Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>CN(C=O)C>[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([O:12][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH:21]=1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1OC1C=CCCC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 18.6 g of methyl 5-chlorosalicylate, 28 g of K2CO3 and 20 g of 3-bromocyclohexene in 200 ml of DMF is stirred at 90° C. overnight. The mixture is then poured onto water, extracted with ethylacetate, washed with water, dried over magnesium sulfate and evaporated to dryness to obtain crude product. This is purified by flash chromatography using hexane as the eluent to give pure methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzoate as the first fraction which is used directly in the next step.
Reaction SMILES: C([O:5][C:6]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:7]=1[CH2:8][NH:9][C:10]([C@:12]12[CH2:19][C@H:18]([NH:20]C(=O)OC(C)(C)C)[CH2:17][C@H:13]1[O:14][CH2:15][CH2:16]2)=[O:11])(C)(C)C.[ClH:36]>CO>[ClH:36].[ClH:36].[NH2:20][C@@H:18]1[CH2:17][C@H:13]2[O:14][CH2:15][CH2:16][C@@:12]2([C:10]([NH:9][CH2:8][C:7]2[CH:28]=[C:29]([C:32]([F:33])([F:34])[F:35])[CH:30]=[CH:31][C:6]=2[OH:5])=[O:11])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2O)C1

Procedure:
A solution of the product of Step A (11.07 g, 20.57 mmol, 1 eq) in methanol (60 mL) and solution of HCl in methanol (82 mL of 1.25 M solution, 103 mmol, 5 eq) was heated to 55° C. for 2.5 days. The solution was concentrated to give the product of step B. Calculated for C16H19F3N2O3: 345.1 (M+1). found: 345.3.
Reaction SMILES: [S:1]([O-])(=O)(=O)[CH3:2].S[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[N:10]1[CH:11]=[CH:12][CH:7]=[CH:8][C:9]=1[S:1][C:2]1[CH:12]=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: CS(=O)(=O)[O-]
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc(Sc2ccccn2)nc1
Yield: 71 %

Procedure:
This product (4) is treated with 4-mercaptopyridine (2.45 g; 1.3 equivalents) and sodium carbonate (1.8 g; 1 equivalents) at room temperature for 2 hours to give 4-pyridyl sulfide (7) (7.87 g) as in Example F-2. Yield: 71%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:16]2[N:15]=1.[OH:25]S(O)(=O)=O.O.CCCCCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH2:24])=[O:25])=[C:16]2[N:15]=1
Reactant: N#Cc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The product from Step B (3.00 g, 8.85 mmol) was added in small portions over 5 minutes to concentrated H2SO4 (30 mL) and the mixture was stirred at ambient temperature for 2 hours (homogeneous after 5 minutes). The solution was slowly added to chilled H2O (300 mL) with stirring and the mixture was extracted with EtOAc. The combined EtOAc portions were washed with H2O, 1M Na2CO3 and saturated NaCl. The EtOAc solution was dried over MgSO4/activated carbon, filtered through a packed Celite pad and concentrated to give a white foam. The foam was dissolved in minimal CH2Cl2 and hexane was added to induce formation of a white precipitate. The mixture was concentrated to provide the title compound as a flowing white solid after drying in vacuum (2.80 g, 92%). MS (apci) m/z=344.1 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].CN(C)P(N(C)C)(N(C)C)=O.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1.Cl>O1CCCC1.CCCCCC>[CH3:15][C:14]([CH3:16])([CH2:36][C:35]1[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=1)[C:13]([OH:18])=[O:17]
Reactant: CC(C)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: COc1ccc(CC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
A cooled (−78° C.) solution of diisopropylamine (65 g, 642 mmol) in tetrahydrofuran (THF, 800 mL) was treated with 244 mL of 2.5 M n-butyl lithium (610 mmol) in hexane. The reaction was stirred for 30 minutes at room temperature, cooled to −78° C. and treated dropwise with isobutyric acid (26.8 g, 305 mmol) and hexamethylphosphoramide (HMPA, 54.7 g, 305 mmol). The reaction was stirred for 30 minutes at room temperature and treated with 4-methoxybenzyl chloride (43.4 g, 277 mmol). The reaction was stirred for 48 hours at room temperature and treated with 10% HCl (200 ml). The reaction was concentrated to 300 mL and diluted to 600 mL with water. The resulting solution was extracted with diethyl ether (2×300 mL) and the combined ether extracts were washed with 10% HCl (2×200 mL). The ether extract was then extracted with 1N NaOH (3×200 mL). The combined 1N NaOH washes were made acidic (pH 1) by the addition of concentrated HCl, and the resulting solution was extracted with diethyl ether (3×300 mL). The combined ether extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 32.6 g of 2,2-dimethyl-3-(4-methoxyphenyl)propionic acid as an oil: GC/EI-MS, m/z (rel. int.) 208 (M+, 7), 121 (100), 91 (5), 77 (6).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:20]=[C:21]=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1.[NH2:25][OH:26]>C(Cl)Cl>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:22])[NH:25][OH:26])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: NO
Reactant: O=C=Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(NO)Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Yield: 97.5 %

Procedure:
3-Trifluoromethyl-4-(2-naphthyloxy)phenyl isocyanate (16.5 g) was dissolved in 100 ml of methylene chloride, and the resulting solution was added dropwise to 10 ml of an aqueous solution containing 4 g of hydroxylamine at a temperature below 20° C. Precipitated crystals were collected on a filter, washed with water and dried to obtain 17.7 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N-hydroxyurea. Thereafter, 17.7 g of the product and 12.5 g of dimethyl sulfate were dissolved in 200 ml of toluene, and after addition of 0.16 g of tetra-n-butylammonium bromide to the mixture, 11 ml of 10 N sodium hydroxide were dropwise added thereto at 20°-22° C. After stirring at room temperature, the reaction mixture was diluted with water, followed by extraction with benzene. The benzene layer was washed with water, and the solvent was removed under reduced pressure. The oily substance obtained was purified by column chromatography (silica gel, 100-120 mesh; eluting solvent, tetrahydrofuran-benzene (1:3) mixture) to obtain 16.2 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N-methoxy-N-methylurea. The product was confirmed to be the same product as obtained in Example 1 by IR, NMR, TLC and melting point.
Reaction SMILES: C(O)(=O)C.[C:5]1([N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C:20]([OH:22])=[O:21])[CH2:15]2)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH2:38]([N:43]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:44](Cl)=[O:45])[CH2:39][CH2:40][CH2:41][CH3:42]>CN(C=O)C>[CH2:38]([N:43]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:44]([N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[N:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:15][C@H:16]1[C:20]([OH:22])=[O:21])=[O:45])[CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=C(O)[C@@H]1CN(C(=O)N(c2ccccc2)c2ccccc2)CCN1
Reactant: CCCCCN(C(=O)Cl)c1ccccc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C[C@H]1C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A stirred solution of 0.383 g (1.00 mmole) of (S)-4-(diphenylcarbamoyl)piperazine-2-carboxylic acid acetate salt (from Step C) and 0.400 g (3.09 mmole) of N,N-diisopropylethylamine in 6 ml of DMF at 0° C. was treated with 0.253 g (1.12 mmole) of N-pentyl-N-phenylcarbamoyl chloride (from Step B) and then was warmed to 25° C. for 16 hours. The DMF was removed in vacuo and the residue was partitioned between 20 ml of 1N HCl and 50 ml of chloroform which was dried over sodium sulfate and concentrated in vacuo to a yellow oil. The oil was flash chromatographed over 100 cc of silica gel with 12×25 ml of chloroform, 10×25 ml of 80:20:2 chloroform-methanol-ammonia water. Fractions 19-26 were combined and concentrated to 0.338 g (ammonium salt) of clear glass which was homogeneous by TLC (80:20:2 chloroform-methanol-ammonia water, Rf =0.4). The product was partitioned between 20 ml. of 1N HCl and 30 ml of chloroform which was dried over sodium sulfate and concentrated in vacuo to 0.337 g (72%) of a clear glass.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:25]([C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[O:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][S:13]([C:10]2[CH:11]=[CH:12][C:7]([C:4]3[O:3][C:2]([CH3:1])=[N:6][CH:5]=3)=[CH:8][CH:9]=2)(=[O:15])=[O:14])=[C:19]([C:25]([C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[O:26])[CH:20]=1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Reactant: Cc1ncc(-c2ccc(S(=O)(=O)Cl)cc2)o1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnc(C)o3)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the preparation of N-aryl-benzenesulfonamides using 4-(2-methyl-oxazol-5-yl)-benzenesulfonyl chloride and (2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and purified by HPLC. MS: m/z 468.0 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:14]=[N:13][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)=[N:17][CH:16]=1
Reactant: OCCc1ccc(O)cc1
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(Oc2ncc(Cl)cn2)cc1
Temperature: 110 °C
Yield: 89.6 %

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (555 mg, 4.02 mmol) in DMF (15 mL) was added 2,5-dichloropyrimidine (570 mg, 3.83 mmol) and K2CO3 (635 mg, 4.59 mmol). The mixture was heated at 110° C. overnight. Purification via reverse phase flash chromatography then afforded the title compound (861 mg, 3.43 mmol, 90% yield). LCMS: rt=2.38 min, [M+H+]=251
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:21])=[O:5]
Reactant: CO
Reactant: CCC(=O)c1cc(C(=O)O)c(C)cc1C
Agent: O=S(=O)(O)O
Product: CCC(=O)c1cc(C(=O)OC)c(C)cc1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a 100-mL round-bottom flask, was carefully added 2,4-dimethyl-5-propionylbenzoic acid (compound 1.4, 1.2 g, 5.8 mmol), sulfuric acid (1.0 mL, 19 mmol) and methanol (30 mL). The resulting solution was stirred at 70° C. for 5 h, then concentrated under reduced pressure. The residue was carefully diluted with H2O (50 mL) and extracted ethyl acetate (100 mL). The organic layer was washed with H2O (2×100 mL) and brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100) as the eluent to yield the title compound as a light yellow solid (0.90 g, 70%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[S:6]1[CH2:9][CH:8]([O:10][N:11]=[C:12]([C:16]2[N:17]=[C:18]([NH:21][CH:22]=[O:23])[S:19][CH:20]=2)[C:13]([OH:15])=O)[CH2:7]1.C[Si](CC(N)=O)(C)C.Cl.[Cl-].[NH2:34][CH:35]1[C:52](=[O:53])[N:37]2[C:38]([C:49]([OH:51])=[O:50])=[C:39]([CH2:42][N+:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:40][S:41][C@H:36]12>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[S:6]1[CH2:7][CH:8]([O:10][N:11]=[C:12]([C:16]2[N:17]=[C:18]([NH:21][CH:22]=[O:23])[S:19][CH:20]=2)[C:13]([NH:34][CH:35]2[C:52](=[O:53])[N:37]3[C:38]([C:49]([O-:51])=[O:50])=[C:39]([CH2:42][N+:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:40][S:41][C@H:36]23)=[O:15])[CH2:9]1
Reactant: NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12
Reactant: O=CNc1nc(C(=NOC2CSC2)C(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CNc1nc(C(=NOC2CSC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)cs1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Vilsmeir reagent was prepared from N,N-dimethylformamide (0.52 g) and phosphorus oxychloride (1.1 g) in a usual manner. 2-(3-Thietanyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.5 g) was added to the stirred suspension of Vilsmeir reagent in tetrahydrofuran (15 ml) under ice-cooling and the mixture was stirred for 30 minutes at below 5° C. The mixture became clear solution [Solution A]. A mixture of trimethylsilylacetamide (7.2 g) and 1-[(7-amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride (2.0 g) in tetrahydrofuran (40 ml) was stirred at 45° C. for 30 minutes. To the mixture was added the above Solution A all at once at -30° C., and the resulting solution was stirred at -15° C. for 30 minutes. Water (50 ml) and ethyl acetate (50 ml) were added to the reaction mixture at -10° C. The organic layer was separated and the aqueous layer was extracted twice with a mixture of ethyl acetate (50 ml) and tetrahydrofuran (50 ml). The combined organic layers were dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diisopropyl ether to give 7-[2-(3-thietanyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.2 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([N:21]=[C:22]=[O:23])[CH:18]=[CH:19][CH:20]=1>>[C:15]1([CH3:14])[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[O:23])[CH:16]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: Cc1cccc(NC(=O)N2CCC(Cc3ccccc3)CC2)c1

Procedure:
The title compound was prepared from 4-benzylpiperidine and 3-methylphenyl isocyanate. 1H NMR (400 MHz, CDCl3): 7.32-7.07 (m, 8H), 6.84-6.80 (m, 1H), 6.41 (br s, 1H), 4.06-4.00 (m, 2H), 2.78 (td, J=13 Hz, 2.4 Hz, 2H), 2.55 (d, J=7.0 Hz, 2H), 2.30 (s, 3H), 1.77-1.64 (m, 3H), 1.28-1.16 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O.C(=O)([O-])O.[Na+]>[C:22]1([NH:28][C:29]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[C:11]([F:21])[CH:10]=3)[CH3:8])[N:6]=2)=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=S)Nc2ccccc2)n1
Yield: 15.8 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl) thiazole (0.50 g, 1.68 mmol) in acetone (10 ml) were added phenylisothiocyanate (0.25 g, 1.85 mmol) in acetone (5 ml) and sodium hydrogen carbonate (0.30 g). After the mixture was refluxed to 10 h, phenyisothiocyanate (0.50 g, 3.70 mmol) was added to the mixture, and then the mixture was refluxed for 2 h. The mixture was evaporated under reduced pressure to a residue, which was chromatographed and recrystallized to afford N-phenyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)thiourea (0.115 g, 16% yield) as crystalline material: mp 176°-177.0° C.
Reaction SMILES: [C:1]1([C:7]([CH3:14])([CH3:13])[CH:8]([SH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][CH3:27])[N:19]=1>CC(C)=O.O>[C:1]1([C:7]([CH3:14])([CH3:13])[CH:8]([S:12][C:18]2[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][CH3:27])[N:19]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(c1ccccc1)C(S)C(=O)O
Reactant: COc1nc(Cl)nc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1nc(OC)nc(SC(C(=O)O)C(C)(C)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
1.9 g of 3-phenyl-3-methyl-2-mercaptobutyric acid was dissolved in 50 ml of acetone, and 1.2 g of potassium hydroxide dissolved in 5 ml of water was added thereto under cooling with ice. 1.5 g of 2-chloro-4,6-dimethoxy-S-triazine dissolved in 20 ml of acetone was added thereto. The mixture was stirred for 30 minutes. Then, the reaction solution was poured into water and extracted with 50 ml of ethyl acetate. The aqueous layer was acidified with a citric acid aqueous solution and extracted with 100 ml of chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain 2.2 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Li+].[CH3:13][CH:14]([N-]C(C)C)[CH3:15].C1CCCCC1.C(Br)C=C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:15][CH:14]=[CH2:13])=[N:7][C:6]=2[CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1nc2cc(Br)ccc2s1
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCCc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-bromo-2-methylbenzothiazole (1.00 g, 4.38 mmol) in THF (25 mL) at −78° C. was treated with 1.5M LDA in cyclohexane (4.40 mL, 6.60 mmol), stirred for 45 minutes, treated with allyl bromide (1.33 g, 10.99 mmol), stirred for 1 hour, quenched with 1M HCl, warmed to room temperature, added to water (50 mL), and extracted with ethyl acetate (3×200 mL). The combined extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 8% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:6]2[C:11]([CH2:12]N(CC3C=C(C(F)(F)F)C=C(C(F)(F)F)C=3)C#N)=[CH:10][CH:9]=[C:8]([F:31])[N:7]=2)[CH2:3][CH2:2]1.[OH2:36].[N-]=[N+]=[N-].[Na+]>C(O)(C)C.[Br-].[Zn+2].[Br-]>[CH:1]1([CH2:4][N:5]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:6]2[C:11]([CH:12]=[O:36])=[CH:10][CH:9]=[C:8]([F:31])[N:7]=2)[CH2:3][CH2:2]1
Reactant: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1ccc(F)nc1N(CC1CC1)CC1CC1
Reactant: O
Agent: [Br-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=Cc1ccc(F)nc1N(CC1CC1)CC1CC1

Procedure:
To [2-(bis-cyclopropylmethy-amino)-6-fluoro-pyridin-3-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide (244 mg, 0.5 mmol) stirred in isopropanol (5 mL) and water (10 mL) was added sodium azide (38.4 mg, 0.55 mmol) and zinc bromide (115.6 mg, 0.5 mmol). After stirring at reflux overnight, the solution was extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give the title compound as an orange oily product (248 mg, yield: 91%) and was used as is without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:57]([O:61][C:62]([N:64]1[CH2:69][CH2:68][N:67]([CH2:70][CH2:71][NH2:72])[CH2:66][CH2:65]1)=[O:63])([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C>[C:57]([O:61][C:62]([N:64]1[CH2:65][CH2:66][N:67]([CH2:70][CH2:71][NH:72][C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:68][CH2:69]1)=[O:63])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (519 mg, 1 mmol) in DMF (5 mL) was added HOBt (202 mg, 1.3 eq.), EDAC.HCl (288 mg, 1.5 eq.) and TEA (302 mg, 3 eq.). After stirring at rt for 30 mins, to the mixture was added 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (298 mg, 1.3 eq.). After stirring at 40° C. for 24 hours, the reaction was concentrated and the residue was purified on a silica gel column to give 4-[2-(2-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[OH-].[Na+:37]>O>[CH3:17][C:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18].[Na+:37]
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A suspension of the product of Example 34C (0.049 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.095 mL, 0.095 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.051 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.46 (m, 1 H) 0.69 (m, 6 H) 0.80 (m, 1 H) 1.29 (m, 1 H) 1.38 (m, 3 H) 1.72 (m, 1 H) 2.14 (m, 1 H) 2.90 (m, 3 H) 7.34 (m, 6 H) 8.05 (m, 1 H) 15.42 (m, 1 H). MS (ESI−) m/z 516 (M−H)−.