Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[Cl-].[Na+].[BH4-].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CO>[OH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(CCCO)cc2)CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
The 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-dihydrocinnamic acid ethyl ester (68 g, 0.18 mol) obtained in Example 8(2) was dissolved in toluene (1 L) and cooled to −78° C. A diisobutylaluminum hydride-hexane solution (607 ml, 0.6 mol) was added dropwise. After stirring for 1.5 hours, methanol (10 ml) and a saturated sodium chloride aqueous solution (550 ml) were added, followed by stirring for 3 hours. The insoluble material was filtered with Celite. The solvent was evaporated from the filtrate, and the obtained residue was dissolved in methanol (500 ml) and THF (250 ml). Sodium borohydride (6.9 g, 0.18 mol) was added thereto at 0° C. After stirring for 1 hour, a saturated ammonium chloride aqueous solution was added thereto, followed by extraction with chloroform and drying over magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated, thereby obtaining N-(4-(3-hydroxypropyl)phenyl)-4-tert-butoxycarbonylaminopiperidine (60 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]([O:19][CH2:20][CH2:21]Cl)=[O:18]>C(#N)C>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([N:1]2[CH2:21][CH2:20][O:19][C:17]2=[O:18])=[N:3][CH:4]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(N2CCOC2=O)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2-amino-4-methyl-5-bromo-pyridine (3 g, 16 mmol) and K2CO3 (5.5 g, 40 mmol) were added into acetonitrile (35 mL), cooled to 0° C. on ice-salts cooling bath. 2-chloroethyl chloroformate (2.75 g, 19.2 mmol) was added dropwise, and after its completion, the mixture was raised to room temperature, agitated for 1 hr, and refluxed under heat for 3 hrs. TLC (petroleum ether/ethyl acetate=3:1) was employed to monitor the reaction. After the starting materials completely reacted, acetonitrile was removed by evaporation. The resulting mixture was diluted by adding dichloromethane (100 mL), washed sequentially with water and saturated saline solution, and dried over anhydrous sodium sulfate. Column chromatography afforded 2.6 g of white solid, yield 63%.
Reaction SMILES: [Na+].[NH2:2][C@H:3]([C:8]([O-:10])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].S(=O)(=O)(O)O.[S]>>[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][S:6][CH3:7]
Reactant: CSCC[C@H](N)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [S]
Product: CSCC[C@H](N)C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To 150 g of the aqueous solution of methionine sodium salt containing 8.0% by weight of methionine sodium salt, which was prepared by hydrolysis of MMH was added 9.4 g of 72% by weight of sulfuric acid, and the reducing sulfur compound as given in the following Table II. The mixture was stirred at 80° C. for 60 minutes, and concentrated with an evaporator. The precipitated crystals were collected and dried to give 8 g of colorless methionine.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([O:22]CC=C)=[O:21])=[C:18]([OH:28])[CH:17]=2)=[CH:9][C:8]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:3])[CH3:2].Cl.[NH2:35][OH:36]>N1C=CC=CC=1>[C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:35][OH:36])[CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([OH:22])=[O:21])=[C:18]([OH:28])[CH:17]=2)=[CH:9][C:8]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: NO
Reactant: C=CCOC(=O)c1ccc(OCC(=O)c2ccc(NCCC(C)=O)c(C(C)(C)C)c2)cc1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)CCNc1ccc(C(COc2ccc(C(=O)O)c(O)c2)=NO)cc1C(C)(C)C

Procedure:
In a manner similar to that of Example 1.g, by reaction of 370 mg (0.8 mmol) of allyl 4-{2-[4-(acetylethylamino)-3-tert-butylphenyl]-2-oxoethoxy}-2-hydroxybenzoate with 284 mg (4 mmol) of hydroxylamine hydrochloride and 320 μl of pyridine. A yellowish paste is obtained (m=380 mg, yield=99%).
Reaction SMILES: C(C1C(C/C=C(\C)/CCC(OC)=O)=C(OC)C(C)=C2C=1C(=O)OC2)(O)=O.[N:27]([C:30]1[C:38]([CH2:39]/[CH:40]=[C:41](\[CH3:48])/[CH2:42][CH2:43][C:44]([O:46]C)=[O:45])=[C:37]([O:49][CH3:50])[C:36]([CH3:51])=[C:35]2[C:31]=1[C:32](=[O:52])[O:33][CH2:34]2)=C=O.O.O.[OH-].[Li+]>O1CCOCC1.C(O)(=O)C.C(OCC)(=O)C>[NH2:27][C:30]1[C:38]([CH2:39]/[CH:40]=[C:41](\[CH3:48])/[CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[C:37]([O:49][CH3:50])[C:36]([CH3:51])=[C:35]2[C:31]=1[C:32](=[O:52])[O:33][CH2:34]2
Reactant: COC(=O)CC/C(C)=C/Cc1c(N=C=O)c2c(c(C)c1OC)COC2=O
Agent: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1C(=O)O)C(=O)OC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g (5.5 mmol) of methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, a compound of Formula 5, was converted to crude methyl E-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, a compound of Formula 6, as described in Preparation 6 above without purification. The resulting 4-isocyanate was redissolved in 50 ml of 1,4-dioxane and treated with 16 ml of water and 2.0 g (47.7 mmol) of lithium hydroxide monohydrate. The mixture was stirred at room temperature for 2 hours and then partitioned between aqueous 1N sodium hydrogen sulfate and ethyl acetate. The organic phase was washed twice with water, once with brine, and was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, using 50:40:1 hexane:ethyl acetate:acetic acid as eluant to give 1.28 g (4.0 mmol) of (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid as a white solid, mp 130°-131° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccncc1-c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccncc1-c1cccc(N)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(3-nitrophenyl)-4-pyridinecarboxyiic acid ethyl ester in ethyl acetate (20 mL) was added tin(II) chloride (1.47 g). The mixture was heated at 80° C. for 45 min, then allowed to cool to ambient temperature. The mixture was poured into ice and saturated aqueous sodium bicarbonate was added until the mixture attained a pH of approximately 7. Celite and ethyl acetate were added, and the mixture was stirred for 10 min. The mixture was filtered and placed in a separatory funnel. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to yield the crude product. Purification by silica gel chromatography (4:1 hexane: ethyl acetate) afforded the title compound as an orange oil (216 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:40])[C:26]=1[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1)=[O:29]>>[Cl:40][C:25]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:20])[C:26]=1/[CH:27]=[C:28](\[O:29][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)/[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OC

Procedure:
The compound was obtained starting from 3-benzyloxy-4-methoxy-benzoyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy -phenyl)-ethanone, following the procedure of Example 7.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]#[N:19])[CH:14]=[N:15]2)=[CH:10][CH:9]=1.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[C@@H:31]1[CH2:33][O:32]1>CCO>[OH:32][C@H:31]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=[O:30])[O:27][CH2:28][C:29]=2[C:21]=1[CH3:20])[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18]#[N:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)[C:2](=[O:1])[CH2:7]1
Reactant: N#Cc1cnc2cc(N3CCNCC3=O)ccc2c1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(c3ccc4cc(C#N)cnc4c3)C(=O)C2)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
A mixture of 7-(2-oxopiperazin-1-yl)quinoline-3-carbonitrile [I-9] (20 mg, 0.079 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (30 mg, 0.16 mmol) in EtOH (1.5 mL) in a 5 mL microwave tube was heated to 140° C. for 2 hours. LC showed formation of the title product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 443 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.CN.C[CH2:15][N:16](C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:16][CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: CN
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
4-Bromo-2-fluoronitrobenzene (Aldrich, 1 eqvt), methylamine (2 eqvt), and hunig's base (3 eqvt) in DMF (1 Molar in substrate) were placed in a sealed vial and heated to 85° C. overnight. The crude mixture was diluted with water, and the product collected by filtration. Purification by chromatography (gradient: 92:8 hexanes:ethyl acetate to 68:32 hexanes:ethyl acetate) provided the title compound. 1HNMR (DMSO-d6, 400 MHz) δ 8.22 (bd, J=4.4 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.14 (d, J=2 Hz, 1H), 6.80 (dd, J=9.2, 2.4 Hz, 1H), 2.92 (d, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19].[H-].[Na+].Cl.Cl[CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1)[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:19]
Reactant: ClCc1cscn1
Reactant: CCOC(=O)c1cnc2c(F)c(F)c(F)cc2c1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cscn2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 22.6 %

Procedure:
1.5 g of ethyl 6,7,8-trifluoro-4-hydroxyquinoline-3-carboxylate was dissolved in 30 ml of DMF, and 0.43 g of 60% oily sodium hydride was added, followed by stirring at 80° C. in a nitrogen gas stream for 20 minutes. To this solution, 1.9 g of 4-chloromethylthiazole hydrochloride was added, followed by stirring at constant temperature for 15 hours, after which the reaction mixture was concentrated to dryness. The residue was dissolved in CHCl3 ; the organic layer was washed with water and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:2) to yield 0.46 g of ethyl 6,7,8-trifluoro-1-(4-thiazolylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate as a colorless powder. This product was suspended in a mixture of acetic acid and water (3 ml:3 ml); 0.33 ml of sulfuric acid was added, followed by stirring at 120° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and the resulting crystal was collected by filtration to yield 0.38 g of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([OH:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][C:36]([O:23][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[N:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)=[O:37]
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(C)CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)CCCC(C)C)nc2n1
Yield: 60.3 %

Procedure:
The procedure is as in Example 7, but starting with 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (6.8 g) in methylene chloride (100 cc), triethylamine (10.1 g), 5-methylhexanoyl chloride (6.4 g) and 4-dimethylaminopyridine (50 mg). The residue obtained after treatment is purified by chromatography on silica gel (0.063-0.2 mm; 100 g) contained in a column 2.8 cm in diameter (eluant: methylene chloride), collecting 30-cc fractions. Fractions 19 to 94 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After the residue obtained has been recrystallized in heptane (75 cc), 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (5.6 g), m.p. 105° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: c1cn[nH]c1
Reactant: Fc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncccc1-n1cccn1
Yield: 39 %

Procedure:
A solution of 2-chloro-3-fluoro-pyridine (1.3 g, 10.0 mmol), 1H-pyrazole (749 mg, 11.0 mmol) and K2CO3 (4.1 g, 30.0 mmol) was stirred in DMF (15 mL) at 80° C. for 16 hours. The reaction mixture was poured into water and extracted with EtOAc (3×). The organics were combined, washed with water (3×), brine, dried (Na2SO4) and evaporated to dryness. Purification by column chromatography (5 to 30% EtOAc in hexanes) gave the desired product (0.7 g, 40%) as a white solid. ESI-MS m/z calc. 179.3. found 180.3 (M+1)+. Retention time: 0.74 minutes (3 min run).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1I
Product: Cc1ccc(C(=O)Cl)cc1I
Temperature: 25 °C

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (10.0 g, 38.2 mmol) in thionyl chloride (30.0 mL) was heated at reflux for 3 hours. The resulting yellow solution was cooled to room temperature and concentrated under reduced pressure to afford 3-iodo-4-methylbenzoyl chloride. A solution of 3-iodo-4-methylbenzoyl chloride (1 g, 4 mmol) in dichloromethane (10 mL) was added slowly to a 0° C. solution of 3-amino-4-fluorobenzotrifluoride (0.7 ml, 4 mmol) and diisopropylethylamine (0.9 ml, 5 mmol) in dichloromethane (10 mL). The reaction stirred at 0° C. and warmed to room temperature over 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 100% ethyl acetate-hexane) to afford N-(2-fluoro-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide 34 MS m/z found 423.9 [MH+]; calc. for C15H10F4INO=423.14.
Reaction SMILES: [N:1]1([C:6]2[CH:53]=[CH:52][C:9]([CH2:10][NH:11][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]4[CH:25]=[C:24]([N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:23]=[CH:22][C:21]=4[NH:32][C:33]([C:35]4[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=4)[CH2:38][S:39][CH2:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])=[O:34])[CH:15]=3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]4[CH:25]=[C:24]([N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:23]=[CH:22][C:21]=4[NH:32][C:33]([C:35]4[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=4)[CH2:38][S:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:34])[CH:15]=3)=[O:13])=[CH:52][CH:53]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(-n4cccn4)cc3)ccn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(-n4cccn4)cc3)ccn2)c1
Yield: 71.5 %

Procedure:
Into a 50-mL 3-necked round bottom flask, was placed tert-butyl 3-(3-((2-(4-((4-(1H-pyrazol-1-yl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)-propanoate (130 mg, 0.18 mmol, 1.00 equiv), and dichloromethane (2 mL). This was followed by dropwise addition of trifluoroacetic acid (3 mL) with stirring. The resulting solution was stirred for 60 min at room temperature. The solution was adjusted to pH 7 with sodium bicarbonate (aq). The resulting solution was diluted with 30 mL of dichloromethane and washed with 2×10 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (300 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 86.9 mg (72%) of a yellow solid. 1H-NMR: (300 MHz, DMSO-d6+D2O, ppm): δ 1.63 (m, 2H), 1.82 (m, 4H), 2.58-2.62 (m, 4H), 3.47 (t, 4H), 3.87 (s, 2H), 4.56 (d, 2H), 6.53 (s, 1H), 7.44-7.54 (m, 4H), 7.72-7.79 (m, 3H), 7.87-7.89 (m, 2H), 8.36 (s, 1H), 8.42 (s, 1H), 8.99 (d, 1H), 9.53 (s, 1H), 11.97 (s, 1H). MS (ES, m/z): 675 [M+H]+.
Reaction SMILES: O.O.S([O-])([O-])(=O)=O.[Ca+2].CC(N)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.CC(NC)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.C[C@@]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC1.OS(O)(=O)=O.[CH3:110][C@H:111]([C:124]([O-:126])=[O:125])[C:112]1[CH:117]=[CH:116][C:115]2[CH:118]=[C:119]([O:122][CH3:123])[CH:120]=[CH:121][C:114]=2[CH:113]=1.[Na+]>>[CH3:110][C@H:111]([C:124]([OH:126])=[O:125])[C:112]1[CH:117]=[CH:116][C:115]2[CH:118]=[C:119]([O:122][CH3:123])[CH:120]=[CH:121][C:114]=2[CH:113]=1
Reactant: COc1ccc2cc([C@H](C)C(=O)[O-])ccc2c1
Agent: CNC(C)[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@](C)(O)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)O1
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](C(C)N)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Solvent: O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1

Procedure:
A mixture of 1,000.0 mg calcium sulfate dihydrate (Fluka), 250.0 mg poly-L-lactide (M-10,000 g/mol), 49.7 mg gentamicin sulfate (AK 628) and 86.8 mg naproxen sodium salt (produced through the neutralization of naproxen (Fluka)) is ground up. 200 mg of this mixture, respectively, are pressed with a press at a pressure of 5 tons within a period of two minutes into disk-shaped molded bodies with a diameter of 13 mm.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)O1.Br[C:35]1[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:14]([N:12]1[CH:13]=[CH:9][C:10]([C:35]2[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=2)=[N:11]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
Reactant: Nc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ncccc1-c1ccn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
4-(4,4,5,5-Tetramethyl-(1,3,2)dioxaborolan-2-yl)-1-trityl-1H-pyrazole (3.2 g, 7.33 mmol) described in Manufacturing Example 32-1-2, 3-bromo-pyridine-2-ylamine (1.14 g, 6.60 mmol), tetrakis (triphenylphosphine)palladium (0) (424 mg, 0.37 mmol), toluene (40 mL), 2 M aqueous sodium carbonate solution (10 mL) and ethanol (20 mL) were stirred for 1 hour at 95° C. The reaction solution was allowed to room temperature, and partitioned into water and ethyl acetate. The ethyl acetate layer was washed with water once, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (2.3 g, 78.0%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[C:20]([Cl:25])[CH:19]=1)(=[O:17])=[O:16])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:21]2[CH:22]=[CH:23][C:18]([S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=2[Cl:25])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1cc(O)cc(Br)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Br)cc(C(=O)OC)c2)c(Cl)c1

Procedure:
The subtitle compound was prepared as described in example 2 step (iii) but instead using the product from step (i) and the product from example 3 step (i).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[CH:10]=1.[Br:16]N1C(=O)CCC1=O>CN(C)C=O.S(=O)(O)[O-].[Na+]>[Br:16][C:10]1[C:11]([CH3:15])=[N:12][N:13]([CH3:14])[C:9]=1[C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2c(F)cccc2F)n(C)n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(-c2c(F)cccc2F)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-(2,6-difluorophenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step B) (1.53 g, 7.3 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added portionwise N-bromosuccinimide (1.37 g, 7.7 mmol). After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with ice water (20 mL) and saturated aqueous sodium bisulfite solution (15 mL), briefly stirred, and then partitioned between water (75 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by MPLC (10 to 40% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a solid (1.84 g).