Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.Br[CH2:38][C:39]#[N:40]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][CH2:38][C:39]#[N:40])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: N#CCBr
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Product: CC(OCC#N)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 8 %

Procedure:
In analogy to Example 2, 250 mg (0.39 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using bromoacetonitrile and, after workup and purification, 16 mg (8%) of the title compound were isolated as a colourless foam.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][C:11]([C:13]1([C:18](=[O:21])[CH2:19]Br)[CH2:17][CH2:16][CH2:15]C1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:3]([N:10]1[CH2:19][C:18](=[O:21])[C:13]2([CH2:17][CH2:16][CH2:15]2)[C:11]1=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CBr)C1(C(=O)NCc2ccccc2)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CN(Cc2ccccc2)C(=O)C12CCC2
Temperature: 0 °C
Reaction time: 0.92 h

Procedure:
Sodium hydride (60% mineral oil dispersion) (0.366 g, 9.14 mmol) was added to a somewhat turbid solution of N-benzyl-1-(2-bromoacetyl)cyclopentanecarboxamide (2.28 g, 7.03 mmol) in THF (68.3 mL) at 0° C. under a nitrogen atmosphere during which time gas evolution was noted. Stirring @ 0° C. was continued for 55 minutes. HPLC and LC/MS after 30 minutes indicated that the reaction was essentially complete (m/e 244.19, M+H for desired product; no sm detected). The reaction, was maintained at 0° C., diluted with EtOAc (100 mL) and 40 mL of sat. aq NH4Cl solution, and finally 40 mL of water. The layers were separated, the organic layer was washed with 40 mL of water, and 40 mL of brine, the organic layer was dried over Na2SO4, and concentrated under vacuum to yield 1.86 g of a tan viscous oil. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 40 g column), eluting with 100 mL of 95:5, 400 mL of 90:10, and 300 mL of 80:20 hexane:EtOAc yielded 1.44 g of the title compound as a viscous pale yellow oil. LC/MS: m/e 244.16 (M+H), 276.2 (M+H+methanol, hemiacetal formation). +/−MS: m/e 244.2 (M+H), 242.4 (M−H). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.41-7.23 (m, 5H), 4.64 (s, 2H), 3.69 (s, 2H), 2.10-1.97 (m, 2H), 1.97-1.81 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C@H:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([C:31](O)=[O:32])[CH2:19]3)[C:5]2=[N:6][CH:7]=1.[Na].[N:35]1([CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][NH:43]2)[CH:39]=[CH:38][N:37]=[CH:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C@H:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@@H:20]([C:31]([N:43]4[CH2:44][CH2:45][CH2:46][CH2:47][CH:42]4[CH2:41][CH2:40][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[O:32])[CH2:19]3)[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2c3ccc(Cl)cc3CCc3cc(Br)cnc32)C[C@@H]1C(=O)O
Reactant: c1cn(CCC2CCCCN2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN([C@H]2c3ccc(Cl)cc3CCc3cc(Br)cnc32)C[C@@H]1C(=O)N1CCCCC1CCn1ccnc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 10.6 %

Procedure:
Sodium 1.1-dimethylethyl 4-(3-bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(S)-yl)-2(R)-carboxy-1-piperazinecarboxylate (prepared as described in Preparative Example 6 (sodium salt)) (0.1 g, 0.79 mmoles), 2-[2-(1H-imidazol- 1-yl)ethylpiperdidine (prepared as described in Preparative Example 57, Step D) (0.0417 g, 0.233 mmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0446 g, 0.233 mmoles), 1-hydroxybenzotriazole (0.0314 g, 0.233mmoles) and 4-methylmorpholine (0.0512 mL, 0.466 mmoles) were dissolved in anhydrous DMF (4 mL) and the mixture was stirred under argon at 25° C. for 42 h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with 1N NaOH, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2.5%-4.5%-7.5% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (0.0172 g, 14%): HRFABMS: m/z 697.2285 (MH+) (Calcd. m/z 697.2269); δH (CDCl3) 1.38/1.41 (9H, s, CH3), 4.31 (1H, s, H11), 4.68 (1H, bs, H2), 7.03-7.20 (5H, bm, Ar—H and Im-H4 and Im-H5), 7.57 (1H, Im-H2), 7.83/8.19 (s, Ar—H) and 8.38 ppm (1H, s, Ar—H2): δC (CDCl3) CH3: 28.4, 28.4, 28.4; CH2: 19.1, 24.8/24.9, 28.3, 30.3, 30.5, 31.4, 40.3, 42.9/43.2, 44.1/44.6, 45.6, 50.2/50.5; CH: 44.1/44.6, 52.4, 78.4, 119.2, 126.2, 127.9, 130.8/130.9, 132.6, 136.7, 141.6, 146.9/147.2: C: 80.4, 119.8/120.2, 134.4, 135.9, 137.0, 141.5, 155.0, 156.7/157.1, 170.3/170.9.
Reaction SMILES: O.[F:2][C:3]1[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:12][CH:13]=2)=[C:5]([N+:35]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:35][C:5]1[CH:4]=[C:3]([F:2])[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:12][CH:13]=1
Reactant: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2[N+](=O)[O-])cn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2N)cn1
Temperature: 35 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a mixed solution of 1.2 g of an iron powder, 5 ml of acetic acid and 0.5 ml of water was added a solution of 0.93 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine in 4 ml of acetic acid dropwise while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred for 2 hours, then, filtrated through Celite, and concentrated. The residue was diluted with water, and extracted with ethyl acetate. The organic layer was mixture was washed with saturated aqueous sodium bicarbonate solution, then saturated saline, dried over anhydrous magnesium sulfate, and concentrated. Then, the resulted residue was subjected to silica gel chromatography to obtain 0.83 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([O:30][CH2:31]Cl)[CH3:29]>O>[Br:1][C:2]1[C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:5]([CH2:31][O:30][CH2:28][CH3:29])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C(=O)OC)c(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h
Yield: 123.4 %

Procedure:
A mixture of methyl 4-bromo-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carboxylate (9.2 g, 24.1 mmol), potassium carbonate (4.96 g, 36 mmol) and chloromethyl ethyl ether (3.3 mL, 36 mmol) is stirred at room temperature for 21 hours, treated with potassium carbonate (4.9 g) and chloromethyl ethyl ether (3.3 mL), stirred for 1 hour, treated with potassium carbonate (4.9 g) and chloromethyl ethyl ether (3.3 mL) stirred for 3 hours, diluted with water and extracted with diethyl ether. The combined organic extracts are washed with water, dried over anhydrous MgSO4 and concentrated in vacuo to obtain the title product as a brown oil (13.1 g) which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.CO.[CH:16](=O)[CH3:17].[BH4-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:6]([NH:7][CH2:16][CH3:17])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNc1cn(-c2cccnc2)nc1Cl
Reaction time: 0.08 h
Yield: 57.3 %

Procedure:
A 3-neck, 100 mL round bottom flask was charged with 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (5d) (500 mg, 2.57 mmol) and methanol (5 mL) The mixture was stirred for 5 minutes to give a clear solution. Acetaldehyde (136 mg, 3.09 mmol) was added and the reaction was stirred at 20° C. for 6 hours. Sodium borohydride (194 mg, 5.14 mmol) was added and the reaction was stirred at 20° C. for 1 hour, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that some starting material remained and a major product formed. The reaction mixture was quenched with water (10 mL) and concentrated under reduced pressure to remove methanol. Ethyl acetate (10 mL) was added and the organic layer was concentrated to dryness. The residue was purified by flash column chromatography using 20-40% ethyl acetate/hexanes as eluent. The fractions containing pure product were combined and concentrated to afford a white solid (328 mg, 58%). The spectral characterization was in agreement with the product prepared previously.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1)[CH3:2].[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][N:6]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Nc1nnn[nH]1
Reactant: CCc1ccnc(C(=O)O)c1
Product: CCc1ccnc(C(=O)Nc2nnn[nH]2)c1
Yield: 24.1 %

Procedure:
0.46 g of 4-ethyl-2-pyridinecarboxylic acid, 0.5 g of N,N'-carbonyldiimidazole and 0.28 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.16 g of N-(5-tetrazolyl)-4-ethyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31]O)[CH2:27][CH2:26]1.[I-].[K+]>O>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][CH2:31][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CN)cc2)c(C)c1
Reactant: OCC1CCOCC1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CNCC3CCOCC3)cc2)c(C)c1
Temperature: 150 °C

Procedure:
4-(aminomethyl)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (25 mg, 0.072 mmol), (tetrahydro-2H-pyran-4-yl)methanol (16.76 mg, 0.144 mmol), potassium iodide (23.95 mg, 0.144 mmol) and [Cp*IrCl2]2 (1.150 mg, 1.443 μmol) were dissolved in water (2 mL) in a microwave vial. The reaction vessel was sealed and heated by microwaves (Biotage Initiator) to 150° C. for 1 hour. After analysis the reaction vessel was resealed and heated again by microwaves (Biotage Initiator) to 150° C. for a further 1 hour. After further analysis an additional 1 eq of [Cp*IrCl2]2 and 1 eq of (tetrahydro-2H-pyran-4-yl)methanol were added and the reaction heated for a third time by microwaves (Biotage Initiator) to 150° C. for 1 hour. The reaction was cooled and the mixture concentrated in vacuo (Biotage V10). The crude product was extracted to the organic phase of an aqueous workup between ethyl acetate (5 mL) and water (5 mL). The organic phase was passed through a hydrophobic frit and concentrated in vacuo. The crude was purified by mass directed autoprep (formic acid modifier). The appropriate fractions were evaporated in vacuo (Biotage V10) to give the required product, 1.2 mg. LCMS [LCMS1] Rt 0.97 min, m/z (ES+) 445 (M+H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:21]1[CH:25]=[CH:24][N:23]=[N:22]1)=[CH:6][NH:7][NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[CH:11][N:10]=1)C.C[O-].[Na+].[ClH:30]>C(O)C.CO>[ClH:30].[N:15]1([C:13]2[N:12]=[CH:11][N:10]=[C:9]([N:8]3[C:4](=[O:3])[C:5]([N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)=[CH:6][NH:7]3)[CH:14]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=CNNc1cc(N2CCOCC2)ncn1)n1ccnn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCOCC2)ncn1
Temperature: 10 °C

Procedure:
Batch 2: A further amount of the title compound is obtained as follows: The residue (2.4 g) obtained from the mother liquor during the synthesis of Example Compound 71, which contains the open-ring intermediate state of the cyclization, 3-[2-(6-morpholin-4-ylpyrimidin-4-yl)hydrazino]-2-(1H-1,2,3-triazol-1-yl)prop-2-enoic acid ethyl ester, is dissolved in 12 ml ethanol and 1.5 ml 30% strength sodium methylate solution in methanol are added at RT, while stirring. The mixture is subsequently stirred at RT for 45 min, then adjusted to pH 5 with 2 N hydrochloric acid and subsequently stirred at RT for a further 16 h. The mixture is cooled to 10° C. and the solid is filtered off and washed with 3.5 ml dioxane. The mixture is dried under a high vacuum for 16 h, 5 ml methanol are then added and the mixture is subsequently stirred at RT for 1 h. The solid is filtered off, washed with 2 ml methanol and dried under a high vacuum to give a further 997 mg of the title compound in this way.
Reaction SMILES: N.C([O-])(=O)/C=C\C([O-])=O.[NH4+].[NH4+].[NH2:12][CH:13]([C:18]([O-:20])=[O:19])[CH2:14][C:15]([O-:17])=[O:16].[NH4+].[NH4+].N[C@H](C(O)=O)CC(O)=O.Cl>>[NH2:12][CH:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: NC(CC(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: N
Agent: N[C@@H](CC(=O)O)C(=O)O
Product: NC(CC(=O)O)C(=O)O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Reaction vessel was a 0.33 liter autoclave which was charged with a saturated aqueous solution of ammonia (150 g) and diammonium maleate (30 g) at a temperature of about 25-40 degrees C. The autoclave was sealed and then pressurized through a gas inlet valve with ammonia gas to a constant pressure of about 114 psig for a period of 30 minutes. The gas inlet valve was then closed and the autoclave maintained at 40 degrees C. for 30 minutes. The autoclave was thereafter heated to about 140-150 degrees C. over a period of 40 minutes and maintained in this temperature range for an additional 50 minutes. The pressure within the reaction vessel rose from about 114 psig to about 700 psig during this heating period. After the temperature of about 140-150 degrees C. and the autogenous pressure had been maintained for 50 minutes, the contents of the reactor were expelled into a second vessel at ambient pressure. The resulting solution of diammonium D,L-aspartate was then neutralized while in the second vessel to a pH of 2.8 (isoelectric point of aspartic acid) with concentrated hydrochloric acid (about 12 molar). A white precipitate of D,L-aspartic acid formed within a few minutes of neutralization with the acid. The precipitated D,L-aspartic acid was isolated by filtration and dried to afford a 71% yield of white crystalline powder. The product was identical to an authentic sample of D,L-aspartic acid obtained by both NMR (Nuclear Magnetic Resonance) and IR (InfraRed) techniques.
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:70]([O:72][C:73]([N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1)=[O:74])[CH3:71]>CN(C=O)C.CCOC(C)=O.O>[CH2:70]([O:72][C:73]([N:75]1[CH2:76][CH2:77][N:78]([C:27](=[O:28])[C@@H:2]([NH:1][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6]/[C:7](/[NH2:26])=[N:8]/[S:9]([C:12]2[C:13]([CH3:14])=[C:15]([CH3:16])[C:17]3[O:18][C:19]([CH3:20])([CH3:21])[CH2:22][C:23]=3[C:24]=2[CH3:25])(=[O:10])=[O:11])[CH2:79][CH2:80]1)=[O:74])[CH3:71]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c2c1OC(C)(C)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)NC(=O)OC(C)(C)C)CC1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
To a solution of Boc-Arg(Pbf)-OH (13.3 g, 25.3 mmol) in DMF (10 mL) was added DIEA (22.0 mL, 126.5 mmol) at room temperature and stirred for 15 min. The reaction mixture was then cooled to ˜5° C. and HATU (11.5 g, 30.3 mmol) was added in portions and stirred for 30 min, followed by the dropwise addition of ethyl-1-piperazine carboxylate (4.0 g, 25.3 mmol) in DMF (30 mL). After 40 min, the reaction mixture was diluted with EtOAc (400 mL) and poured in to H2O (1 L). Extracted with EtOAc (2×400 mL) and washed with H2O (800 mL), 2% H2SO4 (500 mL), H2O (2×800 mL) and brine (800 mL). Organic layer was separated, dried over MgSO4 and solvent removed in vacuo. The resultant oily residue was dried in vacuo to afford compound F (16.4 g, 24.5 mmol) as foamy solid. LC-MS [M+H] 667.2 (C31H50N6O8S+H, calc: 667.8). Compound F was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>S(Cl)(Cl)=O.O>[CH2:13]([N:15]([CH2:16][CH3:17])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:12])[CH3:14]
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)c1ccc(OC)cc1C
Temperature: 80 °C
Yield: 57.6 %

Procedure:
4-methoxy-2-methylbenzoic acid (3.0 g, 18.05 mmol) was taken in thionyl chloride (20 ml) and refluxed for 1 h at 80° C. The reaction mixture was evaporated under reduced pressure. Under nitrogen the crude was quenched with diethyl amine (1.870 ml, 18.05 mmol) slowly under cooling conditions. The reaction mixture was dissolved in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (2.3 g, 54.7%) as oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.06-7.04 (d, J=8 Hz, 1H), 6.79 (s, 1H), 6.78-6.76 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.43 (br, s, 2H), 3.06-3.05 (m, 2H), 2.16 (s, 3H), 1.14 (d, J=8 Hz, 3H), 0.95 (d, J=8 Hz, 3H).
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:66]3[C:71]([C:72]([F:75])([F:74])[F:73])=[CH:70][N:69]=[C:68]([NH:76][C:77]4[CH:91]=[CH:90][C:80]([CH2:81][P:82](=[O:89])([O:86]CC)[O:83][CH2:84][CH3:85])=[CH:79][C:78]=4[O:92][CH3:93])[N:67]=3)=[C:61]([C:94](=[O:97])[NH:95][CH3:96])[C:60]=2[CH3:98])[CH:56]=[N:55]1>>[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:66]3[C:71]([C:72]([F:73])([F:74])[F:75])=[CH:70][N:69]=[C:68]([NH:76][C:77]4[CH:91]=[CH:90][C:80]([CH2:81][P:82](=[O:86])([OH:89])[O:83][CH2:84][CH3:85])=[CH:79][C:78]=4[O:92][CH3:93])[N:67]=3)=[C:61]([C:94](=[O:97])[NH:95][CH3:96])[C:60]=2[CH3:98])[CH:56]=[N:55]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(C)c3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(C)c3C(=O)NC)n2)c(OC)c1

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-3-methyl-2-(methyl carbamoyl)phenyl}amino)-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 29B). 1H NMR (CD3OD, 400 MHz): δ 8.25 (s, 1H), 7.92 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 6.59 (d, J=6.8 Hz, 1H), 4.35 (t, J=6.8 Hz, 2H), 3.88 (s, 3H), 3.79 (m, 2H), 3.60 (t, J=6.1 Hz, 2H), 2.87 (d, J=21.5 Hz, 2H), 2.85 (s, 3H), 2.36 (s, 3H), 2.12 (m, 2H), 1.13 (t, J=7.1 Hz, 3H). MS (ESI): m/z=678.23 [M+H]+. UPLC: tR=1.03 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSc3ccc(Cl)cc3)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc(Cl)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-chlorophenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26]Cl)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I-:50].[Na+]>C(#N)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][I:50])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCI
Temperature: 60 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
To a solution of chloromethyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate (7.8 g, 11 mmol) in acetonitrile (100 mL), was added sodium iodide (6.5 g, 44 mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (NA2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1%MeOH in CH2Cl2), to give 7.84 g of iodomethyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate.