Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12](I)[N:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:10]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)CCC.CC(O)=O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[N:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:10]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(I)n1-c1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2ccccn2)n1-c1ccc(OC)cc1
Temperature: 140 °C
Yield: 84.7 %

Procedure:
To a solution of ethyl 3,4-bis(benzyloxy)-5-iodo-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (28) (300 mg, 0.51 mmol) in DMF (5 mL) was added 2-(tributylstannyl)pyridine (280 μL, 0.87 mmol), copper(I) iodide (19.6 mg, 0.10 mmol) and dichlorobis(triphenylphosphine)palladium(II) (36.1 mg, 0.05 mmol). The mixture was heated in a microwave at 140° C. for 30 min, AcOH (2 mL) was added and the crude product was loaded onto a column of SCX (5 g). The column was washed with MeOH and then the product was eluted with 1% NH3 in MeOH. The resultant mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (12 g, 20-100% EtOAc in isohexane) to afford ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(pyridin-2-yl)-1H-pyrrole-2-carboxylate (UL1-082) (231 mg, 83%) as a pale yellow oil: m/z 535 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1H NMR (400 MHz, DMSO-d6) δ: 8.47-8.40 (m, 1H), 7.71-7.63 (m, 1H), 7.54-7.47 (m, 2H), 7.45-7.16 (m, 10H), 7.12-7.03 (m, 2H), 6.83-6.76 (m, 2H), 5.18 (s, 2H), 4.96 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 1.03 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)CCOC([NH:26][C@@H:27]1[CH2:29][C@H:28]1[S:30][C:31]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1)=O>O1CCCC1.C(#N)C>[NH2:26][C@@H:27]1[CH2:29][C@H:28]1[S:30][C:31]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H]1Sc1nc2ccccc2cc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Product: N[C@@H]1C[C@H]1Sc1nc2ccccc2cc1-c1ccccc1
Reaction time: 5 h

Procedure:
A 1 M-solution of tetra-n-butylammonium fluoride in tetrahydrofuran (12 ml.) was added to a solution of 2-{trans-2-[2-(trimethylsilyl)ethoxycarbonylamino]-cyclopropylthio}-3-phenylquinoline (3.5 g.) in dry acetonitrile (35 ml.), and the mixture was stirred at 50° under argon for 5 hr. The mixture was cooled, the solvent was evaporated, and the residual oil was partitioned between ethyl acetate (70 ml.) and water (35 ml.). The mixture was separated and the organic phase was washed with water (2×30 ml.) and dried (Na2SO4). The solvent was evaporated and the residual brown oil (2.7 g.) was chromatographed on basic alumina (180 gm., Brockmann, Grade III) eluted with 30% v/v chloroform in petroleum ether to give 2-(trans-2-aminocyclopropylthio)-3-phenylquinoline as a pale yellow oil, which gave a hydrochloride of m.p. 140°.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][NH2:28])[NH:23][CH:22]=1.CN1CCOCC1>CO>[N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][NH:28][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])[NH:23][CH:22]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCCc1cnc[nH]1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCc3cnc[nH]3)cc2s1
Yield: 6.6 %

Procedure:
the title compound (8 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 2-(3H-imidazol-4-yl)-ethylamine (68 mg, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 404.3 (M+1, 100%). Yield=6%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:10]([OH:12])=O.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:33])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:33][C:10](=[O:12])[C:9]#[C:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][C:2]=2[Br:1])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br
Reactant: Nc1ccc(CCN2CCCC2)c(Cl)c1
Product: O=C(C#Cc1ccc(-c2ccccc2)cc1Br)Nc1ccc(CCN2CCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 2.3.f. from (3-bromobiphenyl-4-yl)propynoic acid and 3-chloro-4-(2-pyrrolidin-1-ylethyl)phenylamine. Yield: 140 mg (27.2% of theory); C27H24BrClN201 (M=507.84); calc.: molecular ion peak (M+H)+: 507/09/11; found: molecular ion peak (M+H)+: 507/09/11.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:42])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][O:31][Si](C(C)C)(C(C)C)C(C)C)=[CH:26][CH:25]=3)[CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[OH:31][CH2:30][C:27]1[CH:26]=[CH:25][C:24]([CH:13]([C:12]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[O:42])[CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:29][CH:28]=1
Reactant: CC(C)[Si](OCc1ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-((thisopropylsilyloxy)methyl)phenyl)Propyl(methyl)carbamate (E205) in THF under N2 at 0° C. was added TBAF, and the solution was stirred for 30 min at 0° C. The reaction was warmed to room temperature and stirred another 4.5 h. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-20% MeOH/CH2Cl2 gradient) gave pure tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropyl(methyl)carbamate (E205-1)
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24]>>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])=[O:20]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: OCCNCCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCO)CCO
Temperature: 182 °C

Procedure:
Oleic diethanolamide was prepared by stirring equimolar quantities of oleic acid and diethanolamine in a nitrogen atmosphere while heating to 182° C. and maintaining the temperature for 2 hours while removing water. The product (Additive D), which also contained a significant amount of ester, was representative of another commercial amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].C(N(CC)CC)C.[C:20](Cl)(Cl)=[S:21]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH2:5][N:6]=[C:20]=[S:21]
Reactant: S=C(Cl)Cl
Reactant: COc1c(F)cc(CN)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(F)cc(CN=C=S)cc1F
Temperature: -10 °C
Reaction time: 2.75 h
Yield: 85.5 %

Procedure:
A solution of 3,5-difluoro-4-methoxybenzylamine (8.7 g, 0.05 mole) and triethylamine (15.5 ml, 0.11 mole) in 50 ml of tetrahydrofuran was added dropwise to a solution of thiophosgene (4.2 ml, 0.055 mole) in 50 ml of tetrahydrofuran with cooling to -10° C. over a period of twenty minutes. The mixture was stirred at 25° C. for 2.75 hours and then filtered. The filtrate was treated with charcoal, filtered, and evaporated to an oil. The oil was diluted with hexane:ethyl acetate (90:10) and purified on a flash silica column using hexane:ethyl acetate (90:10) as the eluant to yield 9.2 g (79%) of 3,5-difluoro-4-methoxybenzyl isothiocyanate.
Reaction SMILES: C(=O)([S:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:7][CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][SH:3])=[CH:10][CH:9]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(=O)SCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CS)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
to a stirred solution of ethanethioic acid, S-[4-(tert-butyldimethylsilyloxy)benzyl] ester (30.7 g, 104 mmol) in dry THF (300 mL) at 0° C. under an argon atmosphere was added lithium aluminium hydride (5.9 g, 156 mmol). The reaction was stirred for 3 h at 0° C. The mixture was quenched by careful addition of EtOAc then water. The pH was brought to 5 with an aqueous solution of 10% HCl and the resulting slurry was filtered. The filtrate was extracted with EtOAc (2×100 mL) and the combined organic layers were washed successively with Rochelle's salt, brine, dried (MgSO4), filtered and concentrated to give the product as a green oil (22.1 g, 84%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)=[O:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)=[O:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:1]
Reactant: COC(=O)c1cc(CO)cc(C(=O)N2CCC[C@@H]2c2nc(C)cs2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)cc(C(=O)N2CCC[C@@H]2c2nc(C)cs2)c1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of (R)-methyl 3-(hydroxymethyl)-5-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoate (560 mg, 1.554 mmol) in DCM (60 mL), Dess-Martin periodinane (790.8 mg, 1.864 mmol) was added at rt. After stirring for 2 hrs, the mixture was poured into a mixture of aqueous 1 M Na2S2O3 (30 mL) and aqueous saturated NaHCO3 (30 mL), and it was extracted with DCM three times. The combined organic layers were concentrated in vacuum and the residue was purified by flash silica chromatography to give the product (530 mg). 1H NMR (CDCl3): d: 10.094, 9.933 (s, s, 1H), 8.592-7.908 (m, 3H), 6.796 (s, 1H), 5.661 (m, 0.65H), 5.083 (m, 0.35H), 3.969-3.743 (m, 4H), 3.515 (m, 1H), 2.429-2.308 (m, 5H), 2.145-1.939 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:35])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:2]([C@:3]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:35])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=[O:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (1 g, 1.789 mmol) in CH2Cl2 (70 ml) was added PCC (1.157 g, 5.37 mmol). The resulting dark brown mixture was stirred at rt for 4 h. TLC analysis showed the reaction was complete. The mixture was filtered through a short bed of Celite and silica gel, washed with excess of CH2Cl2. The filtrate was concentrated in vacuo. The crude mixture was purified by Biotage on normal phase silica gel. The fractions containing the expected product were combined and concentrated in vacuo to afford methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a solid (0.8 g). LCMS: m/e 557.2 (MH+), 3.67 min (method 2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12](Br)[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12]([C:17]#[N:18])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(Br)c(C(=O)OC)cc1N
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C(=O)OC)cc1N
Temperature: 120 °C
Yield: 98 %

Procedure:
2-Amino-5-bromo-terephthalic acid dimethyl ester (15.0 g, 52.1 mmol), zinc (II) cyanide (6.11 g, 52.1 mmol) and tetrakis(triphenylphosphine)palladium (0) (3.0 g, 2.6 mmol) were suspended in DMF (50 ml) and the resultant reaction mixture degassed was purged with argon. The reaction mixture was heated at 120° C. for 30 minutes then concentrated in vacuo. The resultant residue was triturated with hot water (100 ml) and the product collected by filtration to yield the title compound as a dark grey solid (12.0 g, 98%). 1H NMR (d6-DMSO, 400 MHz) 8.11 (1H, s), 7.62 (2H, br s), 7.52 (1H, s), 3.89 (3H, s), 3.85 (3H, s).
Reaction SMILES: [I-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][CH2:19][O:20][CH3:21])[C:10](N2C=C[N+](C)=C2)=[O:11])=[CH:5][CH:4]=1.[F:22][C:23]([F:41])([F:40])[C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32][NH:31]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:18][CH2:19][O:20][CH3:21])[C:10]([N:31]2[CH2:32][CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:30]2[C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:40])[F:41])=[CH:29][CH:28]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: COCCN(C(=O)n1cc[n+](C)c1)c1ccc(F)cc1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(C(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 28 h

Procedure:
To a 50 mL round-bottomed flask was added 1-((4-fluorophenyl)(2-methoxy-ethyl)carbamoyl)-3-methyl-1H-imidazol-3-ium iodide (70 mg, 173 μmol, from step 3), (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (24 mg, 87 μmol), CH2Cl2 (1 mL), triethylamine (12 μL, 87 μmol). The reaction mixture was stirred at 40° C. for 28 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give (R)—N-(4-fluorophenyl)-N-(2-methoxyethyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 473 (M+1).
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:26](=[O:29])([OH:28])[OH:27])[P:22](=[O:25])([OH:24])[OH:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-]CC.[Na+:33].C(O)C>O1CCCC1>[C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:26](=[O:27])([O-:28])[O-:29])[P:22](=[O:23])([O-:24])[O-:25])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:33].[Na+:33].[Na+:33].[Na+:33]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(O)O)P(=O)(O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)([O-])[O-])P(=O)([O-])[O-]
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
[2-[2-(1-Tridecynyl)phenyl]ethenylidene]bisphosphonic acid (0.102 g, 0.23 mmol) prepared according to Example 10 was dissolved in dry tetrahydrofuran (10 ml) and stirred while sodium ethoxide in ethanol (0,177M, 5.19 ml, 0.92 mmol) was added. After 20 minutes, the solvent was removed under reduced pressure to give a light solid. The solid was powdered and washed with dry ethanol, then dried under vacuum, 40.8 mg, 0.084 mmol, 36.5% yield; mp darkens above 233° C. under N2 ; 1H NMR (D2O) ∂ 0.89 (m, 3H), 1.21 to 1.57 (m, 16H), 1.67 (m, 2H), 2.55 (t, J=7.1 Hz, 2H), 7.35 (m, 2H), 7.51 (m, 1H), 7.90 (dd, J=42.4, 26.3 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H).
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30]>>[NH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[C:31]1[C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:11]([CH3:12])[C:4]2[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])(=[O:15])=[O:14])=[CH:17][CH:18]=1)=[O:30]
Reactant: O=C(NCCCO)c1cc2ccccc2[nH]1
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCNC(=O)c2cc3ccccc3[nH]2)cc1
Yield: 91 %

Procedure:
The product of Example 2 (0.27 g, 0.83 mmol) was coupled to N-(3-hydroxypropyl)-1H-indole-2-carboxamide, prepared according to Example 18, (0.20 g, 0.91 mmol) using the procedure of Example 3 to provide 0.4 g (91% yield) of yellow solid powder. MP 199° C.; 1H NMR (DMSO-d6): δ 1.9 (s, CH3), 2.0-2.1 (m, CH2), 3.20 (s, CH3), 3.32-3.51 (m, CH2, CH2), 6.8-7.2 (m, 8 Ar H), 7.36 (d, 1 Ar H), 7.58 (d, 1 Ar H), 7.78 (d, 1 Ar H), 7.93 (s, 1 NH), 8.52 (s, NH), 12.0 (s, OH). Electrospray Mass Spec: m/z 522.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C(O[C:44]([C@@H:46]1[CH2:50][CH2:49][CH2:48][C@@H:47]1[NH:51][CH2:52][CH2:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:45])C.[O-]CC.[Na+].C(O)C.Cl>CN(C)C=O>[CH3:57][C:54]([CH3:55])([CH3:56])[CH2:53][CH2:52][N:51]1[C@@H:47]2[C@@H:46]([CH2:50][CH2:49][CH2:48]2)[C:44]([OH:45])=[C:16]([C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[N:12]=2)[C:17]1=[O:18]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.060 g, 0.315 mmol) and N-methylmorpholine (0.070 mL, 0.630 mmol) were added sequentially to a solution of (1R,2S)-2-(3,3-dimethyl-butylamino)-cyclopentanecarboxylic acid ethyl ester (0.072 g, 0.300 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 3 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (110 mL) and ethyl acetate (2×110 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was dissolved in ethanol (4 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (0.244 mL, 0.600 mmol) was added and the reaction mixture was heated to 60° C. for 2 h. After cooling to 25° C. and stirring for 16 h, the reaction mixture was slowly added to 1.0 M aqueous hydrochloric acid solution (50 mL) at 0° C. The resulting precipitate was collected by filtration and dried in vacuo, then was triturated with a small amount of methanol (ca. 0.5 mL) to afford the desired product, (4aR,7aS)-N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.083 g, 0.163 mmol, 54%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.00 (s, 9H), 1.50-1.82 (m, 6H), 1.94-2.47 (m, 4H), 2.94-3.39 (m, 2H), 3.06 (s, 3H), 3.68-3.82 (m, 2H), 6.99 (bs, 1H), 7.21 (dd, 1H, J1=28.7 Hz, J2=8.4 Hz), 7.63 (t, 1H, J=8.9 Hz), 7.67-7.69 (m, 1H). LC-MS (ESI) calcd for C22H30N4O6S2 510.16, found 511.4 [M+H+].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[CH3:10][N:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH:25]2[CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][N:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH:25]2[CH2:30][CH2:29][N:28]([C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[CH2:27][CH2:26]2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: CN1CCC(C2c3ccccc3N(C)c3ccccc32)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1c2ccccc2C(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
Trichloroethyl chloroformate (1.06 mL, 7.7 mmol) is added over a 10 minute period to a solution of 9,10-dihydro-10-methyl-9-(1-methyl-4-piperidinyl)acridine (453 mg, 1.55 mmol) [(Tetrahedron Letters, 29, 5701 (1988)] and triethylamine (649 μl, 4.65 mmol) in 20 mL of dry toluene at 85° C. The reaction is worked up after 30 minutes by extracting with EtOAc and washing with a 10% NaOH solution. The crude product is obtained after the solvent is removed.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].[C:20]1([C:26]2[O:27][C:28]([CH3:34])=[C:29]([CH2:31][CH2:32]O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:32][CH2:31][C:29]2[N:30]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:27][C:28]=2[CH3:34])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester was reacted with 2-(2-phenyl-5-methyl-oxazol-4yl)-ethanol in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester as colorless oil.