Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7]C1C=C(C2C=CC(C(NCC3CC3)=O)=CC=2)C(C)=CC=1)=[O:6]>C(NCC)C>[C:5]([NH2:7])(=[O:6])[C:4]1[CH:28]=[CH:29][N:30]=[CH:2][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: CCNCC
Product: NC(=O)c1ccncc1
Reaction time: 84 h

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in diethylamine (2 ml) was heated at 80° C. for 48 h and then at 110° C. for 84 h in a sealed tube. The reaction was concentrated under vacuum, the residue triturated with water and purified by preparative HPLC. The solvent was evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-diethylamino)isonicotinamide. NMR; δH [2H6]—DMSO 10.27,(1H, s), 8.62,(1H, t), 8.19,(1H, d), 7.93,(2H, d), 7.69,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 0.43,(4H, m), 0.24,(2H, m). LCMS: retention time 3.09 min, MH+457.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:4][CH:3]=1.C([Sn]([N:53]=[N+:54]=[N-:55])(CCCCCCCCCCCC)CCCCCCCCCCCC)CCCCCCCCCCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:10]3[N:55]=[N:54][NH:53][N:11]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCC[Sn](CCCCCCCCCCCC)(CCCCCCCCCCCC)N=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 120 °C
Reaction time: 37.5 h
Yield: 82.3 %

Procedure:
A mixture of 1.50 g of 2-(4-methylphenyl)benzonitrile, 19.5 g of tridodecyltin azide (tri-n-dodecyltin azide) and 7 ml of toluene was stirred for 37.5 hours at 120° C. The reaction mixture was, after cooling, concentrated, and there were added 18 ml of ethanol, 1 ml of methylene chloride and 2.4 g of sodium nitrite dissolved in 9 ml of water, whose pH was adjusted at 3.4 with conc. hydrochloric acid. To the mixture were added 2 ml of ethyl acetate and 100 ml of hexane. Insolubles were filtered off. The filtrate was shaken, then left standing to form two layers. The organic layer was subjected to extraction with 1N NaOH. The alkaline layer was adjusted at pH 3 with conc. hydrochloric acid, and then subjected to extraction with ethyl acetate. The extract was concentrated, and there were added ethyl acetate and hexane to cause crystallization. The crystals were collected by filtration, washed with hexane and dried to afford 1.51 g (yield 82.3%) of 5-[2-(4'-methylbiphenyl)]tetrazole. Spectrum data were in good agreement with those in Example 4.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Mg+2].[Cl-].[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.S(Cl)(Cl)(=O)=O.Cl>C(#N)C.CCOC(C)=O>[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:23]1([C:29]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)C1(c2cccc(F)c2F)CCOCC1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(=O)(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2cccc(F)c2F)CCOCC1
Temperature: 0 °C
Yield: 33 %

Procedure:
A mixture of diethyl malonate (4.2 g, 26 mmol) in 50 mL ACN was stirred at 0° C. and treated with magnesium chloride (2.5 g, 26 mmol) in one portion and TEA (5.9 g, 58 mmol) dropwise. The mixture was stirred at room temperature for 2.5 hours. In a separate flask, a mixture of 4-(2,3-difluorophenyl)-tetrahydro-2H-pyran-4-carboxylic acid (6.4 g, 26 mmol) in sulfuryl dichloride (31 g, 264 mmol) was refluxed for 2 hours, then concentrated in vacuo. This residue was diluted with 30 mL ACN, and added to the malonate/magnesium chloride mixture dropwise. The resulting reaction was stirred at 50° C. for 1.5 hours. The mixture was cooled to room temperature, diluted with 200 mL EtOAc, neutralized to pH=5 with concentrated HCl, washed with H2O (2×50 mL), saturated NaCl (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (10-20% EtOAc/hexane) to give the intermediate 3.3 g as pale yellow oil. MS m/e: (M+H)+ 385.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:19][C@H:20]([OH:32])[C:21]1[C:29]2[S:28][C:27](=[O:30])[NH:26][C:25]=2[C:24]([OH:31])=[CH:23][CH:22]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].FC(F)(F)C(O)=O.[F:40][C:41]([F:56])([F:55])[C:42]([N:44]1[CH2:49][C:48]2([CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[O:47][CH2:46][CH2:45]1)=[O:43].C(N(CC)CC)C>CC#N>[OH:32][C@H:20]([C:21]1[C:29]2[S:28][C:27](=[O:30])[NH:26][C:25]=2[C:24]([OH:31])=[CH:23][CH:22]=1)[CH2:19][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:52]1[CH2:53][CH2:54][C:48]2([O:47][CH2:46][CH2:45][N:44]([C:42](=[O:43])[C:41]([F:40])([F:55])[F:56])[CH2:49]2)[CH2:50][CH2:51]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCBr)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC2(CC1)CN(C(=O)C(F)(F)F)CCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of (R)-tert-butyl 9-bromononyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate (example 183-222, step b) (1.68 g) in MeCN (8 mL) was added dropwise to a solution of 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (1.18 g) and triethylamine (0.81 mL) in MeCN (8 mL). The resulting mixture was stirred at 80° C. for 18 h. The reaction was allowed to cool to RT and the solvent was removed in vacuo. The brown residue was taken up in DCM and the organic layer was washed with water (×2) and brine, dried over sodium sulphate, filtered and evaporated in vacuo. The brown foam was purified by silica gel chromatography eluting with 0-10% MeOH/DCM to give the subtitled compound as a white solid. Yield 500 mg.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]1[N:16]2[CH:17]=[C:18]([O:21][C@H:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@@H:25]([NH2:32])[CH2:24][CH2:23]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1)(C)C.ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO.C(Cl)Cl>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:32][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([N:8]5[CH2:9][CH2:10][CH2:11][C@@H:7]5[CH2:6][OH:5])=[N:13][N:14]=4)[CH:17]=3)[CH2:23][CH2:24]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OC[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@@H]5CO)n4c3)c3ccccc32)cc1
Yield: 36 %

Procedure:
A solution of Intermediate 27c (50 mg, 0.093 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 56 mg, 0.140 mmol) and DIPEA (70 mg, 0.54 mmol) in DMF (2 mL) was stirred at 60° C. for 1 h. The reaction mixture was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as an off-white foam (27 mg, 36%). LCMS (Method 4): Rt 4.58, m/z 791 [MH+].
Reaction SMILES: COC(OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[CH:11]=[CH:12][N:13]=C2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:16](=O)[C:15]=12.[Cl-].[NH4+].C(O)(=O)C>CN(C)C=O>[CH:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:25])[C:5]3[C:15]4[C:10]([CH:9]=[CH:6][N:4]=3)=[CH:11][CH:12]=[N:13][C:16]=4[C:18]=2[CH:19]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-c2nccc3ccnc1c23
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Dimethylformamide dimethyl acetal (1.50 mL, 11.34 mmol, Aldrich) was added to a solution of cleistopholine, (1.95 g, 8.73 mmol) in dimethylformamide (5 mL). The mixture was then heated for 30 min by submerging the reaction vessel into an oil bath preheated to 120° C. At this point, ammonium chloride (4.5 g) and glacial acetic acid (15 mL) were added to the reaction and the heating (120° C.) continued for an additional 30 min. After allowing to cool, the reaction was poured onto water (200 mL) and partitioned with methylene chloride (5×100 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (3×100 mL), water (3×100 mL), dried over potassium carbonate, and concentrated to dryness. The residual dark brown solids were chromatographed on silica gel (4×70 cm column, Merck 230-400 mesh) while eluting with ethyl acetate. Concentration of the appropriate column fractions provided pure sampangine (1.60 g, 79 %), mp 220-222 (lit. mp 216°-218° C.). IR 1670, 1615, 1590, 1400, 1380, 1320, 1275, 1225, 760, 725 cm-1 ; 1H and 13C NMR.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:33][CH:34]2[CH2:43][CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[O:44][CH3:45])[CH2:35]2)(=O)=O)=CC=1>CN(C)C=O>[CH3:45][O:44][C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[CH2:42][CH2:43][CH:34]([CH2:33][N:12]1[C:11](=[O:14])[CH:10]=[CH:9][C:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:13]1)[CH2:35]2
Reactant: COc1cccc2c1CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A suspension of 6-diphenylmethyl-3(2H)-pyridazinone (0.58 g) and sodium hydride (60%, 110 mg) in dry N,N-dimethylformamide (7 ml) was stirred at 0° C. for 30 minutes. A solution of (5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)methyl p-toluenesulfonate (0.77 g) in dry N,N-dimethylformamide (5 ml) was added dropwise to the suspension at room temperature. The mixture was stirred for 6 hours and poured into ice-1N hydrochloric acid and extracted with ethyl acetate. The extract was separated, washed with water (twice) and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=5:1~3:1) to give 2-[(1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.61 g) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:28]=1[N:42]1[N:51]=[CH:50][C:49]2[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=2)[C:43]1=[O:57])(=[O:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].O.O1CCOCC1>[C:52]([C:47]1[CH:48]=[C:49]2[C:44](=[C:45]([F:56])[CH:46]=1)[C:43](=[O:57])[N:42]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:21]=[CH:20][C:14]([C:15](=[O:16])[N:17]([CH3:19])[CH3:18])=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:27]=1[CH2:26][O:25][C:22](=[O:24])[CH3:23])[N:51]=[CH:50]2)([CH3:53])([CH3:54])[CH3:55]
Reactant: CN(C)C(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N(C)C)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 85 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
In a 250 mL round-bottomed flask, 6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-N,N-dimethylnicotinamide (1.053 g, 3.42 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (2.2 g, 4.45 mmol) and Cs2CO3 (3.34 g, 10.3 mmol) were combined with dioxane (20 ml) and water (2.00 ml) to give a dark brown suspension. The suspension was purged with argon and PdCl2(DPPF) (83.8 mg, 10.3 mmol) was added. The reaction mixture was heated to 85° C. and stirred for 3 h. Cooled to 25° C. and diluted with DCM. Na2SO4 was added and the mixture was filtered through celite. The filter cake was washed with DCM until clear and the brown filtrate was conc. in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 0% to 5% MeOH in DCM). The product was isolated impure and repurified by flash chromatography (silica gel, 220 g, 100% EtOAc) to afford 1.1412 g (52%) of the title compound as a cream colored solid. (M+H)+=640 m/e.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:15]=3)=[CH:11][C:5]=2[C:4]=1[CH3:32])#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:6]2[S:7][C:3]([C:1]3[NH:35][N:34]=[N:33][N:2]=3)=[C:4]([CH3:32])[C:5]=2[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C#N)sc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2nnn[nH]2)sc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc12
Temperature: 80 °C

Procedure:
A solution-suspension of 2-cyano-5-[3-(2-quinolinylmethyloxy)benzyloxy]-3-methylbenzo(b)thiophene (300 mg, 0.69 mmol), sodium azide (134 mg, 2.1 mmol) and ammonium chloride (110.3 mg, 2.1 mmol) in DMF (3 ml) is heated to 80° C. for 16 hours. The reaction mixture is cooled to room temperature and poured over ice-water. The pH is adjusted to 10 (1N NaOH) and the aqueous layer washed with ether and then acidified to pH 3. The precipitated solid is filtered and washed successively with water, ethanol and methylene chloride and dried to afford 5-(5-[3-(2quinolinylmethyloxy)benzyloxy]-3-methylbenzo(b)thiophen -2-yl)tetrazole (M.P. 195-196° C. (dec)).
Reaction SMILES: [NH2:1][C@@H:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:4].[O:32]1[CH2:35][C:34](=O)[CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:25][C:20]1[CH:19]=[C:18]([N:5]([CH2:6][CH2:7][C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[C:3](=[O:4])[C@@H:2]([NH:1][CH:34]2[CH2:35][O:32][CH2:33]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: O=C1COC1
Reactant: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](N)c2ccccc2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](NC2COC2)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 25 mg (S)-2-Amino-N-(3,4-dimethyl-phenyl)-2-phenyl-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (from example 1) in 1.5 ml dry CH2Cl2 under argon in a sealed tube was added 1.1 eq. oxetan-3-one. The reaction mixture was stirred at RT for 20 min, followed by the addition of 3.0 eq., Sodium triacetoxyborohydride and the reaction stirred for 16 h at RT. The reaction mixture diluted with 10 ml CH2Cl2 and washed with 2M aq. Na2CO3 2M, dried and concentrated then chromatographed on silica gel (EtOAc/Heptane, gradient elution) to give the desired compound. MS(m/e): 484.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([NH:20]C(=O)C)([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)C(OCC)=O)C.C(NC(C(OCC)=O)C(OCC)=O)(=O)C.BrCC1C=CC(C#N)=CC=1.[O-]CC.[Na+].[ClH:54]>C(O)(=O)C>[ClH:54].[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:5]([C:4]([OH:24])=[O:3])[NH2:20])=[CH:17][CH:16]=1)#[N:19]
Reactant: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC
Agent: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccc(CC(N)C(=O)O)cc1

Procedure:
A mixture of 235 g (0.707 Mol) of diethyl -(acetamido)-α-[(4-cyanophenyl)methyl]-malonate (Mp. 163-165° C.; prepared from diethyl α-(acetamido)-malonate and 4-(bromomethyl)-benzonitrile in the presence of sodium ethoxide), 1.28 l (3.84 Mol) of 3N aqueous hydrochloric acid and 0.64 l of glacial acetic acid were refluxed for 7 hours. The mixture cooled to +5° C. was filtered and the filtrate was evaporated down in vacuo. The residue was intensively washed with isopropanol and then dried in vacuo. 92.9 g (58% of theory) of colourless crystals were obtained, Mp. 219° C. (D.).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[O:28])[C:21](=[O:27])[NH:22]2.O1C2C=CC(O)=CC=2OC1.[O:39]1[C:43]2[CH:44]=[C:45]([OH:48])[CH:46]=[CH:47][C:42]=2[CH2:41][CH2:40]1>>[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([OH:28])([C:46]1[C:45]([OH:48])=[CH:44][C:43]3[O:39][CH2:40][CH2:41][C:42]=3[CH:47]=1)[C:21](=[O:27])[NH:22]2
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: Oc1ccc2c(c1)OCC2
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1Nc2cccc(Br)c2C1(O)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 4-bromoisatin, and 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compound was obtained (78%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.15 (s, 1H), 7.49 (1H), 7.04 (t, 1H), 6.89 (d, 1H), 6.74 (d, 1H), 6.35 (br, 1H), 5.90 (s, 1H), 4.45 (t, 2H), 3.05 (t, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.4, 160.2, 154.0, 145.7, 131.6, 130.7, 125.5, 125.4, 118.9, 117.7, 116.1, 108.8, 96.8, 76.9, 71.8, 29.1; MS (ES−) m/z 344.4 (M−17), 360.4 (M−1).
Reaction SMILES: [Na].C([O:4][C:5]([C:7]1[N:8]=[N:9][NH:10][N:11]=1)=[O:6])C.Br[CH2:13][C:14]1[CH:18]=[C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[O:16][N:15]=1>CN(C=O)C>[Cl:24][C:21]1[S:20][C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][N:9]3[N:10]=[N:11][C:7]([C:5]([OH:4])=[O:6])=[N:8]3)[CH:18]=2)=[CH:23][CH:22]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1nn[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(O)c1nnn(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg 2H-Tetrazole-5-carboxylic acid ethyl ester sodium salt in 1 ml DMF, 59 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2] were added and the mixture was stirred at room temperature for 16 h. Then the reaction mixture was concentrated under reduced pressure. The residue was taken-up in 1 ml THF and after addtion of 1 ml of a 1M NaOH solution stirred for 16 h at RT. The mixture was acidified with half concentrated hydrochloric acid to pH 3 and the precipitate collected by filtration. The product was obtained as a white solid, which was dried under reduced pressure. Yield: 49 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]2[CH:19]=1)=[O:5])[CH3:2].[N+:20]([O-])([OH:22])=[O:21].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]2[C:19]=1[N+:20]([O-:22])=[O:21])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cn2cccc(C(=O)OCC)c2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1nc2c(C(=O)OCC)cccn2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
Ethyl 2-ethoxycarbonylimidazo[1,2-a]pyridine-8-carboxylate (3.8 g, 14.5 m mol) was dissolved in conc. sulfuric acid (10 ml), and to the solution was slowly added 70% nitric acid (1.5 ml) at 10° C. The mixture was stirred at room temperature for 30 minutes, poured into ice water and adjusted to pH 7 by adding 20% sodium hydroxide. The precipitated crystals were filtered to obtain ethyl 2-ethoxycarbonyl-3-nitro-imidazo[1,2-a]pyridine-8-carboxylate (2.4 g, yield 53.8%) as crystals of m.p. 139°-140° C. A solution of the crystals in conc. hydrochloric acid (35 ml) was refluxed for 1.5 hours and cooled to room temperature. The precipitated crystals were collected by filtration and dried to give the object compound (1.2 g, yield 74.3%) of m.p.>300° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1.C1CCN2C(=NCCC2)CC1>C(O)(C)C>[CH3:17][C:18]1[N:19]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH:20]=[CH:21][N:22]=1
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Reactant: Cc1ncc[nH]1
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nccn1CCCOc1ccc2c(c1)CCC(=O)N2

Procedure:
2.0 Grams (7.0 mM) of 6-(3-bromopropoxy)-3,4-dihydrocarbostyril, 2.2 g (7.7 mM) of 2-methylimidazol and 1.3 ml (8.4 mM) of DBU were dissolved in 80 ml of isopropanol, and the resulting solution was refluxed by heating for 20 hours. The reaction mixture was concentrated, and to the resulting residue was added water, then extracted with chloroform. The chloroform extract was washed with water, dried with anhydrous sodium sulfate, then concentrated. The resulting residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=20:1), and recrystallized from ethanol-n-hexane to yield 1.0 g of 6-[3-(2-methyl-1-imidazolyl)propoxy]-3,4-dihydrocarbostyril. White powdery substance.