Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]([NH:17][NH2:18])=[O:16])[S:13][CH:14]=2)=[CH:6][CH:5]=1.Cl.[C:22](N)(=[NH:24])[CH3:23].[OH-].[Na+]>C1COCC1>[NH:24]=[C:22]([NH:18][NH:17][C:15]([C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:9][CH:8]=2)[N:11]=1)=[O:16])[CH3:23]
Reactant: CC(=N)N
Reactant: NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=N)NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)cs1
Temperature: 100 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 4-(4-(trifluoromethoxy)phenyl)thiazole-2-carbohydrazide (10.0 g, 33.0 mmol) in THF (100 mL) were added acetamidine hydrochloride (62 g, 66 mmol) and sodium hydroxide (4 g, 99 mmol). The mixture was stirred at 100° C. for 16 h, and then concentrated under reduced pressure. The white solid residue was washed with H2O (30 mL), filtered and dried to afford the title compound as a white solid (10 g, 88%). MS (ES+) C13H11F3N4O2S requires: 344. found: 345 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][C@H:20]4[C:23](=[O:24])[N:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[C@@H:21]4[C:32]4[CH:46]=[CH:45][C:35]([O:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[CH:34][CH:33]=4)OCC(C)(C)C[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>C(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:11])[CH2:18][S:19][C@H:20]3[C:23](=[O:24])[N:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C@@H:21]3[C:32]3[CH:33]=[CH:34][C:35]([O:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:45][CH:46]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC1(C)COC(CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccc3c(c2)OCO3)OC1
Solvent: O=CO
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1
Reaction time: 2 h

Procedure:
tert-Butyl {4-[(2R,3R)-3-({[2-(1,3-benzodioxol-5-yl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetate (Method 16) (10.0 g, 15.35 mmol) was dissolved in formic acid (100 mL) at room temperature and stirred for two hours. The mixture was concentrated under reduced pressure (temperature<30° C.) and the crude oil was purified by flash-chromatography (heptane:acetone:formic acid 6:4:0.01 and then 5:5:0.01) to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([N:9]2C(=O)C3=CC=CC=C3C2=O)[CH2:7][S:6][CH:5]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:4][N:3]1[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CNN>>[NH2:9][CH:8]1[CH2:7][S:6][CH:5]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:4][N:3]([CH2:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CNN
Product: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(N)C1=O
Yield: 65.2 %

Procedure:
Following the procedure described in Example 42(g), 1.1 g of t-butyl α-[5-oxo-6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] was dephthaloylized with methylhydrazine, to afford 0.52 g of the title compound as a crystalline powder, melting at 84°-86.5° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C>C(OCC)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C#N)ccc1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A solution of 4-bromo-3-methoxybenzonitrile (Combi-Blocks, San Diego, Calif., 2.500 g, 11.79 mmol) in 100 mL of diethyl ether was cooled to −78° C. and was treated with n-butyllithium (4.95 ml, 12.38 mmol). After stirring for 10 minutes, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.07 ml, 16.51 mmol) was added, and the cooling bath was removed. After stirring for an additional 2 hours, LC/MS showed mostly product, so the reaction mixture was quenched with saturated NH4Cl solution. After stirring for 20 minutes, the reaction mixture was poured into a separatory funnel charged with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.62 g, 6.25 mmol, 53.0% yield) with minor impurities. m/z (ESI) 260.1 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])[CH:3]=1.[C:18]1([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:17][C:9]1[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=1[C:4]1[CH:3]=[C:2]([NH:27][S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[N:7]=[N:6][CH:5]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cnnc(Cl)c2)s1
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(C)c(-c2cnnc(NS(=O)(=O)c3ccccc3)c2)s1
Temperature: 200 °C
Yield: 9.2 %

Procedure:
A mixture of N-[5-(6-chloropyridazin-4-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (55 mg), benzenesulphonamide (49 mg), caesium carbonate (101 mg), cuprous iodide (30 mg) and DMA (1.5 mL) was heated in a microwave reactor to 200° C. under an argon atmosphere for 3 hours. The resultant mixture was evaporated and the residue was purified by preparative HPLC on reversed phase silica using a solvent gradient of 10% to 100% acetonitrile in water (containing 1% acetic acid) as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a solid (7.3 mg); 1H NMR Spectrum: (DMSOd6+CD3CO2D) 2.20 (s, 3H), 2.43 (s, 3H), 7.51-7.64 (m, 3H), 7.75 (s, 1H), 7.89 (d, 2H), 8.51 (s, 1H); Mass Spectrum: M+H+ 390.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:8][N:9]2[C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([F:21])=[C:14]([F:22])[C:13]=2[F:23])=[CH:4][C:3]=1[F:30]>CO.C(O)(=O)C.[Pd]>[NH2:18][C:16]1[CH:17]=[C:12]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:30])=[C:2]([Cl:1])[N:11]=3)[C:6](=[O:29])[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:8]2)[C:13]([F:23])=[C:14]([F:22])[C:15]=1[F:21]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)c(F)c2F)c2nc(Cl)c(F)cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cn(-c2cc(N)c(F)c(F)c2F)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
Ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-(2,3,4-trifluoro-5-nitrophenyl)-1,8-naphthyridine-3-carboxylate (780 mg) was dissolved in 5 ml of methanol and 10 ml of acetic acid, to which was added 80 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred overnight at room temperature. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Ethanol was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 200 mg of the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:18]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[N:19][S:20][N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:55]1[CH:64]=[C:63]2[C:58]([CH:59]=[CH:60][C:61](=[O:65])[O:62]2)=[CH:57][CH:56]=1>C1COCC1>[O:65]=[C:61]1[CH:60]=[CH:59][C:58]2[C:63](=[CH:64][C:55]([O:13][CH2:14][CH2:15][O:16][C:17]3[C:18]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)=[N:19][S:20][N:21]=3)=[CH:56][CH:57]=2)[O:62]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCO)CC1
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCOc2ccc3ccc(=O)oc3c2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 123.6 %

Procedure:
Diethyl azodicarboxylate (DEAD, 61 μl, 0.39 mmol) was added drop wise to a mixture of the product obtained in Step 2 (100 mg, 0.30 mmol), triphenylphosphine (102 mg, 0.39 mmol) and 7-hydroxycoumarin (63 mg, 0.39 mmol) in dry THF (5 mL). The reaction mixture was stirred at room temperature for 5 days. After solvent removal, the residue was purified by chromatography on silica gel eluting with hexane/EtOAc (1:1) to give the title product as a white solid (176 mg) which had low purity (67% by HPLC). This material was used directly in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([O:14][CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cc(-c2ccccc2)nc(-c2ccc(Cl)cc2)n1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: O=C(O)c1ccc(COc2cc(-c3ccccc3)nc(-c3ccc(Cl)cc3)n2)cc1

Procedure:
The title compound was prepared from 2-(4-chloro-phenyl)-6-phenyl-pyrimidin-4-ol (which was obtained in Intermediate 1) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; 1H NMR (DMSO-d6, 300 MHz) δ 5.61 (s, 2H), 7.26 (t, J=9.0 Hz, 2H), 7.45-7.70 (m, 8H), 8.25-8.35 (m, 2H), 8.55 (d, J=6.0 Hz, 2H); LC retention time 3.86 min; MS: m/z (ESI) 415 (M−H).
Reaction SMILES: [F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C:3]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C:3]2=[S:25]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2ccccc2C2CCCC12F
Solvent: C1CCOC1
Product: FC12CCCC1c1ccccc1NC2=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 150 mg (0.73 mmol) of 3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 50 ml of THF is mixed with 607 mg (1.5 mmol) of Lawesson's reagent. After 1 hour of stirring at room temperature, the batch is refluxed for 2 hours. Then, the reaction mixture is concentrated by evaporation and the residue is purified by column chromatography on silica gel (eluant: hexane-ethyl acetate): 150 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:31][N+:32]([O-])=O)([C:27]([F:30])([F:29])[F:28])[CH2:10][C:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]3[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:26])[CH:14]=2)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[CH2:31][N:32]=[C:11]([C:13]3[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]4[CH2:23][S:22][CH2:21]4)=[O:18])=[C:15]([CH3:26])[CH:14]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C(=O)CC(C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1CSC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 16.9 %

Procedure:
To a solution of 4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-N-thietan-3-yl-benzamide (Example I21) (78 mg) in DMF (1.5 ml) zinc powder (48 mg) was added at ambient temperature. The reaction mixture was heated to 80° C. and concentrated hydrochloric acid (0.3 ml) was added drop-wise. The reaction mixture was stirred at 80° C. for 4 hours. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by prep. HPLC to give give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-N-thietan-3-yl-benzamide (12 mg). 1H-NMR (400 MHz, CDCl3): 7.75-7.25 (m, 6H), 6.35 (s, 1H), 5.45 (m, 1H), 4.90 (d, 1H), 4.45 (d, 1H), 3.82 (d, 1H), 3.55-3.38 (m, 5H), 2.48 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:16][CH:11](OC(=O)C)[C@@H:10]1[O:28][C:29](=[O:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:32]>C(O)(=O)C.COC>[CH2:1]([O:8][C@H:9]1[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:16][CH:11]([Br:32])[C@@H:10]1[O:28][C:29](=[O:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OCc2ccccc2)[C@@H]1OC(C)=O
Agent: COC
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(Br)[C@H](OC(C)=O)[C@@H](OCc2ccccc2)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
To 16 g of compound 4 in 35 mL of acetic acid precooled to 10° C., a solution of hydrogen bromide in acetic acid (50% w/v; 16 mL)-was added slowly. The solution was stirred at 5°-10° C. for 3 hours, diluted with alcohol-free chloroform (250 mL) then washed sequentially with ice water, aqueous sodium hydrogen carbonate, and water, and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave a syrup which was taken up in methyl ether and adsorbed on silica gel (300 g). Elution with light petroleum ether gave 2.5 g of benzyl bromide, and further elution with ether gave a syrup of 3-O-benzyl-2,4,6-tri-O-acetyl-D-glucopyranosyl bromide (5)-which crystallized on cooling. Recrystallization from dry ether gave 12.2 g of needles with m.p. 79° C. and [α]D25 +145 (c=1 in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13](CC1C=CC(Br)=CC=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].CCCC[Sn]([C:59]1[CH:64]=[CH:63][CH:62]=[N:61][CH:60]=1)(CCCC)CCCC>>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([N:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:59]2[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=2)=[CH:19][CH:18]=1)[NH:13][CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:11])[C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Product: COC(=O)N[C@H](C(=O)N(Cc1ccc(-c2cccnc2)cc1)NC[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method A, using compound 19 (90.0 mg, 0.132 mmol), 3-(1,1,1-tributylstannyl)pyridine (194 mg, 0.527 mmol), Pd(PPh)3Cl2 (4.63 mg, 0.0065 mmol) and CuO (10.5 mg, 0.132 mmol). The product (24.0 mg, 27%) was afforded as a white solid after purification by RP-LC-MS (40 min gradient of 10-100% CH3CN in 0.05% aqueous formic acid).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1>C(O)(=O)C.[Pt]=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:3]1
Reactant: Cc1cccc(CN2CCCC2)n1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: C[C@H]1CCC[C@@H](CN2CCCC2)N1
Reaction time: 18 h
Yield: 62.8 %

Procedure:
A mixture of the product of stage (i) (1.0 g) and platinum oxide (0.25 g) in acetic acid was hydrogenated at 80 p.s.i. for 18 h. The catalyst was filtered off, and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane and washed with 2N sodium hydroxide and water. The organic extracts were dried (MgSO4) and evaporated and the residue (1.0 g) was purified by chromatography on alumina (60 g, UGI) eluting with ether hexane (1:1) to give the title compound (0.65 g) as an oil. T.l.c. Alumina-dichloromethane-ethanol (20:1), Rf 0.8.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)[O:29][N:28]=1>C(#N)C>[CH3:41][C:38]([C:35]1[CH:34]=[CH:33][C:32]([C:30]2[O:29][N:28]=[C:27]([CH2:26][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[N:31]=2)=[CH:37][CH:36]=1)([CH3:39])[CH3:40]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: CC(C)(C)c1ccc(-c2nc(CBr)no2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccc(C(C)(C)C)cc2)n1
Yield: 157 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.100 g, 0.396 mmol) in anhydrous acetonitrile (20 mL) was added Cs2CO3 (1.30 g, 4.00 mmol) and 3-(bromomethyl)-5-[4-(1,1-dimethylethyl)phenyl]-1,2,4-oxadiazole (0.176 g, 0.596 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.29 g, 16% yield): MS (ES) m/z 466 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:15][C@@H:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][C@@H:11]3[CH2:13]2)[CH:17]=[N:18][CH:19]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)NCc4ccccc4C(F)(F)F)c3)C[C@@H]2C1
Temperature: 33 °C
Reaction time: 18 h

Procedure:
A suspension of the product from Example 33B (52.5 mg, 0.16 mmol), 2-trifluoromethylbenzylamine (33.3 mg, 0.19 mmol), 1-hydroxybenzotriazole (30.1 mg, 0.20 mmol), 4-dimethylaminopyridine (4 mg, 0.03 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (34.3 mg, 0.24 mmol) in pyridine (7.0 mL) were stirred at 33° C. for 18 h. The reaction mixture was filtered through a glass microfiber frit and rinsed with methanol. The filtrate was concentrated and the residue was purified by silica gel chromatography (EtOAc, Rf=0.2) to afford the title compound. MS (APCI) m/z 491 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([O:11][C@H:10]([CH2:12][O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][C@H:7]1[OH:8])[OH:6].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][C:5]1([O:11][C@H:10]([CH2:12][O:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@H:7]1[O:8][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[OH:6]
Reactant: COCCC1(O)O[C@H](COC(=O)c2ccccc2)C[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCCC1(O)O[C@H](COC(=O)c2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (2-methoxyethyl)-5-O-benzoyl-3-deoxy-D-xylofuranose (example 122) (9.59 g, 32.40 mmol) and imidazole (3.980 g, 58.47 mmol) in DMF (40 mL ) at room temperature was added t-butyldimethylsilyl chloride (6.35 g, 42.12 mmol). The solution was stirred for 3 h and saturated NaHCO3 was added. The mixture was concentrated under vacuo. The residue was then partitioned between ether (100 mL) and water (50 mL). The aqueous phase was further extracted with ether (2×50 mL). The combined extracts were washed with brine (2×50 mL) dried (MgSO4) and concentrated to give the title compound (13.3 g, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17]C)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:19]=1.Br>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: COc1cccc2c1CCc1cc(Cl)ccc1C2=O
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2ccc(Cl)cc2CCc2c(O)cccc21
Yield: 95 %

Procedure:
For the synthesis of the title compound, 1.0 (4.87 mmol) g of 8-chloro-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 10 ml of HBr (48%, aqueous) and 10 ml of glacial acetic acid are employed in method L. Yield: 95%; m.p.: 185° C.; GC 15.2 min; C15H11ClO2 (Mr=258.71)
Reaction SMILES: O.O1CCOCC1.Cl.[OH:9][N:10]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:11]1=[O:21].[C:22]([O:26][C:27](SC1N=C(C)C=C(C)N=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(OCC)C.CCCCCC.C(N(CC)CC)C>[C:22]([O:26][C:27]([N:18]1[CH2:17][CH2:16][C:12]2([C:11](=[O:21])[N:10]([OH:9])[C:14](=[O:15])[CH2:13]2)[CH2:20][CH2:19]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Reactant: O=C1CC2(CCNCC2)C(=O)N1O
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
In a mixture solvent consisting of water (50 ml) and dioxane (50 ml) was dissolved 2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione.hydrochloride (8.35 g). To the solution were added triethylamine (14 ml) and 2-(tert. butyloxycarbonylthio)-4,6-dimethylpyrimidine (9.6 g). The mixture was stirred for 2 hours at room temperature. The solvent was evaporated off under reduced pressure, and the residual oil was evaporated in 100 ml of ethyl acetate. To the solution was added 100 ml of a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was made acid with a solid citric acid, followed by extraction with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of 1N hydrochloric acid and water, which was then dried over anhydrous magnesium sulfate, followed by evaporating off the solvent to leave an oil. This oil was solidified with diethyl ether-n-hexane, which was collected by filtration to obtain 9.6 g of a colorless solid, m.p. 151° to 154° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:36]O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:36])=[O:27])([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)CCCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)CCCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
8 g of N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-4-amino-n-butyric acid are dissolved in 50 ml of methanol and then 10 ml of concentrated sulfuric acid are slowly added. The reaction mixture is left to stand for some hours, then poured onto ice, made alkaline with sodium hydroxide solution and extracted with toluene. The toluene extract is washed with water until neutral and substantially concentrated in vacuo. The residue is crystallised from hexane, affording 6 g of methyl N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-4-amino-n-butyrate with a melting point of 60°-62° C.