24]([O:26][CH3:27])=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C)P(N(C)C)(N(C)C)=O.IC>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH2:22][C:21]1([CH3:1])[C:24]([O:26][CH3:27])=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1(C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 69.7 %

Procedure:
To a solution of diisopropylamine (1.05 equiv; 5.9 mmol, 0.6 g, 0.83 mL) in anhydrous tetrahydrofuran (15 mL) was added n-butyl lithium (1.05 equiv; 5.9 mmol, 2.36 mL of a 2.5M solution in hexanes) and the resulting light yellow solution was warmed to 0° C. for 10 min. It was then cooled back to −78° C. and N-(tert-butoxycarbonyl)-azetidine-2(S)-carboxylic acid, methyl ester (5.63 mmol, 1.21 g) in dry tetrahydrofuran (3.0 mL) was added dropwise and stirring was continued for 45 min. After this time, hexamethylphosphoramide (2.0 equiv; 11.3 mmol, 2.02 g, 1.96 mL) was added and the reaction mixture was stirred for 0.5 h. At this point, iodomethane (5.0 equiv; 28.2 mmol, 3.99 g, 1.75 mL) was added (−78° C.), the cooling bath was removed, and stirring was continued overnight (16 h) at ambient temperature. Addition of saturated ammonium chloride solution, extraction with ethyl acetate, washing of the combined organic layer with water (2×) and brine, drying (MgSO4), and concentration yielded crude material which was purified by Biotage flash-coloumn chromatography (15% ethyl acetate, 85% hexanes) to provide N-(tert-butyloxycarbonyl)-2(R,S)-methylazetidine-2-carboxylic acid, methyl ester (0.9 g, 70% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.BrC1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[F:25]>>[F:25][C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:6]=1[N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Fc1cc(C(F)(F)F)ccc1N1CCNCC1

Procedure:
The compound 1-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine is synthesized according to the procedure outlined in Example 26 steps 1 and 2 using t-butyl-1-piperazine-carboxylate and 1-bromo-2-fluoro-4-trifluoromethyl-benzene.
Reaction SMILES: [CH2:1]([N:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[C:36]([O-:39])([O-])=O.[K+].[K+].[CH:42]1([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45][CH2:44][CH2:43]1>CC#N>[CH2:1]([N:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:10]2([CH2:11][CH2:12][N:13]([C:36]([N:49]3[CH2:50][CH2:51][N:46]([CH:42]4[CH2:45][CH2:44][CH2:43]4)[CH2:47][CH2:48]3)=[O:39])[CH2:14][CH2:15]2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1N(Cc2ccccc2)c2ccccc2C12CCNCC2
Reactant: C1CC(N2CCNCC2)C1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CC#N
Product: O=C(N1CCN(C2CCC2)CC1)N1CCC2(CC1)C(=O)N(Cc1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1-benzylspiro[indole-3,4′-piperidin]-2(1H)-one (0.417 mmol), 4-nitrophenyl chloroformate (84 mg, 0.417 mmol) and K2CO3 (172 mg, 1.25 mmol) in CH3CN (6 ml) is stirred at ambient temperature for 2 h. A solution of 1-cyclobutylpiperazine (0.417 mmol) and TEA (0.175 ml, 1.25 mmol) in CH3CN (4 ml) is added and the mixture is heated at 110° C. in a sealed tube overnight. Solvent is removed in vacuo and to the residue is added EtOAc (15 ml). The mixture is stirred at rt for 15 min and filtered. The filtrated is evaporated and the residue is purified by PTLC to give the title compound as a white solid. LC-MS (M+1): 458.3.
Reaction SMILES: [Cl-].[Si]([O:9][C:10]1[CH2:11][CH2:12][C:13]2([C:25]([F:28])([F:27])[F:26])[CH:17]([CH:18]=1)[N+:16]([CH3:20])([CH3:19])[C:15]1[CH:21]=[CH:22][CH:23]=[N:24][C:14]2=1)(C(C)(C)C)(C)C.Cl>O1CCCC1>[CH3:19][N:16]([CH3:20])[C:15]1[C:14]([C:13]2([C:25]([F:28])([F:26])[F:27])[CH2:17][CH2:18][C:10](=[O:9])[CH:11]=[CH:12]2)=[N:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OC1=CC2C(C(F)(F)F)(CC1)c1ncccc1[N+]2(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C)c1cccnc1C1(C(F)(F)F)C=CC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
A solution of Example 26A (418 mg, 2.014 mmol) and (E)-3-(tert-butyldimethylsilyloxy)-N,N-dimethylbuta-1,3-dien-1-amine (Aldrich, 527 mg, 2.316 mmol) in toluene (1.5 mL) was heated in a microwave at 140° C. for 2 hours, and then chromatographed on silica gel (AnaLogix SF15-24G; 50 micron silica; elution with 0-50% ethyl acetate in hexane at 20 mL/min) Repeated the reaction in a microwave at 120° C. for 2 hours with a solution of Example 26A (422 mg, 2.033 mmol) and (E)-3-(tert-butyldimethylsilyloxy)-N,N-dimethylbuta-1,3-dien-1-amine (693 mg, 3.05 mmol) in toluene (2 mL), and then chromatographed on silica gel (AnaLogix® SF15-24G; 50 micron silica; elution with 0-50% ethyl acetate in hexane at 20 mL/min). The title compound (165 mg, 0.580 mmol) was isolated as an orange solid. A solution of the isolated intermediate 7-(tert-butyldimethylsilyloxy)-5,5-dimethyl-9a-(trifluoromethyl)-5a,8,9,9a-tetrahydro-5H-pyrido[3,2-b]indol-5-ium chloride (395 mg, 0.908 mmol) in tetrahydrofuran (9 mL) was treated with 1N hydrochloric acid (3.0 mL, 3.0 mmol). The reaction mixture was stirred overnight at ambient temperature, quenched with sodium bicarbonate solution (40 mL), extracted twice with ethyl acetate (40 mL), washed with brine, dried (Na2SO4), and concentrated to an orange oil. The residue was purified by silica gel chromatography (AnaLogix® SF10-8G; 50 micron silica; elution with 0-40% ethyl acetate in hexane at 15 mL/min) to provide additional title compound (131 mg, 0.461 mmol) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.54 (dd, J=4.5, 1.6, 1H), 7.75 (dd, J=8.0, 1.7, 1H), 7.74 (dd, J=10.2, 2.1, 1H), 7.35 (dd, J=8.1, 4.5, 1H), 5.90 (d, J=10.2, 1H), 3.54-3.44 (m, 1H), 2.65 (s, 3H), 2.45-2.35 (m, 2H), 2.33 (s, 3H), 2.13-1.97 (m, 1H); MS (DCI/NH3) m/e 285 (M+H)+.