Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH:23](B(O)O)=[CH2:24].C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.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:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH:23]=[CH2:24])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C=CB(O)O
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: O
Solvent: C1COCCO1
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 100 °C
Yield: 37 %

Procedure:
A suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (6.8 g, 20 mmol), vinyl boronic acid [CAS-No. 4363-34-2] {Bull. Soc. Chim. Fr. 1966, (8), 2557-64} (4.312 g, 60 mmol) and K2CO3 (8.29 g, 60 mmol) in water (10 mL) and dioxane (50 mL) was purged by Ar-stream at 23° C. for 10 min, then tetrakis(triphenylphosphine)palladium(0) (693 mg, 0.6 mmol) was added and the mixture was heated to 100° C. for 20 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1) to yield a light yellow solid (2.476 g, 37%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[S:12][CH:11]=[N:10][CH:9]=1.[OH:13][C:14]([CH3:47])([CH3:46])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1>CN(C)C=O>[OH:13][C:14]([CH3:46])([CH3:47])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:26]=[CH:27][C:28]([C:8]3[S:12][CH:11]=[N:10][CH:9]=3)=[CH:29][CH:30]=2)[CH3:24])[CH2:18][CH2:17]1
Reactant: Brc1cncs1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2cncs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2 M aqueous Na2CO3 solution (0.63 mL) was added to a solution of 5-bromo-thiazole (70 μL) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.30 g) in dimethylformamide (3 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (15 mg) was added. The mixture was heated to 90° C. and stirred at this temperature for 2 h. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 50:50->0:100) to afford the title compound as a solid. Yield: 0.19 g (70% of theory); Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(C(C)=O)c1

Procedure:
1.0 eq. of methyl 3-acetyl-4-hydroxybenzoate was reacted with 1.1 eq. each of K2CO3 and benzyl bromide in absolute DMF to form methyl 3-acetyl-4-benzyloxybenzoate. Colorless crystals, mp 68°-72° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13].[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]#[N:31])=[N:24][NH:25][CH:26]=2)=[CH:18][CH:17]=1>CN(C=O)C>[N:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]#[N:31])=[N:24][N:25]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:26]=2)=[CH:20][CH:21]=1
Reactant: N#Cc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c(-c2cccc(C#N)c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
Cesium carbonate (8.34 g, 25.6 mmol) and (2-chloromethoxy-ethyl)-trimethyl-silane (1.71 g, 10.24 mmol) were added to a solution of 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzonitrile (2.10 g, 8.54 mmol) in dry DMF (70 ml) and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 24 h. A further addition of (2-chloromethoxy-ethyl)-trimethyl-silane (0.57 g, 3.41 mmol) was required to affect reaction completion; the solvent was then removed under reduced pressure and the residue was taken up with DCM (50 ml). The organic layer was washed with a saturated NaHCO3 solution (1×50 ml), brine (1×50 ml), dried over Na2SO4. The filtrate was evaporated to dryness to give a brown oil, which was purified by flash chromatography, over silica gel, using DCM/MeOH/NH4OH (9.8:0.2:0.1) as eluent, to afford 3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzonitrile (2.57 g, 6.82 mmol, 80%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]2[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:33]([NH:36]C(C)(C)C)(=[O:35])=[O:34])=[CH:23][CH:22]=3)[C:15]([CH2:17][CH2:18][CH3:19])=[N:16][C:3]=12>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]2[N:14]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:33]([NH2:36])(=[O:35])=[O:34])=[CH:25][CH:26]=3)[C:15]([CH2:17][CH2:18][CH3:19])=[N:16][C:3]=12
Reactant: CCCC(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c1C
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C

Procedure:
A solution of 7-methyl-2-propyl-3-[2'-(N-tert-butylaminosulfonyl)[1,1']-biphenyl-4-yl]methyl-6-[(1-oxobutyl)amino]-3H-imidazo[4,5-b]pyridine. (516 mg) in trifluoroacetic acid (30 mL) was stirred at r.t. for 12 h. The mixture was concentrated, dissolved in CH2Cl2 (100 mL) and washed with saturated aqueous Na2CO3. The organic extracts were dried (K2CO3) and concentrated to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[CH:23])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[O:9][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]=1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: Oc1ccc(Cl)nc1I
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2nc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.07 g (12.0 mmol) sample of 6-chloro-2-iodo-3-pyridinol, from step 11c above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), CuI (0.380 g, 1.98 mmol) and triethylanue (1.7 mL, 12 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1.95 g (10.0 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1a above, dissolved in 5 mL of DMF, was added carefully. The reaction mixture was stirred at 60° C. for 16 hours, cooled to room temperature, diluted with ether, washed with 50% brine and dried over MgSO4, then the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 1.54 g of title compound: 1H NMR (DMSO, 300 MHz, 130° C.) δ 1.37 (two s, 9H), 1.89-2.07 (m, 3H), 2.37 (m, 1H), 3.40-3.54 (m, 1H), 4.98 (m, 1H), 6.72 (s, 1H), 7.26-7.29 (d, 1H, J=8.6 Hz), 7.93-7.96 (d, 1H, J=8.6 Hz); MS m/z: 323 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH-:5][B:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[Li+].[CH2:15]([N:17]1[CH:21]=[CH:20][C:19]([SiH:23]([CH3:25])[CH3:24])(Cl)[B:18]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:16]>C1COCC1>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]([Si:23]([CH:19]2[CH:20]=[CH:21][N:17]([CH2:15][CH3:16])[B:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:24])[CH3:25])[B:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCN1C=C[CH-]B1c1ccccc1
Reactant: CCN1C=CC(Cl)([SiH](C)C)B1c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1C=CC([Si](C)(C)C2C=CN(CC)B2c2ccccc2)B1c1ccccc1

Procedure:
The title compound was prepared in the same manner as Example 3B) from lithium (1-ethyl-2-phenyl-1,2-azaborolide) (1C), 0.41 g, 2.31 mmol) in 15 mL of THF and 1-ethyl-3-chlorodimethylsilyl-2,3-dihydro-2-phenyl-1H-1,2-azaborole (Ex. 3A), 0.01 g, 2.31 mmol) in 15 mL of THF. The product was obtained as a yellow oil (0.85 g, 92 percent).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[OH:12][C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21](=O)[CH3:22].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:28][O:27][C:25]([CH2:24][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH:21]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:22])=[C:13]([OH:12])[CH:14]=1)=[O:26]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)c(O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(O)c1
Yield: 57.1 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.07 g of methyl 3-hydroxy-4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 34), 70 ml of dry benzene, 60 ml of absolute methanol and 1.7 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 2.62 g of the title compound were obtained as crystals, melting at 68° C.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C(O)C>[CH2:11]([S:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Nc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc(SCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a stirred solution of sodium hydroxide (2.1 g, 52.5 mmol) in water (4 ml) cooled in an ice bath, a solution of 3-aminothiophenol (4.8 g, 38.4 mmol) in ethanol (20 ml) was added drop wise, followed by the addition of solution of benzyl chloride (5 g, 39.5 mmol) in ethanol (5 ml). After the addition, the reaction mixture was stirred at room temperature for 4 hours and became a brown solution with white precipitate. After filtering off the precipitate, the filtrate was concentrated and residue was taken by dichloromethane (40 ml). The dichloromethane solution was washed with aqueous sodium hydroxide solution three times (0.5 M, 3×40 ml) and water once (40 ml). After dried over MgSO4 and filtered, dichloromethane solution was then concentrated in vacuo to afford thick yellow oil as crude product. It was further purified by flash chromatography (SiO2, hexanes/CH2Cl2, 0-100%) to afford 3-(benzylthio)aniline (6.77 g, 82%) as a pale yellow oil, which solidified into white solid after staying at room temperature. Thin layer chromatography: Dichloromethane, Rf=0.37; 1H-NMR (CDCl3) δ(ppm) 6.6-7.4 (m, 9H, Ar—H), 4.15 (s, 2H, S—CH2).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15](=[O:23])[CH2:16]P(=O)(OC)OC)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:25][C@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][C:34]2[S:38][C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:35]=2)[C@@H:29]([CH:43]=O)[C@H:28]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:27]1>C1COCC1>[Si:3]([O:10][C@H:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15](=[O:23])/[CH:16]=[CH:43]/[C@H:29]1[C@H:28]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:27][C@@H:26]([Cl:25])[C@@H:30]1[CH2:31][CH2:32][CH2:33][C:34]1[S:38][C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:35]=1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Reactant: COP(=O)(CC(=O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/C(=O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.9 %

Procedure:
To a suspension of 54 mg of sodium hydride (60% oil dispersion, 1.35 mmol) in 1 ml of THF at 0° C. was added a solution of dimethyl (6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-2-oxoheptylphosphonate 5 (552 mg, 1.57 mmol) in 1 mL THF. The mixture was stirred at 0° C. for 30 min before a solution of aldehyde 7 (460 mg, 1.1 mmol) in 1 ml of THF was added dropwise. The syringe containing the aldehyde was rinsed with 2 mL of THF to complete the addition and the mixture was stirred at 25° C. for 2.5 h. The reaction was worked up with addition of saturated aqueous ammonium chloride (50 mL) and the aqueous layer was extracted with ethyl acetate (2×75 mL). The ethyl acetate layers were combined and washed with brine, dried over 30 g of anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 920 mg of crude products. Flash chromatographic purification using a 24 g silica gel cartridge eluted with 10% EtOAc-hexanes yielded 430 mg (60%) of purified enone 8; 1H NMR (CDCl3): 0.05 (s, 6H), 0.88 (s, 9H), 1.12 (d, J=6.3 Hz, 3H), 1.37-1.80 (m, 14H), 2.00 (m, 1H), 2.20 (m, 1H), 2.34 (m, 1H), 2.53 (m, 1H), 2.54 (t, J=7.2 Hz, 2H), 2.83 (m, 2H), 3.45 (m, 1H), 3.80 (m, 2H), 3.86 (s, 3H), 4.02 (m, 1H), 4.17 (m, 1H), 4.57 (m, 1H), 6.15 (m, 1H), 6.77 (m, 1H), 7.62 (d, J=3.9 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=2[Cl:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:27][C:26]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[O:15][C:4]1[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=[C:2]([S:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2Nc2nc(C)cs2)c1
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Sc3ccccc3)cnc2Nc2nc(C)cs2)c1

Procedure:
Prepared according to the method of Example 13, using Ethyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)-4-chlorobenzoate and benzenethiol.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[CH3:13].II.[Br:22]Br.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([Br:22])=[CH:8][C:7]=1[CH3:13]
Reactant: Cc1ccc(C)c(OCCC(C)CCCC(C)C)c1
Reactant: BrBr
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCCC(C)CCCC(C)C)c(C)cc1Br
Temperature: 0 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Into a 300 ml four-necked flask was placed 31.68 g (0.12 mol) of 1-(3,7-dimethyloctyloxy)-2,5-dimethylbenzene and 10 ml of chloroform and 0.21 g (0.8 mmol) of iodine, and the flask was purged with nitrogen while stirring and the mixture was cooled to 0° C. Bromine in an amount of 19.18 g (0.12 mol) was added dropwise over 1 hour while keeping the temperature not more than 5° C. After addition, the mixture was heated to 30° C. and kept at the same temperature for 5 hours to complete the reaction. The mixture was cooled to room temperature, and the reaction mixture was added into 200 ml of a 5% sodium hydroxide aqueous solution. The mixture was stirred for 10 minutes, then, separated and extracted. The chloroform layer was washed with 200 ml of water, and the organic layer was dried over sodium sulfate. It was concentrated by an evaporator and the resulting residue was purified by column chromatography to obtain 1-(3,7-dimethyloctyloxy)-2,5-dimethyl-4-bromobenzene. The yield amount was 30 g (87.9 mmol) and the yield was 73%.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14]1([CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Mg]Br>>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][C:10]([OH:13])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:22])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1ccccc1[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: Cc1ccccc1C1(O)CCN(C(=O)OC(C)(C)C)C1

Procedure:
Prepared in analogy to Example A1 (a) from N-boc-3-pyrrolidinone and o-tolyl-magnesiumbromide to yield the title compound as an light yellow oil. MS (m/e): 278.2 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:39])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[C:10]([I:39])[N:11]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: CCOC(=O)c1ncc2snc(-c3ccc(F)cc3)c2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCOC(=O)c1nc(I)c2snc(-c3ccc(F)cc3)c2c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (400 mg, 1.25 mmol) in CH2Cl2 (12.5 mL) was added bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.29 g, 2.51 mmol). The reaction mixture was allowed to stir at r.t. for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the title product (382 mg) as a yellow solid: MS (m/z) 442.9 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=1[O:25][CH3:26])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH3:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46]([NH2:49])(=[O:48])=[O:47]>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:49][S:46]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH3:39])(=[O:47])=[O:48])=[O:22])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid (125.9 g) in tetrahydrofuran (3.0 l, distilled from sodium benzophenone ketyl) (prepared by heating at 50° C. until dissolution was complete, followed by cooling to room temperature with an ice-water bath) was added 4-dimethylaminopyridine (56.6 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (102.4 g), and the mixture was stirred one hour. To the mixture was added 2-methylbenzene-sulfonamide (67.1 g), and the reaction mixture was stirred about 3 days (for convenience). The reaction mixture was diluted with ethyl acetate (2.0 l) and washed with 1N hydrochloric acid (twice) and brine (3 times, until neutral), and the aqueous extracts were back washed with ethyl acetate. The combined ethyl acetate solution was dried (MgSO4), and partially evaporated to give a slurry of solid in ethyl acetate (about 0.5 l) which was refrigerated overnight. Collection of the solid afforded the crude product (158.5 g, 88%, essentially pure by TlC) as a light pink solid. Recrystallization by dissolution in hot tetrahydrofuran (1.5 l), filtration while hot, dilution with ethyl acetate (2.0 l), and boiling down to a final volume of about 2.5 l afforded a first crop of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (105.5 g, 59%) as a white solid; mp 211°-213° C.; NMR (250 MHz, DMSO-d6): 2.60 (s, 3H, ArCH3), 3.76 (s, 3H, NCH3), 3.82 (s, 3H, CO2CH3), 3.92 (s, 3H, ArOCH3), 4.04 (s, 2H, ArCH2Ar'), 7.15 (d, 1H), 7.22 (s, 1H), 7.38-7.58 (m, 6H), 7.75 (dd, 1H), 8.03 (dd, 1H), 8.17 (d, 1H). (Two additional crops (35.5 g, 20%) and crude product (39.5 g) from concentration of the mother liquors were also obtained.)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[CH2:39]1[O:47][C:46]2[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=2[O:40]1.C(=O)([O-])[O-].[K+].[K+]>CCO.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>[O:40]1[C:41]2[CH:42]=[CH:43][C:44]([C:2]3[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]4[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=4)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=3)=[CH:45][C:46]=2[O:47][CH2:39]1
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Reactant: OB(O)c1ccc2c(c1)OCO2
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: O
Solvent: CCO
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (100 mg, 0.17 mmol) in EtOH (4 mL)/H2O (1 mL) were added 3,4-methylenedioxyphenylboronic acid (58 mg, 0.35 mmol), potassium carbonate (100 mg, 0.7 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient. HRMS calcd for C36H39NO8 [M+H]+ 614.2749, observed 614.2748