Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH:21][C:22]([C@@H:24]3[CH2:28][CH2:27][CH2:26][N:25]3[C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[O:23])[S:19][CH:20]=2)=[N:12][CH:11]=1)C1C=CC=CC=1.C(OC(N1CCC[C@H]1C(=O)NC1SC(C2C=CC(C(O)=O)=CC=2)=CN=1)=O)C1C=CC=CC=1>>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[C:22]([NH:21][C:18]1[S:19][CH:20]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]([OH:39])=[O:8])=[CH:11][N:12]=2)[N:17]=1)=[O:23])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(OCc1ccccc1)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)nc1
Agent: O=C(O)c1ccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)cc1
Product: O=C(O)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)nc1

Procedure:
Hydrolysis of 6-{2-[((S)-1-Benzyloxycarbonyl-pyrrolidine-2-carbonyl)-amino]-thiazol-4-yl}-nicotinic acid benzyl ester (0.075 g, 0.14 mmol) similar to the procedure described for the synthesis of Compound 5353 (Example 353), gave 6-{2-[((S)-1-Benzyloxycarbonyl-pyrrolidine-2-carbonyl)-amino]-thiazol-4-yl}-nicotinic acid.
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]1[NH:10][C:9](=[S:11])[NH:8][C:7](=[O:12])[CH:6]=1.[Cl-].Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][NH+:17]=1>C(O)C>[CH3:22][C:21]1[C:16]([CH2:15][S:11][C:9]2[NH:8][C:7](=[O:12])[CH:6]=[C:5]([CH3:4])[N:10]=2)=[N:17][CH:18]=[C:19]([CH3:25])[C:20]=1[O:23][CH3:24]
Reactant: COc1c(C)c[nH+]c(CCl)c1C
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(C)cnc(CSc2nc(C)cc(=O)[nH]2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 36 %

Procedure:
After dissolving 0.22 g (4.0 mmol) of potassium hydroxide in the mixture of 15 ml of ethanol and 3 ml of water, first 0.28 g (2.0 mmol) of 6-methyl-2-thiouracil, then a solution of 0.44 g (2.0 mmol) of 2-chloromethyl-3,5-dimethyl-4-methoxypyridinium chloride (m.p.: 127°-128° C.) in 15 ml of ethanol are added. The reaction mixture is stirred at room temperature for 20 hours, then ethanol is evaporated under reduced pressure, 10 ml of water are added to the residue and the product is extracted 3 times with 5 ml of chloroform each. The combined organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from 2-propanol to obtain 0.21 g (36%) of the title compound as a white crystalline product, m.p.: 231°-233° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[CH:5]=[N:6][C:7]=1Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>CC(O)CC>[CH:24]([O:29][C:7]1[C:2]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:3][C:4]([C:9]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])=[O:11])=[CH:5][N:6]=1)([CH2:23][CH3:28])[CH3:25]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCC(C)O
Product: CCC(C)Oc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31, using 5-bromo-6-chloro-3-pyridinecarboxylic acid, rac-2-butanol (commercially available), 4-chlorophenyl-boronic acid (commercially available), and (1R,2R)-2-amino-cyclohexanol (commercially available) as starting materials. MS (ISP): 403.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=1[Cl:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:41](B(CC)CC)[CH3:42]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:41][CH3:42])=[CH:15][C:14]=1[Cl:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2
Reactant: CCB(CC)CC
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(Br)cc3Cl)cc2OC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(CC)cc3Cl)cc2OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To the mixture of 0.3g (0.59 mmol, 1.0 eqv) of ethyl 6-chloro-7-(2-chloro-4-bromophenoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 0.32 g (2.3 mmol) of potassium carbonate, 68 mg (0.059 mmol ) of tetrakistriphenyl-phosphinepalladium (0), and 2.5 mL of anhydrous DMF under nitrogen was added 0.83 mL (0.83 mmol, 1.0 M in THF) of triethylborane. The mixture was heated to 110° C. and shaken for five hrs. LC-MS indicated that the reaction was completed. After cooling to room temperature, the reaction was added to 50 mL of ethyl acetate. The resulting organic phase was washed with brine three times, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:9 EtOAc/hexane to afford 0.23 g (84.7%) of a light yellow solid. The product was used directly in the next step.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1[C:11]([C:12]([C:24]([F:27])([F:26])[F:25])([C:20]([F:23])([F:22])[F:21])[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[C:8]([OH:28])[CH:7]=1.Cl>N1C=CC=CC=1>[S:2]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([C:11]2[CH:10]=[CH:9][C:8]([O:28][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:6]=2)([C:24]([F:25])([F:26])[F:27])[C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=1)([CH3:1])(=[O:4])=[O:3]
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(C(c2ccc(OS(C)(=O)=O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 82 %

Procedure:
11.8 g (0.1 mol) of methanesulfonyl chloride are added dropwise, at a reaction temperature of 0-5° C., to a solution of 16.8 g (0.05 mol) of bisphenol AF in 100 ml of pyridine. Stirring is then continued for a further hour at 5° C. and overnight at room temperature. The reaction mixture is then acidified with sufficient half-concentrated hydrochloric acid to precipitate the product. Filtering off with suction and washing with water gives 24 g of crude product, and recrystallization from toluene gives 20.2 g (82% yield) of 2,2-bis-(4-mesyloxyphenyl)-hexafluoropropane are isolated. M.p 136-138° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][CH2:29][CH:30]2[O:32][CH2:31]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:33]([CH2:31][CH:30]([OH:32])[CH2:29][S:28][CH2:27][C@@H:11]1[CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC2CO2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(O)CN=[N+]=[N-])N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
A solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-[(2,3-epoxypropyl)thiomethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.59 g), sodium azide (0.52 g) and ammonium chloride (0.43 g) in N,N-dimethylformamide (26 ml) was stirred at 80°-90° C. for 2 hours. The reaction mixture was poured into ice-water (100 ml) and extracted 3 times with ethyl acetate (40 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of n-hexane and ethyl acetate (3:1 v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-[(3-azido-2-hydroxypropyl)thiomethyl]-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.95 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.C(OCC)(=O)C>C(N(CC)CC)C>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH:10]1[NH:9][C:5](=[O:7])[CH3:6]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Acetic anhydride (3.55 ml) was dropped to the mixture of 6.37 g 2-amino indane hydrochloride, 60 ml of ethyl acetate and 10.4 ml triethylamine and the reaction mixture was stirred at room temperature for 15 hours. The solvents were evaporated in vacuo and the solid residue was digested with water, filtered and dried at 40° C. in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[N:7][NH:8][C:9]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([Cl:21])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][NH:8][C:9]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([Cl:21])=[CH:15][CH:14]=3)=[O:10])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C=NNC(=O)c2[nH]c3ccc(Cl)cc3c2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(CNNC(=O)c2[nH]c3ccc(Cl)cc3c2C)cc1
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 5-chloro-3-methyl-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide (7 mg, 0.022 mmol) in a mixture of methanol (8.5 mL) and water (1.5 mL) at 50° C. was added sodium borohydride (1.62 mg, 0.044 mmol). It was stirred for 4 h and the solution was evaporated. The residue was purified by column chromatography (silica gel, EtOAc/Hexane=4:1) to give 4 mg (56%) of the title compound. 1H NMR (CD3OD): 7.42 (s, 1H), 7.22−7.19 (m, 3H), 7.07−7.03 (m, 3H), (bs, 1H), 3.91 (s, 2H), 2.27 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:20])[C:18](Cl)=[C:13]3[CH:12]=[C:11]2[I:21])(=O)=O)C=CC=CC=1.BrC1C(Cl)=C2C=C(I)N(S(C3C=CC=CC=3I)(=O)=O)C2=[N:27]C=1.FC(F)(F)C(O)=O.[NH:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[N:52]1>C(O)C(F)(F)F.CO.C(=O)(O)[O-].[Na+]>[Br:20][C:17]1[C:18]([NH:27][C:56]2[CH:55]=[C:54]3[C:59](=[CH:58][CH:57]=2)[NH:51][N:52]=[CH:53]3)=[C:13]2[CH:12]=[C:11]([I:21])[NH:10][C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(c1ccccc1I)n1c(I)cc2c(Cl)c(Br)cnc21
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)c(Br)cnc21
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnc2[nH]c(I)cc2c1Nc1ccc2[nH]ncc2c1
Temperature: 120 °C

Procedure:
To a slurry of a mixture of 1-benzenesulfonyl-5-bromo-4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridine and 5-bromo-4-chloro-2-iodo-1-(2-iodobenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (560 mg, 1.0 mmol) in trifluoroethanol (6 mL) was added trifluoroacetic acid (0.041 mL, 0.52 mmol) and indazole (266 mg, 2.0 mmol), and the reaction was heated in a sealed tube at 120° C. for 4 d. Additional indazole (67 mg, 0.5 mmol) was added twice to the reaction on the second and third days. The reaction was cooled to RT, diluted with methanol (20 mL), saturated sodium bicarbonate solution was added (1 mL) and evaporated to dryness under reduced pressure. The residue obtained was triturated with methanol:DCM (1:1) mixture and filtered. The filtrate was evaporated and the crude obtained was purified by chromatography on silica gel [Jones Flashmaster, 70 g/150 mL cartridge, eluting with DCM:Methanol 100:0→96:4], yielding the product, which was triturated with 4:1 methanol:DCM mixture and filtered. The precipitate obtained was dried under vacuum to afford the title compound as an off-white solid. The low polar fractions from the column were combined, evaporated and the residue was stirred with 3N NaOH in methanol (2 mL) for 30 min and quenched with saturated ammonium chloride solution (2 mL). Water (10 mL) was added and filtered to afford additional title compound. MS (ES+): m/z 453.63 (100) [MH+]; HPLC: tR=2.58 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].FN1C=C[CH:19]=[CH:18][CH:17]1[Cl:22].[CH3:23][N:24]([CH3:27])C=O>O>[Cl:22][C:17]1[C:23]([N:4]2[CH:5]=[C:6]([CH:7]=[O:8])[C:2]([CH3:1])=[N:3]2)=[N:24][CH:27]=[CH:19][CH:18]=1
Reactant: CN(C)C=O
Reactant: Cc1n[nH]cc1C=O
Reactant: FN1C=CC=CC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nn(-c2ncccc2Cl)cc1C=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 3-methyl-pyrazole-4-carbaldehyde (0.5 g, 4.5 mmol) in dry dimethylformamide (15 mL) is added potassium carbonate (2.5 g, 18 mmol,) at room temperature. The reaction mixture is stirred at 40° C. for 30 min and then 1-fluoro-2-chloropyridine (0.77 g, 6 mmol,) is added. The reaction mixture is heated at 70° C. for 16 h. After completion, the reaction mixture is cooled to room temperature, diluted with water and then extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduce pressure. The crude mixture is purified by chromatography on silica gel eluting with hexane/ethyl acetate (75:25, 65:35) to yield 0.525 g (52%) of the title compound. MS (m/z): 222 (M+1).
Reaction SMILES: C(O[CH:5]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[NH:7][C:6]1=[O:22])(=O)C.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K].[I-].[Na+]>CN(C)C=O>[CH:9]1([C:10]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:7][C:6](=[O:22])[CH:5]([N:27]3[C:26](=[O:28])[C:25]4=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]4[C:23]3=[O:33])[N:11]=2)[CH2:8][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(=O)OC1N=C(C2CCCCC2)c2ccccc2NC1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C(C2CCCCC2)=NC1N1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Yield: 69.8 %

Procedure:
To a solution of (3RS)-3-acetoxy-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (2.00 g) in N,N-dimethylformamide (15 ml) was added potassium phthalimide (1.85 g) under stirring and heated at 60° C. To the mixture was added sodium iodide (12.64 g) and stirred for 3 hours at 100° C. The hot resultant mixture was poured into ice-water to give a crude product. The precipitated crude product was collected by filtration. Dryness under the reduced pressure at 40° C. gave (3RS)-5-cyclohexyl-2,3-dihydro-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.80 g) as an yellow powder, which was used in a following reaction step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][C:4]=2[N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:38]([O:40][C:41](=[O:77])[CH2:42][CH2:43][CH2:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][C:59]2[CH:64]=[C:63]([S:65]([CH3:68])(=[O:67])=[O:66])[CH:62]=[C:61](I)[CH:60]=2)[C:47]=1[CH2:70][CH2:71][C:72]([O:74][CH2:75][CH3:76])=[O:73])[CH3:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[CH2:38]([O:40][C:41](=[O:77])[CH2:42][CH2:43][CH2:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][C:59]2[CH:64]=[C:63]([S:65]([CH3:68])(=[O:67])=[O:66])[CH:62]=[C:61]([C:8]3[CH:7]=[CH:6][C:5]4[S:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[CH:60]=2)[C:47]=1[CH2:70][CH2:71][C:72]([O:74][CH2:75][CH3:76])=[O:73])[CH3:39]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4scnc4c3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 100 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a mixture of benzothiazole-5-ylboronic acid pinacol ester (151.5 mg, 0.58 mmol), palladium acetate(II) (6.6 mg, 0.029 mmol), and triphenylphosphine (15.4 mg, 0.058 mmol) in dioxane (5 mL) were added 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (200 mg, 0.29 mmol), potassium phosphate (126.9 mg, 0.58 mmol), and water (10 mg) at room temperature under nitrogen atmosphere. Then, the brown reaction mixture was heated to 100° C. and stirred for 2 h at which time the TLC of the reaction mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with water (50 mL) and ethyl acetate (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic extracts were washed with water (100 mL) and brine solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent under reduced pressure gave the colored residue which was purified by using an ISCO 40 g column, eluting with 2-25% ethyl acetate in hexanes to afford 4-[3-[6-(3-benzothiazol-5-yl-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (110 mg, 54.4%) as a light brown solid: ES(+)-HRMS m/e calcd for C37H45NO8S2 (M+H)+ 696.2660, found 696.2658.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Na].[CH3:10][SH:11].O>C(O)C>[CH3:10][S:11][C:2]1([Cl:1])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: O=C1CCCCC1Cl
Reactant: CS
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CSC1(Cl)CCCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
In a 300-ml egg-plant type flask 7.07 g (0.053 mol) of 2-chlorocyclohexanone was dissolved in 50 ml of ethanol, and 25 ml of 15 % aqueous solution of sodium salt of methylmercaptan was added dropwise with a dropping funnel, and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into 300 ml of water, and an organic layer was extracted with methylene chloride, dried with magnesium sulfate and distilled to remove methylene chloride. After that reduced pressure distillation was performed to obtain 6.0 g of methylmercapto-2-chlorocyclohexanone (78 % yield; b.p. 46.5° -47.5° C./0.3 mmHg).
Reaction SMILES: [O:1]1CCCC1.O1CCOCC1.CC(C)=[CH:14][CH:15]1[CH:17]([C:18]([O:20][CH2:21][C:22]2[C:27]([F:28])=[C:26]([F:29])[C:25]([CH2:30][O:31][CH3:32])=[C:24]([F:33])[C:23]=2[F:34])=[O:19])[C:16]1([CH3:36])[CH3:35].I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH:14]([CH:15]1[CH:17]([C:18]([O:20][CH2:21][C:22]2[C:23]([F:34])=[C:24]([F:33])[C:25]([CH2:30][O:31][CH3:32])=[C:26]([F:29])[C:27]=2[F:28])=[O:19])[C:16]1([CH3:36])[CH3:35])=[O:1]
Reactant: C1CCOC1
Reactant: COCc1c(F)c(F)c(COC(=O)C2C(C=C(C)C)C2(C)C)c(F)c1F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1c(F)c(F)c(COC(=O)C2C(C=O)C2(C)C)c(F)c1F

Procedure:
To a mixture of 25 ml of tetrahydrofuran and 150 ml of 1,4-dioxane, 15.4 g of 4-methoxymethy-2,3,5,6-tetrafluorobenzyl 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (prepared by the method described above) were dissolved and 1.0 g of osmium tetraoxide was added thereto at room temperature. Further, 50 ml of water containing 24.0 g of sodium metaperiodate were added thereto and refluxed for 2 hours under heating. After that, the reaction mixture was poured into about 200 ml of water and extracted with 200 ml of ethyl acetate twice. The combined organic layer was washed with 1% aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, subsequently, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give 10.4 g of 4-methoxymethy-2,3,5,6-tetrafluorobenzyl 3-formyl-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=[O:13].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C(#N)C>[N+:15]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:2][CH2:3][CH2:4][OH:5])=[CH:14][C:11]=1[CH:12]=[O:13])([O-:17])=[O:16]
Reactant: OCCCBr
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=Cc1cc(OCCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.7 %

Procedure:
3-Bromo-1-propanol (3.34 g, 24 mmol) was refluxed in 80 ml of anhydrous acetonitrile with 5-hydroxy-2-nitrobenzaldehyde (3.34 g, 20 mmol), K2CO3 (3.5 g), and Kl (100 mg) overnight (15 h). The reaction mixture was cooled to room temperature and 150 ml of methylene chloride was added. The mixture was filtered and the solid residue was washed with methylene chloride. The combined organic solution was evaporated to dryness and redissolved in 100 ml methylene chloride. The resulted solution was washed with saturated NaCl solution and dried over sodium sulfate. 4.31 g (96%) of desired product was obtained after removal of the solvent in vacuo.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([O:16][CH2:17][CH3:18])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])(OCC)=O.Cl>CCOCC.C(#N)C.O>[CH2:17]([O:16][C:9]1[CH:8]=[C:7]([CH:2]([N:1]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH3:15])[CH3:18]
Reactant: CCOc1ccc(C(N)CC(=O)O)cc1OCC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: CCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OCC
Reaction time: 1 h
Yield: 124.3 %

Procedure:
To a stirred solution of 3-amino-3-(3',4'-diethoxyphenyl)propionic acid (1.03 g, 4.07 mmol) and sodium carbonate (0.453 g, 4.27 mmol) in a 1/1 mixture of 150 mL of acetonitrile/water (heated to 45 C to dissolve) was added N-carbethoxyphthalimide (0.89 g, 4.07 mmol). The reaction mixture was stirred 1 h, then partially concentrated in vacuo to remove the acetonitrile to afford a pale yellow solution. The stirred solution was acidified to pH 0-1 with 4N hydrochloric acid to form a gum. The mixture was stirred overnight. The gum had not solidified, 1 mL of ether was added to mixture. The gum solidified on stirring, the slurry was filtered and the solid dried to afford 1.94 g (94%) of 3-(3',4'-diethoxyphenyl)-3-phthalimidopropionic acid as a yellow solid: 1H NMR (DMSO-d6, 250 MHz) 12.41 (br s, 1 H, COOH), 8.10-7.75 (m, 4 H, Ar), 7.15-6.85 (m, 3 H, Ar), 5.62 (overlapping dd, 1 H), 4.20-3.90 (m, 4 H, 2 OCH2), 3.51 (dd, 1 H, J=16.5, 9 Hz), 3.25 (dd, 1 H, J=16.5, 7 Hz), 1.5-0.9 (m, 6 H, 2 CH3) 13C NMR (DMSO-d6) 1717, 167.6, 147.9, 147.8, 134.6, 131.3, 131.0, 123.1, 119.4, 113.2, 112.7, 63.8, 63.7, 50.0, 36.0, 14.6, 14.6; Anal. Calcd for C21H21NO6 : Theory C, 65.79; H, 5.52; N, 3.65. Found: C, 65.54; H, 5.55; N, 3.62.