Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=3)[C:11]([CH:21]=[CH2:22])=[N:10]2)=[N:6][CH:7]=1>CCO.[OH-].[OH-].[Pd+2]>[CH2:21]([C:11]1[C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][C:17]=2[N:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[N:10]=1)[CH3:22]
Reactant: C=Cc1nn(Cc2ccc(F)cn2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1nn(Cc2ccc(F)cn2)c2cccc(N)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
A solution of 1-((5-fluoropyridin-2-yl)methyl)-4-nitro-3-vinyl-1H-indazole (0.229 g, 0.768 mmol) in EtOH (4 mL) was purged with argon. To this solution was added palladium hydroxide on carbon (91 mg, 40%/wt). The mixture was purged with more argon and then hydrogen. The mixture was then stirred at ambient temperature under hydrogen for 16 hours. The mixture was filtered through GF/F paper, washed with MeOH and concentrated under reduced pressure to give 3-ethyl-1-((5-fluoropyridin-2-yl)methyl)-1H-indazol-4-amine (188 mg) as an amber oil.
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[C-:19]#[N:20].C(OCC)(=O)C>N1C=CC=CC=1>[NH2:18][C:3]1[C:2]([C:19]#[N:20])=[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:6]=[C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:4]=1
Reactant: [C-]#N
Reactant: Nc1nc(-n2cccn2)nc(-n2cccn2)c1Br
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1c(N)nc(-n2cccn2)nc1-n1cccn1
Yield: 39.6 %

Procedure:
A mixture of 0.2 g (0.65 mmol) of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine and 0.06 g (0.72 mmol) of cupper (I) cyanide in 3 ml of pyridine was irradiated with microwaves at 250° C. for 20 min. After nearly complete conversion to the corresponding carbonitrile as was indicated by TLC, ethyl acetate was added and filtered throw celite. The solution was extracted two times with 10 ml of saturated solution of NaHCO3 and Brine. The organic layer was separated, dried with MgSO4 and concentrated to give 0.065 g (39.6%) of the desired product.
Reaction SMILES: ClCC([O:5][C@H:6]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C@@H:21]([O:27][C:28](=[O:31])[CH2:29][Cl:30])[CH2:20][C@@:19]2([CH3:32])[C@H:12]3[CH2:13][CH:14]=[C:15]2[C:16](=[O:18])[CH3:17])[CH2:7]1)=O.O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:30][CH2:29][C:28]([O:27][C@H:21]1[CH2:20][C@@:19]2([CH3:32])[C@@H:12]([CH2:13][CH:14]=[C:15]2[C:16](=[O:18])[CH3:17])[C@H:11]2[C@H:22]1[C@:23]1([CH3:26])[C@@H:8]([CH2:9][CH2:10]2)[CH2:7][C@@H:6]([OH:5])[CH2:25][CH2:24]1)=[O:31]
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OC(=O)CCl)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Yield: 67.7 %

Procedure:
3β,11β-Bischloroacetoxy-5α-pregn-16-en-20-one (1.2 g) was stirred at 100° in dioxan (20 ml) containing water (4 ml) with sodium bicarbonate (1.26 g) for 4 hours. The mixture was cooled, poured into water and the precipitate collected by filtration, dried and filtered through silica gel (20 g) in ethylacetate. The eluate was evaporated and the residue crystallised from petrol containing a little ethyl acetate to yield the title compound (684 mg), m.p. 160.5°-162°, [α]D +75.2°.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][O:12][C:13](=[O:17])[CH2:14][CH2:15][SH:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:11][O:12][C:13](=[O:17])[CH2:14][CH2:15][S:16][CH2:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: COC(=O)CCS
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCSCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
15.5 parts of chloroacetophenone are added to a solution, cooled to 0° C., of 12 parts of 3-mercapto-propionic acid methyl ester and 15.3 parts by volume of triethylamine in 100 parts by volume of chloroform. The mixture is stirred for 2 hours at 0° C. and is washed with water, and the organic phase is separated off, dried and concentrated. 21 parts (90% of theory) of 3-(benzoylmethylthio)-propionic acid methyl ester of boiling point 156°-160° C./0.3 mbar are obtained.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC1C=CC(S(O[C@H:22]([CH2:34][CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:23][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:25]#[N:26])(=O)=O)=CC=1.O>CN(C=O)C>[Cl:33][C:29]1[CH:28]=[C:27]([C@@:24]2([C:25]#[N:26])[CH2:23][C@@H:22]2[CH2:34][CH2:35][O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](CCOCc2ccccc2)CC(C#N)c2cccc(Cl)c2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: N#C[C@]1(c2cccc(Cl)c2)C[C@@H]1CCOCc1ccccc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 66 %

Procedure:
3.2 mL 1M LHMDS in hexanes (3.2 mmol) was added to 15 mL of DMF and cooled to −40° C. To this was added a solution of (1S)-3-(3-chlorophenyl)-3-cyano-1-(2-[(phenylmethyl)oxy]ethyl}propyl 4-methylbenzenesulfonate (1.00 g, 2.12 mmol) in 5 mL of DMF over 10 minutes and stirred for 40 minutes After warming to room temperature the reaction was stirred until no starting material remained by TLC. The reaction mixture was poured into 100 mL water, extracted with 50 mL EtOAc, the organic phase isolated, washed with brine and dried over MgSO4. The resulting residue was purified by silica gel chromatography with 25% EtOAc in hexanes to give the title compound (436 mg, 65% yield). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.4 (dd, J=7.5, 5.6 Hz, 1H) 1.5 (m, 1H) 1.7 (m, 1H) 2.0 (m, 2H) 3.6 (m, 2H) 4.5 (d, J=2.2 Hz, 2H) 7.1 (m, 1H) 7.2 (m, 3H) 7.3 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>ClCCl>[Br:9][C:3]1[N:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[Cl:1]
Reactant: Nc1cncc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1cnc(Br)c(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in dichloromethane (60 mL) and cooled to 0° C. N-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0° C. for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25% ethyl acetate-hexane, gave the title compound as a yellow solid (1.69 g, 8.16 mmol, 42%). 1HMR (d6-DMSO, 400 MHz) δ 7.65 (s, 1H), 7.1 (br s, 2H). LC-MS (1) rt 1.46 min; m/z (ESI−) 205 (M−H).
Reaction SMILES: [CH3:1][CH:2]([S:11][C:12]#[N:13])[C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[BrH:15].C(O)(=O)C>>[Br:15][C:12]1[S:11][C:2]([CH3:1])=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: CC(SC#N)C(=O)c1ccccc1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc(Br)nc1-c1ccccc1
Yield: 73.1 %

Procedure:
A solution of 1-methyl-2-oxo-2-phenylethyl thiocyanate (1.00 g, 5.23 mmol) in 25% hydrogen bromide/acetic acid (10 ml) was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 971 mg (73.1%) of the desired product as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.Cl.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([Br:18])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Br)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCc2ccccc2)c(Br)c1

Procedure:
To a solution of 1-benzyloxy-2-bromo-4-nitrobenzene (50 mg, 0.16 mmol) in ethanol (5 mL) and H2O (0.5 mL) was added iron (134 mg, 2.43 mmol) and one drop of concentrated HCl. The mixture was refluxed for 6 hrs and filtrated. The filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonated solution, dried over sodium sulfate and concentrated to afford crude 4-amino-1-benzyloxy-2-bromobenzene.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20](=[O:22])[CH3:21])=[CH:14][C:13]=2[F:23])[N:4]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[CH:34]1(B(O)O)[CH2:36][CH2:35]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH:34]1([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][C:9]=3[O:11][C:12]3[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20](=[O:22])[CH3:21])=[CH:14][C:13]=3[F:23])[N:4]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:3]=2)[CH2:36][CH2:35]1
Reactant: OB(O)C1CC1
Reactant: CC(=O)Nc1cc(F)c(Oc2ccnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(F)c(Oc2ccnc3c2c(C2CC2)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: 100 °C

Procedure:
1.00 g (1.86 mmol) of N-[4-({3-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)-3,5-difluorophenyl]acetamide, 1.12 g (13.1 mmol) of cyclopropylboronic acid (Wallace, Debra J.; Chen, Cheng-yi; Tetrahedron Lett. 2002, 43(39), 6987-6990), 52.3 mg (0.19 mmol) of tricyclohexylphosphine and 1.39 g (6.53 mmol) of potassium phosphate are suspended in 10 ml of toluene and 0.5 ml of water. The solution is degassed, and 20.9 mg (0.09 mmol) of palladium(II) acetate are added. The mixture is heated at 100° C. for 1.5 h. After cooling, ethyl acetate is added and the organic phase is separated off and washed twice with water. The organic phase is dried over sodium sulfate and concentrated. The product is purified by preparative HPLC.
Reaction SMILES: CCOCC.C([O:10][CH2:11][CH:12]([O:30][CH3:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(C)(C)C>C(OC(=O)C)(=O)C>[CH3:31][O:30][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][OH:10]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(COC(C)(C)C)OC
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(CO)OC

Procedure:
(Z,Z)-(±)-1-t-butoxy-10,13-nonadecadiene-2-ol, from Example 1, was reacted with methyl iodide under Williamson conditions as in Example 1 to yield the mixed ether (Z,Z)-(±)-1-t-butoxy-2-methoxy-10,13-nonadecadiene; and the ether on the C-1 hydroxyl was cleaved by ferric chloride in acetic anhydride to yield (Z,Z)-(±)-2-methoxy-10,13-nonadecadien-1-ol having the following characteristics.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([NH:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Reaction time: 4 h
Yield: 95.6 %

Procedure:
The above nitro compound (0.73 g) was suspended in methanol (100 mL) and 10% palladium on carbon was added. The mixture was hydrogenated at 45 psi for 4 hrs. The mixture was filtered and the filtrate was concentrated to give (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butylamide (0.63 g) as a purple solid. LCMS for C14H23N5O calcd (m/e) 277, obsd 278 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[CH:12]([OH:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].I[CH3:24]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[CH:12]([O:18][CH3:24])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)CC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(OC)CC3
Yield: 112.3 %

Procedure:
To a stirred solution of the product from step (a) (45 mg, 0.16 mmol) in DMF (2 ml) at RT over an argon atmosphere was added NaH (16 mg, 0.41 mmol). The reaction mixture was stirred until gas evolution had ceased and then iodomethane (0.025 ml, 0.41 mmol) was added. The reaction mixture was stirred at RT for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the sub-titled compound as a colorless oil (52 mg). MS: ESI (positive): 290 (M+H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5](Br)=[O:6].[CH3:13][OH:14]>CCCCCCC>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([O:14][CH3:13])=[O:6]
Reactant: CO
Reactant: Cc1cccc(CBr)c1C(=O)Br
Solvent: CCCCCCC
Product: COC(=O)c1c(C)cccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
200 g (240 mmol) of 2-bromomethyl-6-methylbenzoyl bromide solution (35% solution in heptane) are added to 400 ml of methanol. After stirring at RT for one hour, 400 ml of n-heptane are added. The solution is washed successively with 600 ml of sat. sodium hydrogencarbonate solution and three times with 200 ml each time of water. Subsequently, the solvent is removed fully under reduced pressure. 98.8% of methyl 2-bromomethyl-6-methylbenzoate is obtained as a colorless oil having a purity of 80% (included in the yield) and having a molecular weight of 241.99 (C10H11BrO2); MS (ESI): 243.1 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH2:8]([O:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([CH3:20])=[CH:18][N:17]=[C:16]([NH2:21])[C:15]=2[N:22]=1)[CH3:9]>>[NH2:21][C:16]1[C:15]2[N:22]=[C:12]([CH2:11][O:10][CH2:8][CH3:9])[N:13]([CH2:19][CH2:14][CH2:15][CH2:16][NH:17][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:14]=2[C:19]([CH3:20])=[CH:18][N:17]=1
Reactant: CCOCc1nc2c(N)ncc(C)c2[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNS(=O)(=O)N(C)C

Procedure:
Using the method of Examples 115-135, dimethylsulfamoyl chloride was reacted 4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine to the desired product. The observed accurate mass was 385.2029.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[NH:35]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@@H:36]([C:54]([OH:56])=O)[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:53])[NH:42][S:43]([C:46]1[CH:52]=[CH:51][C:49]([CH3:50])=[CH:48][CH:47]=1)(=[O:45])=[O:44].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:35]([C:57]([O:59][C:60]([CH3:62])([CH3:63])[CH3:61])=[O:58])[C@@H:36]([C:54]([NH:1][C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)=[O:56])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:53])[NH:42][S:43]([C:46]1[CH:47]=[CH:48][C:49]([CH3:50])=[CH:51][CH:52]=1)(=[O:44])=[O:45]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1

Procedure:
Using 2.32 g Boc-Tyr(Bzl)-OBzl, 2.37 g Boc-D-Arg(Tos)-OH, 0.75 g HONB and 1.14 g DCC, the desired product was obtained in exactly the same manner as in Example 1-(I).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:9])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc(CCl)cc1
Product: CCOC(=O)CCNC(=O)c1ccc(CCl)cc1

Procedure:
Ethyl 3-(4-(chloromethyl)benzamido)propanoate 13f was prepared by coupling 4-(chloromethyl)benzoic acid 24 with ethyl 3-aminopropionate 25 according to the procedure described for the compound 13e in Example 21 (Scheme 8). The compound 13f was isolated as colorless oil in 84% yield (2.26 g). 1H NMR (400 MHz, CDCl3): δ 1.26 (3H, t, J=7.2 Hz); 2.64 (2H, m); 3.72 (2H, m); 4.14 (2H, q, J=7.2 Hz); 4.61 (2H, s); 6.89 (1H, broad s); 7.53 (1H, s); 7.67 (1H, s); 7.70 (1H, s). 7.80 (1H s). MS (ESI): m/z=270.00 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Br:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([Br:27])[C:20]=1[N:28]=[C:29]=[S:30]>CN(C)C1C=CN=CC=1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:29](=[S:30])[NH:28][C:20]1[C:21]([Br:27])=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[Br:18]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: COc1cc(Br)c(N=C=S)c(Br)c1
Agent: CN(C)c1ccncc1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(Br)cc(OC)cc2Br)c1NCCCO
Temperature: 80 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.00 g, 3.87 mmol), 1,3-dibromo-2-isothiocyanato-5-methoxybenzene (1.50 g, 4.64 mmol) and catalytic amount of 4-dimethylaminopyridine was stirred at 80° C. for 16 h and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown oil (560 mg, 0.963 mmol, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.CS(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a cooled (0° C.) solution of 3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (3.32 g, 8.58 mmol), N,N-diisopropylethylamine (3.14 mL, 18.0 mmol), and anhydrous dimethyl sulfoxide (1.83 mL, 25.7 mmol) in anhydrous dichloromethane (20 mL) under nitrogen was added sulfur trioxide pyridine complex (2.73 g, 17.1 mmol) portionwise over 23 minutes. The solution was stirred at 0° C. for 1 hour then quenched with 5% w/v aqueous citric acid (200 mL, 48 mmol). The mixture was extracted with diethyl ether (250 mL). The aqueous layer was extracted with diethyl ether (2×100 mL), and the combined organic extracts were washed with pH 7 buffer (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. Crude product was purified by flash column chromatography through silica gel (50% to 70% diethyl ether in hexane) to give the title compound as a gold oil (2.34 g, 71%). 1H-NMR (300 MHz, CDCl3) δ 9.81 (t, 1 H, J=1.5 Hz), 7.79 (d, 1 H, J=2.7 Hz), 7.54 (dd, 1 H, J=2.7, 8.9 Hz), 7.01 (d, 1 H, J=8.9 Hz), 6.54-6.60 (m, 1 H), 6.52-6.53 (m, 1 H), 6.43-6.44 (m, 1 H), 4.19 (t, 2 H, J=6.1 Hz), 3.99 (s, 3 H), 2.85 (td, 2 H, J=1.5, 6.1 Hz), 2.25 (d, 3 H, J=0.5 Hz). Mass spectrum (MALDI-TOF, α-cyano4- hydroxycinnamic acid matrix) calcd. for C17H17ClO6S: 407.0 (M+Na). Found: 407.0.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br.O>C1COCC1>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:25]
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CSc1ccc(CC(=O)O)cc1
Reaction time: 0.5 h
Yield: 12 %

Procedure:
4-Mercaptophenylacetic acid (995 mg, 5.915 mmol) in THF (15 ml) was cooled in an ice-bath and sodium hydride (55-65%, 520 mg, ˜13 mmol) was added. The mixture was stirred for 30 minutes and then 2-bromomethyl-benzoic acid methyl ester (1.49 g, 6.507 mmol) in THF (5 ml) was added. The resulting mixture was stirred overnight and the temperature was allowed going up to room temperature. Water was dropped in and the mixture was stirred for ca. 20 minutes. It was then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜3, and then extracted with ethyl acetate. The organic extracts were combined, dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 20 g/70 ml) using DCM, then MeOH/DCM (1:99) as eluant gave 224 mg desired product, yield 65%.
Reaction SMILES: [CH2:1]([C:7]1[CH:15]=[C:14]2[C:10]([C:11](=O)[CH2:12][CH2:13]2)=[CH:9][C:8]=1[O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([C:7]1[CH:15]=[C:14]2[C:10]([C:11](=[N:25][OH:26])[CH2:12][CH2:13]2)=[CH:9][C:8]=1[O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NO
Reactant: CCCCCCc1cc2c(cc1OCCCC(=O)O)C(=O)CC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCc1cc2c(cc1OCCCC(=O)O)C(=NO)CC2
Temperature: 0 °C
Yield: 50.2 %

Procedure:
A mixture of 50 mg (0.157 mmol) of 4-(6-hexyl-3-oxo-5-indanyloxy)butyric acid, 13 mg (0.188 mmol) of hydroxylamine hydrochloride and 32 mg (0.393 mmol) of sodium acetate in 3 ml of 85% ethanol is heated at reflux for 1 hour. After cooling, the mixture is poured into 50 ml of ice-cold water. The solid formed is isolated by filtration, washed with water and dried to give 26.3 mg (50%) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[NH2:30][CH2:31][CH2:32][OH:33].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:30][CH2:31][CH2:32][OH:33])=[O:26])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: NCCO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NCCO)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid was coupled with 2-aminoethanol using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=457.2 [M+H]+.