Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=1>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Yield: 20.9 %

Procedure:
A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (300 mg, 1.02 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (386 mg, 1.02 mmol), N,N-diisopropylethylamine (220 μL, 1.22 mmol), and 2-aminopyridine (144 mg, 1.53 mmol) in dry N,N-dimethylformamide (5 ml) was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate, and the layers were separated. The organic layer was washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 2-biphenyl-4-yl-3-cyclopentyl-N-pyridin-2-yl-propionamide (79 mg, 21%) as a white solid: mp 57-59° C.; EI-HRMS m/e calcd for C25H26NO (M+) 370.2045, found 370.2049.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH:14]([CH2:17][NH2:18])[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[C:2]1([CH2:1][O:8][C:9]2[CH:20]=[CH:19][C:12]3[O:13][CH:14]([CH2:17][NH:18][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[CH:28][C:29]5[CH:30]=[CH:31][C:32](=[O:36])[O:33][C:34]=5[CH:35]=4)[CH2:15][O:16][C:11]=3[CH:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: NCC1COc2cc(OCc3ccccc3)ccc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2ccc(OCCCNCC3COc4cc(OCc5ccccc5)ccc4O3)cc2o1
Temperature: 108 °C

Procedure:
2,3-Dihydro-6-benzyloxy-1,4-benzodioxin-2-methanamine (2.4 g, 8.85 mmole), 7-(3-chloropropoxy)coumarin (2.15 g, 9.0 mmole), diisopropylethylamine (7.0 ml, 40.2 mmole) and sodium iodide (1.35 g, 9.0 mmole) were combined in 200 ml of DMF and heated at 108° C. for 2 days under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of water dried over magnesium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on silica gel using 1% methanol/dichloromethane as eluant. The product-containing fractions (Rf=0.27 on silica gel tlc with 2.5% methanol/dichloromethane) were combined and concentrated in vacuum and the residue redissolved in dichloromethane and boiled on a hot plate, the solvent gradually being replaced with isopropanol. Upon addition of 6 ml of 4N HCl/isopropanol and cooling, 1.22 g of the title compound, m.p. 184°-187° C., precipitated as a beige solid, monohydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C1N=CN([C:16](N2C=NC=C2)=[O:17])C=1.Cl.Cl.[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2[N:32]=[C:33]([NH:35][C:36](=[O:48])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]4[CH2:47][CH2:46][CH2:45][NH:44]4)[CH:38]=3)[S:34][C:28]=2[CH2:27]1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:16]([N:44]2[CH2:45][CH2:46][CH2:47][CH:43]2[C:39]2[CH:40]=[CH:41][CH:42]=[C:37]([C:36](=[O:48])[NH:35][C:33]3[S:34][C:28]4[CH2:27][N:26]([CH3:25])[CH2:31][CH2:30][C:29]=4[N:32]=3)[CH:38]=2)=[O:17])[CH:10]=[CH:9][CH:8]=1)(=[O:6])[NH2:7]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1CCc2nc(NC(=O)c3cccc(C4CCCN4)c3)sc2C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2nc(NC(=O)c3cccc(C4CCCN4C(=O)Nc4cccc(C(N)=O)c4)c3)sc2C1
Temperature: 90 °C

Procedure:
Stir a solution of 3-aminobenzamide (51 mg, 0.362 mmol), CDI (60 mg, 0.362 mmol), and DMAP (45 mg, 0.362 mmol) in DMF (1.5 mL) at 90° C. for 30 min. A precipitate forms from the initial homogenous solution. Add N-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-pyrrolidin-2-yl-benzamide di-HCl (100 mg, 0.241 mmol) to the hot reaction followed by more DMF (1 mL) and continue heating at 90° C. for 20 min. Cool the reaction to room temperature, dilute with water (1 mL), acidify with TFA (0.2 mL), and purify directly by reverse phase prep HPLC. Concentrate the fractions containing product to a solid which contains symmetric benzamide urea (30%). Suspend the solid in MeOH (4 mL) and sonicate—filter off the solid side product washing with MeOH (1 mL). Concentrate the filtrate, dry the residue in vacuo and triturate in EtOAc and hexane to give the title compound as a solid (97 mg). MS, electrospray 505.4 (M+H), rt 1.05 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:23]=1.C([Sn](CCCC)(CCCC)CCCC)=C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH:22]=[CH2:23])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: C=Cc1cc2c(cc1C(F)(F)F)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
To a stirred solution 0.61 mmol 5-iodo-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A35(d)) in 3 ml dioxane were added 0.04 mmol palladium(II) acetate and 0.18 mmol triphenylarsine and the mixture was stirred at RT for 10 min. 0.91 mmol vinyltributylstannane was then added and the mixture was heated at 100° C. for 16 h. The reaction mixture was then cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a yellow solid (93% yield). MS (m/e): 258.0 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH:35]12[O:40][CH:39]1[CH2:38][CH2:37][CH2:36]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:38]3[CH2:37][CH2:36][CH2:35][C@H:39]3[OH:40])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: C1CC2OC2C1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 50.2 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.99 g) in N,N-dimethylacetamide (10 mL) were added 6-oxabicyclo[3.1.0]hexane (0.56 g) and cesium carbonate (1.4 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature. The insoluble material was filtered off, diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give the title compound (0.59 g, 50%) as a solid.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([CH2:15][S:16][CH3:17])[CH:7]=1.[Cl-].[NH4+]>O1CCCC1>[F:5][C:6]1[CH:11]=[C:10]2[C:9](=[C:8]([CH2:15][S:16][CH3:17])[CH:7]=1)[NH:12][CH:2]=[CH:1]2
Reactant: CSCc1cc(F)ccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSCc1cc(F)cc2cc[nH]c12
Temperature: -40 °C
Reaction time: 3 h

Procedure:
180 ml (180 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran were added dropwise to a solution of 9.00 g (44.7 mmol) of the compound from Example 4A in 100 ml of tetrahydrofuran under argon at −40° C., and the mixture was stirred at −40° C. for 3 h. The reaction mixture was then added to saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate 9/1) to result in 5.00 g (57% of theory) of the title compound.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][CH2:6][OH:7])[CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][CH2:5][CH:3]2[CH2:4][O:1][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCCC1COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2COC2)cc1
Temperature: 0 °C
Yield: 56.2 %

Procedure:
Using the same reaction conditions and procedure as described for the preparation of Intermediate (I-16a), 2-(oxetan-3-yl)ethanol (1 g, 6.944 mmol) was reacted with p-Toluene sulfonyl chloride (1.9 g, 10.416 mmol) in dry pyridine (10 mL) to afford the crude product. The reaction mass was poured into ice-water and extracted using ethyl acetate. The organic layer was washed with 1N HCl, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 1 g of the product (40% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.O1CCCC1.[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](Cl)=[O:29]>O>[Br:7][C:5]1[S:4][C:3]([C:8](=[O:9])[NH2:10])=[C:2]([NH:1][C:28]([C:24]2[S:23][CH:27]=[CH:26][N:25]=2)=[O:29])[CH:6]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(Cl)c1nccs1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1sc(Br)cc1NC(=O)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, triethylamine (0.19 mL) and tetrahydrofuran (4.0 mL) was added 1,3-thiazole-2-carbonyl chloride (0.22 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. Water was poured into the reaction system, and the precipitate was collected by filtration to give N-(5-bromo-2-carbamoylthiophen-3-yl)-1,3-thiazole-2-carboxamide (290 mg) as a pale-yellow solid. To N-(5-bromo-2-carbamoylthiophen-3-yl)-1,3-thiazole-2-carboxamide produced above were added 2M aqueous sodium hydroxide solution (1.75 mL) and 1,2-dimethoxyethane (4.0 mL), and the mixture was stirred at 100° C. for 18 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. The precipitate was collected by filtration to give the title compound (236 mg) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[OH:7][CH2:8][C:9](=O)[CH3:10]>[Pt](=O)=O>[OH:7][CH2:8][CH:9]([NH:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])[CH3:10]
Reactant: CC[C@H](N)CO
Reactant: CC(=O)CO
Agent: O=[Pt]=O
Product: CC[C@@H](CO)NC(C)CO
Reaction time: 30.5 h
Yield: 72928.5 %

Procedure:
A mixture of (S)-2-aminobutan-1-ol (14.5 g, 0.163 mmol), 1-hydroxypropan-2-one (13.3 mL, 0.195 mmol) and platinum(IV) oxide (100 mg, 0.440 mol) were stirred under a hydrogen atmosphere (1 atm). After 30.5 h, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by distillation to give (S)-2-(1-hydroxypropan-2-ylamino)butan-1-ol (17.5 g, 74%) as a colorless oil. 1H NMR consistent.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.CN(C)C=O>[C:7]1([S:13][CH2:12][CH2:7][CH2:8][CH2:9][CH2:1][C:2]([OH:4])([CH3:5])[CH3:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[O-]
Reactant: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCSc1ccccc1

Procedure:
To a solution of 7-bromo-2-methyl-2-trimethylsilyloxyheptane (10) (14.0 g) in methanol (55 ml) at room temperature was added ethanolic hydrogen chloride (ca. 1M, 0.2 ml). After 10 minutes the solution was concentrated in vacuo (at room temperature) to constant weight. The residue was taken up in chloroform and reconcentrated to constant weight to give 7-bromo-2-methyl-2-heptanol (H, n=4, R1 =R2 =Me) as a chromatographically homogenous oil. The product was dissolved in THF (10 ml) and added to a premixed, stirred solution of potassium tert-butoxide (6.7 g) and thiophenol (3.6 ml) in N,N-dimethylformamide (50 ml) at room temperature. After a few minutes a precipitate started forming, and after 30 minutes the mixture was partitioned between ethyl acetate (300 ml) and water (200 ml). The organic layer was washed consecutively with 2N sodium hydroxide solution, water and brine. Drying and concentration in vacuo gave 6-hydroxy-6-methylheptyl phenyl sulphide as a chromatographically homogenous oil. This was dissolved in methanol (60 ml), and to the stirred solution was added sodium hydrogen carbonate (4.7 g), aqueous sodium tungstate solution (2%, 5 ml) and hydrogen peroxide (100 vol, 11.8 ml). The initial exothermic reaction which ensued was checked by momentary ice-cooling. The reaction mixture was then stirred at 50° C. for 1 hour. After cooling, the mixture was partitioned between dichloromethane (200 ml) and water. The aqueous layer was extracted with more dichloromethane, and the combined dichloromethane layers were washed with water, brine, and dried. Concentration in vacuo gave a crude product which was purified by chromatography (150 g silica gel; ether as eluant) to give the sulphone (13) as a viscous oil, δ (300 MHz) 1.18 (6H, s), 1.4 (7H, m), 1.75 (2H, m), 3.09 (2H, m), 7.5-7.75 (3H, m), 7.90 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:17]3[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=3)[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)n1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (1.20 g, 5.6 mmol), 2-chloro-4,6-dimethyl-pyrimidine (1.03 g, 7.2 mmol), Cs2CO3 (2.12 g, 6.5 mmol) and DMF (15 mL) were combined and heated to 100° C. for 24 hours. The reaction was then allowed to cool and water and EtOAc were added. The products were extracted into EtOAc, dried over Na2SO4, and concentrated. The resulting crude mixture was purified by flash column chromatography (EA/hex) to give the title compound (1.27 g, 71%). MS (ESI) mass calcd. for C17H26N4O2, 318.42; m/z found, 319.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 6.25 (s, 1H), 3.85-3.75 (m, 2H), 3.69-3.46 (m, 4H), 3.38-3.20 (m, 2H), 2.94 (br s, 2H), 2.29 (s, 6H), 1.44 (s, 9H).
Reaction SMILES: [CH:1]([Si:4]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]1[S:11][CH:12]=[CH:13][N:14]=1)([CH3:3])[CH3:2].[CH2:21]([Li])CCC.IC.O>O1CCCC1>[CH3:21][C:12]1[S:11][C:10]([C:6]2[N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:15]([CH3:17])[CH3:16])[CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:8][CH:7]=2)=[N:14][CH:13]=1
Reactant: [Li]CCCC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1-c1nccs1
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2cccn2[Si](C(C)C)(C(C)C)C(C)C)s1
Reaction time: 0.67 h
Yield: 65.1 %

Procedure:
2-[1-(Triisopropylsilyl)-1H-pyrrol-2-yl]-1,3-thiazole (317 mg, 1.03 mmol) synthesized in Example (3a) was dissolved in tetrahydrofuran (10 mL), and cooled to −78° C. n-Butyl lithium (2.64M hexane solution, 0.51 mL, 1.35 mmol) was added dropwise, followed by stirring for 40 minutes, and subsequently iodomethane (0.13 mL, 2.09 mmol) was added and stirring was carried out for 3 hours with the temperature being gradually raised from −78° C. to room temperature. Water (10 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: hexane) to afford the desired compound (215 mg, yield 65%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[N:36]1([CH2:42][C:43]2[CH:44]=[C:45]([CH:51]=[CH:52][CH:53]=2)[O:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:24]([NH:50][CH2:49][CH2:48][CH2:47][O:46][C:45]2[CH:51]=[CH:52][CH:53]=[C:43]([CH2:42][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:44]=2)=[O:25])[CH3:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.63 g (2.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propylamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=591 ([M+H]+, 7), 229 (86), 109 (100). For further analysis, a portion of the compound is converted into the hydrochloric acid salt and is extracted from ether in the form of a dry foam by stirring; m.p.: 123°-125° C. (ether).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][P:10]=[O:11].C1C(C(OOC(C)(C)C)=O)=CC=CC=1.O>CC(O)C.CCCCCCC>[CH2:1]([PH:10](=[O:9])[OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=PO
Reactant: C=CCCCCCC
Agent: CC(C)(C)OOC(=O)c1ccccc1
Solvent: CCCCCCC
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCC[PH](=O)O
Yield: 98.6 %

Procedure:
In a round bottom flask, 1 L (715 g, 6.38 mots) of 1-octene and 1.3 L (12.76 mols) of hypophosphorus acid (50% aqueous solution), 50 mL of tert-butyl perbenzoate, as initiator, and 1.7 L of 2-propanol as solvent are stirred at 80° C. for 7 h. The completed reaction mixture is combined with 2.0 L of water and 2.0 L of n-heptane. The mixture is separated and the organic phase is further washed with 1 L water. The water layer is further washed with 1 L of heptane and all the heptane layers are combined. This mixture is treated with 1 kg of anhydrous sodium sulfate and the solvent is evaporated to obtain 1.12 kg of crude n-octyl phosphinic acid with 85% purity (31P NMR).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]([F:30])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:5])=[O:4].[CH2:31]([CH:33]1[O:35][CH2:34]1)Cl.C[O-].[Na+].[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH2:31][CH:33]1[O:35][CH2:34]1)[S:3]([C:6]([F:30])([F:29])[C:7]([F:27])([F:28])[C:8]([F:25])([F:26])[C:9]([F:23])([F:24])[C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:5])=[O:4]
Reactant: ClCC1CO1
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CC1CO1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
N-methyl-N-glycidyl-perfluorooctanesulfonamide ("epoxide A") was prepared by placing 450 grams N-methyl-perfluorooctanesulfonamide ("amide A") in a two-liter three-necked round-bottom flask and heating to 80° C., 101 grams epichlorohydrin was then added followed by 91 grams methanol. The temperature was reduced to 65° C. before 30 grams 25 wt % sodium methoxide in methanol solution was slowly added keeping the temperature below 70° C. 60 grams 50 wt % aqueous sodium hydroxide solution was slowly added keeping the temperature below 70° C. After addition the reaction was stirred at 65° C. overnight. Water-aspirator vacuum was applied to the flask and excess methanol and epichlorohydrin were removed. 450 grams water was then added to the flask with stirring at 65° to wash the product. The water was decanted after allowing the product to settle. This washing step was repeated a second time. Vacuum was applied to 20 mm Hg and the temperature of the flask was raised to 90° C. to remove volatile materials.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]2[C:28](=[C:29]([NH2:31])[CH:30]=1)[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1.CCN=C=NCCCN(C)C.CCOC(C)=O>N1C=CC=CC=1.O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14](=[O:16])[NH:31][C:29]1[CH:30]=[C:18]([Cl:17])[CH:19]=[C:20]2[C:28]=1[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of morpholine-3(S),4-dicarboxylic acid 4-tert-butyl ester (2.83 g, 12.7 mmol) in pyridine (106 ml) was stirred at RT. 6-chloro-9H-β-carbolin-8-ylamine (2.30 g, 10.6 mmol) was added, followed by EDCI (4.06 g, 21.2 mmol). The clear orange-to-brown solution was stirred at RT for 14 hr. The solution was diluted with H2O (120 ml) and poured into a separatory funnel containing EtOAc (200 ml), H2O (100 ml) and brine (100 ml). The mixture was shaken and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 ml) and the combined organic layers were washed with brine. The organic layer was dried, filtered and concentrated to a reduced volume, then added drop-wise to a stirring solution of 1:1 Et2O/hexanes (500 ml). The precipitate which formed was filtered and washed with 1:1 Et2O/Hexanes. The filtrate was concentrated to a reduced volume and a second crop of precipitate was collected. The solid product was placed under high vacuum for 2 hr to yield 3(S)-(6-chloro-9H-β-carbolin-8-ylcarbamoyl)-morpholine-4-carboxylic acid tert-butyl ester as a pale yellow to pale brown solid (4.36 g).