Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[CH3:18].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[NH4+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:15][C:11]1[C:10]([CH3:18])=[C:9]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][CH:12]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cccc(N)c1C
Temperature: 125 °C
Reaction time: 36 h

Procedure:
Under argon, 10.844 g (108 mmol) of ethyl prop-2-enoate were added dropwise to a solution of 7.8 g (36.1 mmol) of 1-bromo-2-methyl-3-nitrobenzene, 25 ml (180.5 mmol) of triethylamine, 2.197 g (7.22 mmol) of tri-2-tolylphosphine and 810 mg (3.6 mmol) of palladium(II) acetate in 200 ml of DMF, and the mixture was then stirred at 125° C. for 36 h. After cooling to room temperature, the reaction mixture was stirred with saturated aqueous ammonium chloride solution and the organic phase was separated off. The aqueous phase was extracted three times with tert-butyl methyl ether, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. After filtration, the solvent was removed to dryness under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 3:1). This gave 6.6 g (27.2 mmol, content 97%, 75% of theory) of the intermediate ethyl (2E)-3-(2-methyl-3-nitrophenyl)prop-2-enoate as a colourless solid. 6.6 g (27.2 mmol, content 97%) of this solid were dissolved in 200 ml of ethanol, 500 mg of palladium on carbon (10%) were added at room temperature and the mixture was hydrogenated under atmospheric pressure overnight. After the reaction had gone to completion, the reaction solution was filtered through kieselguhr and the filtrate obtained was concentrated under reduced pressure. This gave 5.47 g (26.38 mmol, content 97%, 97% of theory) of the title compound as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:14])[NH:8][N:7]=[CH:6][C:5]=3[C:4]=2[CH2:3]1.[Br:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21](Br)[C:18]=1[CH:19]=[O:20].N(CC(O)=O)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Br:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([N:8]2[N:7]=[CH:6][C:5]3[C:4]4[CH2:3][C:2]([CH3:15])([CH3:1])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:14])[C:18]=1[CH:19]=[O:20]
Reactant: CC1(C)Cc2sc3c(=O)[nH]ncc3c2C1
Reactant: O=Cc1c(Br)cc(F)cc1Br
Agent: CNCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(C)Cc2sc3c(=O)n(-c4cc(F)cc(Br)c4C=O)ncc3c2C1
Temperature: 95 °C

Procedure:
A 100-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with 131h (330 mg, 1.5 mmol), 2,6-dibromo-4-fluorobenzaldehyde (1.26 g, 4.5 mmol), CuBr (113 mg, 0.8 mmol), sarcosine (142 mg, 1.6 mmol), K2CO3 (420 mg, 3.0 mmol), and dioxane (20 mL). See FIG. 15. After three cycles of vacuum/argon flush, the mixture was heated at 95° C. for 15 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography 5:1 eluting with petroleum ether/ethyl acetate to 131i as a white solid (380 mg, 60%). MS-ESI: [M+H]+ 420.6
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([O:34]C)[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=2[C:20]2[NH:21][C:22]3[CH:28]=[C:27]([C:29]([NH:31][CH3:32])=[NH:30])[CH:26]=[C:25]([CH3:33])[C:23]=3[N:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:34])[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=2[C:20]2[NH:21][C:22]3[CH:28]=[C:27]([C:29]([NH:31][CH3:32])=[NH:30])[CH:26]=[C:25]([CH3:33])[C:23]=3[N:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CNC(=N)c1cc(C)c2nc(-c3c(NCC(OC)c4ccc(OC)c(Cl)c4)cc[nH]c3=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=N)c1cc(C)c2nc(-c3c(NCC(O)c4ccc(OC)c(Cl)c4)cc[nH]c3=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 18.7 %

Procedure:
To a solution of 2-{4-[2-(3-chloro-4-methoxy-phenyl)-2-methoxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7,N-dimethyl-3H-benzimidazole-5-carboxamidine (40 mg, 0.08 mmol) in methanol (5 mL) was added 2 N NaOH (0.5 mL) and the reaction mixture was stirred at room temperature for 14 h. After concentration in vacuo, the residue was purified by prep. HPLC to yield the title compound (7.2 mg, 19%) as oil. 1H NMR (300 MHz, CD3OD) δ 7.78 (1H, narrow d, J=1.6 Hz), 7.52 (1H, narrow d, J=2.1 Hz), 7.30–7.36 (3H, m), 6.99 (1H, d, J=8.5 Hz), 6.27 (1H, d, J=7.6 Hz), 4.94 (1H, t, J=5.9 Hz), 3.82 (3H, s), 3.68–3.72 (2H, m), 3.13 (3H, s), 2.63 (3H, s). LCMS (M+H)+ m/z 481 (t=1.44 min.).
Reaction SMILES: [C:1]1([C:7]2[CH:23]=[CH:22][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH2:21])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([N-:31][S:32](N1C=CC(=[N+](C)C)C=C1)(=[O:34])=[O:33])=[O:30])([CH3:27])([CH3:26])[CH3:25]>ClCCl.[NH4+].[Cl-]>[C:1]1([C:7]2[CH:23]=[CH:22][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])(=[O:33])=[O:34])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reaction time: 72 h
Yield: 98.1 %

Procedure:
To a solution of (5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)methanamine (788 mg, 2.44 mmol) (described in WO 2011/074560) in dichloromethane (10 mL) was added N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (737 mg, 2.44 mmol), Winum, J.-Y. et al., Org. Lett., 3(14):2241-2243 (2001), and the reaction mixture stirred for 3 days. The reaction mixture was diluted with sat′d NH4Cl and the solution extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 10-100% EtOAc/DCM to give Compound 24a (1.2 g, 95% yield) as a brown oil. LCMS=0.99 min using analytical method (B), 502.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 7.74 (dd, J=8.4, 1.9 Hz, 1H), 7.68-7.61 (m, 2H), 7.49 (t, J=7.4 Hz, 2H), 7.44-7.36 (m, 1H), 6.96 (br. s., 1H), 5.26 (br. s., 2H), 4.79 (s, 2H), 4.63 (s, 2H), 1.37 (s, 9H).
Reaction SMILES: CS(O)(=O)=O.N[C@H](C(O)=O)CCSC.C[O:16][C:17]1[CH:18]=[C:19]([C@H:23]([CH2:30][CH3:31])[C@@H:24]([CH3:29])[CH2:25][N:26]([CH3:28])[CH3:27])[CH:20]=[CH:21][CH:22]=1.O>CC1CCCCC1>[CH3:28][N:26]([CH3:27])[CH2:25][C@H:24]([CH3:29])[C@H:23]([C:19]1[CH:18]=[C:17]([OH:16])[CH:22]=[CH:21][CH:20]=1)[CH2:30][CH3:31]
Reactant: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Solvent: O
Solvent: CC1CCCCC1
Product: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Temperature: 82 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
18.9 kg of methanesulfonic acid and 2458 g D,L methionine were placed in methyl cyclohexane and then 3192 g (2R,3R)-[3-(3-methoxy-phenyl)-2-methyl-pentyl]-dimethylamine were added and the mixture was stirred at 82° C. for 18 hours. Subsequently, dilution was carried out with 10.3 l water at a maximum of 80° C. and 9 l methyl cyclohexane were added. At a maximum of 42° C., 17.3 l ammoniac were added until the pH was 8.8. A phase separation took place at 45° C. and 3.2 g (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol were added to the organic phase at 40° C. and stirred for 1 hour at 36° C. Subsequently, after cooling slowly to 5° C. and a further hour of stirring, the precipitate which formed was extracted by suction, washed with 12 l methyl cyclohexane and dried in a drying chamber. 2685 g (89.5%) (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol were obtained in modification B.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]([O:13]CC(C1C=CC=CC=1)=O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][CH:9]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCC(OCc1ccccc1)C(CCCCCCCCCCCCCC)C(=O)OCC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(OCc1ccccc1)C(CCCCCCCCCCCCCC)C(=O)O
Yield: 58.2 %

Procedure:
Finally, phenacyl 3-benzyloxy-2-n-tetradecyl-octadecanoate (V) (1.81 g, 2.57 millimole) was dissolved in a mixed solvent (70 ml) of tetrahydrofuran and methanol (1:1) and 1N sodium hydroxide (7.70 ml, 7.70 millimole) was added thereto, and the mixture was reacted at 65° C. for 2.5 hours. The solvent was distilled off from the reaction mixture, and water and tetrahydrofuran were added to dissolve the residue. Then the solution was acidified with 2N hydrochloric acid (to pH of about 2) with ice cooling, and extracted with ethyl acetate, and the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic phase, the residue was dissolved in a developing solvent (n-hexane:ethyl acetate=8:2), and the obtained solution was purified over a silicagel column (n-hexane:ethyl acetate=8:2). The fast eluting fractions comprising impurities were discarded and the later colorless fractions were pooled. The solvent was evaporated off from the pooled fractions, and the residue was purified over a silicagel column (benzene:ethyl acetate=9:1) again, to give 3-benzyloxy-2-n-tetradecyl-octadecanoic acid (VI) (878 mg, yield 58%) in the form of colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:32]2[CH:33]=[CH:34][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc([N+](=O)[O-])cc2)c1C
Yield: 74.6 %

Procedure:
To a mixture of (6-chloro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (200 mg, 0.5 mmol), 4-nitrophenylboronic acid (170 mg, 1.1 mmol) and cesium carbonate (331 mg, 1 mmol) in dimethoxyethane (3 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55.3 mg, 0.07 mmol) at room temperature under nitrogen. The resulting mixture was reacted using a microwave reactor (Personal Chemistry) at 120° C. for 30 minutes. Ethyl acetate (10 mL) was added and the organic layer was washed with water (20 mL) and brine solution (20 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the crude product which was purified by using an ISCO (40 g) column chromatography eluting with 5-15% ethyl acetate in hexanes to give [6-chloro-3-methyl-4-(4-nitro-phenyl)-naphthalen-2-yl]-acetic acid methyl ester (138 mg, 74%) as a light yellow solid. 1H NMR (300 MHz, CDCl3), δ ppm 8.40 (d, J=8.6 Hz, 2 H), 7.82 (dd, J=8.9, 5.7 Hz, 1 H), 7.77 (s, 1 H), 7.46 (d, J=8.6 Hz, 2 H), 7.21 (td, J=8.9, 2.4 Hz, 1 H), 6.76 (dd, J=11.2, 2.4 Hz, 1 H), 3.87 (s, 2 H), 3.74 (s, 3 H), 2.14 (s, 3 H). HRMS calcd. for C20H15ClNO4 [(M−H)−] 368.0695, obsd. 368.0695.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][S:8]([CH2:11]P(C1C=CC=CC=1)(C1C=CC=CC=1)=O)(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[Si:38]([O:45][C@H:46]1[CH2:50][C@H:49]([N:51]2[C:55]3[N:56]=[CH:57][N:58]=[C:59]([NH:60][C@@H:61]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[CH2:63][CH2:62]4)[C:54]=3[CH:53]=[CH:52]2)[CH2:48][C@H:47]1[CH:70]=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][S:8](/[CH:11]=[CH:70]/[C@@H:47]1[CH2:48][C@@H:49]([N:51]2[C:55]3[N:56]=[CH:57][N:58]=[C:59]([NH:60][C@@H:61]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[CH2:63][CH2:62]4)[C:54]=3[CH:53]=[CH:52]2)[CH2:50][C@@H:46]1[O:45][Si:38]([C:41]([CH3:43])([CH3:44])[CH3:42])([CH3:39])[CH3:40])(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1C=O
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)CP(=O)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NS(=O)(=O)/C=C/[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
tert-Butyl{[(diphenylphosphoryl)methyl]sulfonyl}carbamate (602 mg, 1.45 mmol) was dissolved in THF (50.0 mL) under an atmosphere of argon, a 1.60 M solution of n-butyllithium in hexane (1.81 mL, 2.89 mmol) was added at −50° C., and the resultant mixture was stirred for 1 h. A solution of (1R,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanecarbaldehyde (300 mg, 0.60 mmol) in THF (8.0 mL) was added to the mixture, and the resulting mixture was stirred for 30 min at room temperature. After quenching by addition of water (200 mL), the mixture was extracted with EtOAc (100 mL×3). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 10 to 60% EtOAc in hexane to afford the title compound (84.0 mg, 21%). LC/MS: Rt=1.90 min, ES+ 654 (FA standard).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:34]2[S:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[S:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4s3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1f from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl)-benzothiazole.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C1COC(=O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a stirring solution of 1.6 g (16 mmol) of tetronic acid in 75 mL of methylene chloride is added 2.5 mL (17.86 mmol) of triethylamine and 640 mg of 4-dimethylaminopyridine at 0° C. Next, 5.0 g (17.6 mmol) of stearoyl chloride is added and the reaction is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted with two 100 mL portions of methylene chloride. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording crude compound. Pure material was obtained by trituration with ethyl acetate as affording 3.3 g (58%) of 4-hydroxy-3-(1-oxooctadecyl)-2(5H)-furanone.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33](=[N:35][OH:36])[NH2:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]1[N:34]=[C:22]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH2:9]2)[O:36][N:35]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: NC(Cc1ccccc1Cl)=NO
Product: CCc1ccc(C2CC(c3nc(Cc4ccccc4Cl)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 41 mg (0.22 mmol, 1.1 eq.) of 2-(2-chlorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 21 mg (22% of theory)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>CCO.C1COCC1>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: O=C(CCl)CCl
Solvent: C1CCOC1
Solvent: CCO
Product: Fc1ccc(-c2nc(CCl)co2)cc1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
A mixture of 4-fluorobenzamide (2.5 g, 17.9 mmol) and 1,3-dichloroacetone (2.7 g, 21.6 mmol) in EtOH-THF (20 mL-10 mL) was heated to 85° C. for 24 h. The reaction mixture was cooled to room temperature and quenched with 10% NaHCO3 solution. The organic product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 6-10% EtOAc in petroleum ether) to afford 4-(chloromethyl)-2-(4-fluorophenyl)oxazole (1.2 g, yield 32%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.07-8.02 (m, 2H), 7.70 (m, 1H), 7.19-7.13 (t, J=8.8 Hz, 2H), 4.58 (m, 2H). MS (ESI) m/z: Calculated for C10H7ClNO: 211.02. found: 212.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[OH:3].[CH3:21]I>>[CH3:21][O:3][CH:2]([C:4]1[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH3:1]
Reactant: CI
Reactant: CC(C)Cn1c(C(C)O)nc2cnc3ccccc3c21
Product: COC(C)c1nc2cnc3ccccc3c2n1CC(C)C

Procedure:
Using the general method of Example 49, α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (3 g; 11 mmol, Example 63) was reacted with methyl iodide to provide 2.4 g of the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH:12]([CH3:17])[C:13]([O:15]C)=[O:14])=[CH:8][N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Na+].Cl.[Cl-].[Na+]>O.C1COCC1>[N:1]1([C:6]2[N:7]=[CH:8][C:9]([CH:12]([CH3:17])[C:13]([OH:15])=[O:14])=[CH:10][N:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)C(C)c1cnc(-n2cnnn2)nc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1cnc(-n2cnnn2)nc1

Procedure:
A solution of methyl 2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)propanoate (70.2 mg, 0.300 mmol) in the mixture of THF (2.6 mL)/Water (0.4 mL) was treated with sodium hydroxide (1M, aqueous) (450 μl, 0.450 mmol) at room temperature under nitrogen for 1 h. The reaction was quenched with hydrochloric acid (450 μl, 0.450 mmol). Solvent was removed under reduced pressure and residue was freeze dried overnight. Product contains 1.5 equivalents of sodium chloride: LC/MS: [(M+1)]+=220.9.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[S:11][C:10]([C:12]3[S:13][C:14]([C:17]4[S:18][C:19]([C:27]5[S:28][C:29]([Br:32])=[CH:30][CH:31]=5)=[CH:20][C:21]=4[CH2:22][C:23]([O:25]C)=[O:24])=[CH:15][CH:16]=3)=[C:9]([CH2:33][C:34]([O:36]C)=[O:35])[CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[Br:32][C:29]1[S:28][C:27]([C:19]2[S:18][C:17]([C:14]3[S:13][C:12]([C:10]4[S:11][C:7]([C:5]5[S:6][C:2]([Br:1])=[CH:3][CH:4]=5)=[CH:8][C:9]=4[CH2:33][C:34]([OH:36])=[O:35])=[CH:16][CH:15]=3)=[C:21]([CH2:22][C:23]([OH:25])=[O:24])[CH:20]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1cc(-c2ccc(Br)s2)sc1-c1ccc(-c2sc(-c3ccc(Br)s3)cc2CC(=O)OC)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1cc(-c2ccc(Br)s2)sc1-c1ccc(-c2sc(-c3ccc(Br)s3)cc2CC(=O)O)s1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Intermediate O (707 mg, 0.989 mmol) was dissolved in dioxane (5 ml) and 2 M NaOH (5 ml) was added. The mixture was heated at 80° C. for 1 h and dioxane (10 ml) and 2 M NaOH (10 ml) was added. The mixture was stirred for 1 h at 80° C. Water was added and the mixture acidified using 6 M HCl. The precipitated material was isolated by centrifugation, washed with water and dried at high vacuum overnight. Yield: 679 mg (100%); orange solid. 1H NMR (400 MHz, DMSO-d6): δ 3.75 (s, 4H), 7.21 (d, J 3.8 Hz, 2H), 7.25 (d, J 3.8 Hz, 2H), 7.29 (s, 2H), 7.31 (s, 2H),
Reaction SMILES: [C:1]([CH:9]1[C:13](=[O:14])[N:12](C2C=CC=CC=2)[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]1[C:27]([O:29]CC)=[O:28])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:2]1([C:1]2[O:29][C:27](=[O:28])[C:10]3[C:9]=2[C:13](=[O:14])[N:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]=3[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)N(c2ccccc2)C(=O)C1C(=O)c1ccccc1
Solvent: CO
Product: O=C1OC(c2ccccc2)=C2C(=O)N(c3ccccc3)C(c3ccccc3)=C12
Temperature: 200 °C
Yield: 103.5 %

Procedure:
Benzoyl pyrrolinone ester 17 (74 mg) was irradiated with microwave radiation (at 300 Watts) without solvent, heating to 200° C. for 10 minutes. The crude product was then allowed to cool, methanol was added and the solid filtered off and washed with methanol. This gave the furopyrrole 18 as an orange solid (34 mg, 52%), m.p 230-232° C. (lit. [H. Langhals, T. Grundei, T. Potrawa, K. Polborn, Liebigs Ann. Chem., 1996, 679] 230-232° C.). δH (CDCl3) 8.48-8.42 (2H, m, Ar—H) and 7.61-7.20 (13H, m, Ar—H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:39]=[CH:38][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:37])[N:21]([N:30]=[C:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC2NC(C3C(=O)N(N=C4CCC4)C4C(C=3O)=CC=CC=4)=NS(=O)(=O)C=2C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:39]=[CH:38][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:37])[N:21]([NH:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1N=C1CCCCC1
Agent: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1N=C1CCC1
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1NC1CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Example 304H, substituting the product of Example 306A for the product of Example 304G (0.11 g, 78%).