Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]#[C:11][CH2:12][NH:13][C:14](=[NH:16])[CH3:15])=O)CCC.Cl.O1CCOCC1>>[NH2:8][CH2:9][C:10]#[C:11][CH2:12][NH:13][C:14](=[NH:16])[CH3:15]
Reactant: CCCCOC(=O)NCC#CCNC(C)=N
Agent: Cl
Solvent: C1COCCO1
Product: CC(=N)NCC#CCN
Reaction time: 1 h

Procedure:
1-Butoxycarbonylamino-4-(1-iminoethylamino)but-2-yne (0.332 g) was deprotected by treatment with 4 N HCl/dioxane (3 ml) at 0° C. and stirring at 0° C. for 1h then at room temperature for 1h. After this time the mother liquor was decanted off and the sticky residue subjected to an oil pump vacuum to remove residual solvent. The resulting material was triturated with dry diethyl ether (×2), filtered off and washed with more dry diethyl ether. The yellow solid was finally dried in a drying pistol to yield 1-amino-4-(1-iminoethylamino)but-2-yne 2.5hydrochloride (0.184 g), Mpt 182°-185° C.(dec), FAB M.S. M+1+126.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C(=O)([O-])O.[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:17]([O:16][C:12](=[O:15])/[CH:13]=[CH:14]/[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1cccc(CC(=O)O)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of m-bromophenylacetic acid (4.0 g, 18.6 mmol), t-butyl acrylate (4.85 g, 37.8 mmol), triethylamine (3.8 g, 37.6 mmol), tri-o-tolylphosphine (310 mg, 1.02 mmol) and palladium acetate (130 mg, 0.580 mmol) in N,N-dimethylformamide (50 ml) was stirred for 4 hours at 50° C. and then 10 hours at 90° C. The reaction mixture was diluted with an aqueous sodium hydrogencarbonate solution and washed with ethyl acetate. The aqueous layer was acidified (about pH 3) and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the crude subject compound (5.50 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:55])[CH2:7][O:6][C:5]([CH2:14][S:15][C@@H:16]([C:41](=[O:54])N2[C@@H](C3C=CC=CC=3)COC2=O)[C@H:17]([C:26]2[CH:40]=[CH:39][C:29]([O:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:27]=2)[NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:55][C:2]1([CH3:1])[CH2:7][O:6][C:5]([CH2:14][S:15][C@H:16]2[C:41](=[O:54])[N:18]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C@@H:17]2[C:26]2[CH:40]=[CH:39][C:29]([O:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:27]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:4][CH2:3]1
Reactant: CC1(C)COC(CS[C@@H](C(=O)N2C(=O)OC[C@@H]2c2ccccc2)[C@@H](Nc2ccc(F)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccccc2)OC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC1(C)COC(CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccccc2)OC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-Butyl (4-{(1S,2R)-2-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl)methyl]thio}-1-[(4-fluorophenyl)amino]-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate (2.6 g, 3.4 mmol) was dissolved in dry toluene (250 ml) and heated to 90° C. under inert atmosphere. N,O-Bis(trimethylsilyl)acetamide (BSA, 2.5 ml, 10.3 mmol) was added and the mixture was stirred at 90° C. for one hour. The mixture was cooled to 45° C. and tetrabutylammonium fluoride (TBAF, cat., 0.5 g) was added. The mixture was stirred at 45° C. for two hours. The mixture was concentrated under reduced pressure and purified by flash-chromatography (hexane:EtOAc 7:1). This afforded 0.65 g (31%) of the title compound as a yellow solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.2 (s, 3H), 1.5 (s, 9H), 2.9-3.1 (q, broad, 2H), 3.4 (q, 4H), 4.0 (s, 1H), 4.5 (s, 2H), 4.8 (s, 1H), 6.9-7.0 (m, 4H), 7.2-7.3 (m, 5H), 4.3-4.4 (m, 4H).
Reaction SMILES: [CH2:1]([S:4]([C@:7]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]1)(=[O:6])=[O:5])[CH:2]=[CH2:3]>[Pd].CO>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:31][C:26]([C@@:7]2([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:27][CH:28]=1
Reactant: C=CCS(=O)(=O)[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCCS(=O)(=O)[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a vessel containing (2S,4R)-1-benzyl 2-methyl 4-(allylsulfonyl)-4-(biphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (1.90 g, 3.66 mmol) and MeOH (100 mL) was added palladium/C (0.195 g, 0.183 mmol). The vessel was placed on Parr shaker under hydrogen with 25 psi pressure for 4 h. Quenched with CELITE®. Filtered, evaporated to afford the desired product (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-(propylsulfonyl)pyrrolidine-1,2-dicarboxylate (1.77 g, 3.39 mmol, 93% yield) as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 0.85-1.06 (m, 3 H) 1.64 (dt, J=14.87, 7.50 Hz, 2 H) 2.71-2.82 (m, 1 H) 3.01 (dt, J=13.05, 9.16 Hz, 1 H) 3.25-3.41 (m, 1 H) 3.60-3.84 (m, 3 H) 4.16-4.35 (m, 2 H) 4.69 (dd, J=11.42, 6.65 Hz, 1 H) 4.91-5.28 (m, 2 H) 7.14-7.43 (m, 6 H) 7.44-7.53 (m, 2 H) 7.63-7.88 (m, 6 H). LC-MS (retention time: 1.75 min, method A), MS m/z 522 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:15])=[O:4].CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50]Cl)=[CH:46][N:45]=1>O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH2:50][C:47]1[CH:46]=[N:45][C:44]([Cl:43])=[CH:49][CH:48]=1)=[O:4]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: ClCc1ccc(Cl)nc1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COC(=O)c1ccc2ccccc2c1OCc1ccc(Cl)nc1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a solution of 1.0 g 1-hydroxy-2-naphthoic acid methyl ester in 20 ml abs. DMF 3.22 g cesium carbonate was added, followed by addition of 0.16 g potassium iodide and 0.96 g 2-chloro-5-chloromethyl-pyridine. Under argon-atmosphere the reaction mixture was heated to 60° C. for 1 h. The mixture was then poured into water and extracted with ethyl acetate at pH9 three times. The combined organic layers were dried over magnesium sulphate, filtrated and after removal of the solvent a crude product was obtained which was recrystallized from diethyl ether to yield 1.62 g 1-(6-chloro-pyridin-3-ylmethoxy)-naphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: C(Br)C.[Mg].Cl[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[NH4+]>[Ni](Cl)Cl.C1COCC1>[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][CH:8]=1)[CH:13]=[C:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)=CCc1ccc(Cl)cc1
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(CC=C(C)C)cc1
Reaction time: 4 h
Yield: 49 %

Procedure:
Under a nitrogen atmosphere, 0.3 ml of ethyl bromide was added to a mixture of 0.97 g of magnesium turning for Grignard reaction and 2 ml of THF. After the starting of the reaction, a solution composed of 6.01 g of p-chloroprenylbenzene and 1 ml of THF was added dropwise while maintaining the temperature at 115° to 130° C. After the addition, THF was added further as required, and the mixture was stirred at 110° to 120° C. for 4 hours. After cooling, 20 ml of THF was further added, and the resulting reaction mixture was added dropwise to a solution composed of 5.43 g of ethyl α-bromopropionate, 0.016 g of nickel chloride and 5 ml of THF. After the addition, the mixture was further stirred for 1 hour, and an aqueous solution of ammonium chloride was added. The mixture was extracted with diethyl ether. The ethereal extract was washed with an aqueous solution of sodium chloride, dried, concentrated and distilled to give 3.62 g (yield 49.1%) of ethyl α-(p-prenylphenyl)propionate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[C:3]=1[CH2:10][OH:11].N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].O>O1CCCC1>[Si:21]([O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:10][OH:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cccc(CO)c1CO
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
A solution of 3-methyl-1,2-benzenedimethanol (4.16 g, 27.3 mmol) obtained from Example 22-(1) in tetrahydrofuran (50 ml) was cooled to 0° C., and imidazole (1.86 g, 27.3 mmol) and tert-butylchlorodimethylsilane (4.12 g, 27.3 mmol) were added thereto. The mixture was stirred at room temperature for 3 hours, and then after adding water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, then the solvent was distilled off under reduced pressure, and the residue was subjected to chromatography on a silica gel (120 g) column (eluent; ethyl acetate:hexane=1:4) to afford the title compound (4.93 g, 68% yield) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:26])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24]O)[CH:18]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[H][H]>C(O)C.C(Cl)(Cl)Cl.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:26])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=2)[CH3:13])=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(O)c(C)c2)cc1

Procedure:
N-(2-[4-Carbomethoxyphenyl]-1-methylethyl)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine (3.0 g) was hydrogenated in a mixture of ethanol (200 ml) and chloroform (20 ml) at 1 atmosphere and room temperature in the presence of 5% palladium on charcoal (150 mg) until hydrogen uptake was complete. The catalysts was removed and the product was recrystallised as the hydrochloride from ethyl acetate as a 32.5:67.5 mixture of diastereoisomers, mp 103°-107° (2.0 g). τ(d6DMSO) 8.88 (3H, d, J=6 Hz), 7.90 (3H, s), 6.10-7.20 (7H, m), 6.20 (3H, s), 5.02 (1H, m), 2.70-3.30 (3H, m), 2.62 (2H, d, J=8 Hz), 2.10 (2H, d, J=8 Hz), 0.62 (1H, br).
Reaction SMILES: P(Br)(Br)[Br:2].C(Cl)Cl.[F:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[CH:17](O)[CH3:18]>O>[Br:2][CH:17]([C:10]1[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=1[F:8])[CH3:18]
Reactant: CC(O)c1cc(F)c(F)cc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(Br)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Phosphorus tribromide (0.275 mL) and anhydrous methylene chloride (12 mL) were combined and the solution cooled over ice water for 15 minutes. The solution was added to a mixture of 1-(2,4,5-trifluorophenyl)ethanol (0.506 g) and methylene chloride (8 mL), and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was then poured into H2O and extracted into methylene chloride. The organic phase was isolated, dried with magnesium sulfate, filtered and concentrated (without heat) to give the title compound. 1H-NMR (CD3OD, 400 MHz) δ 2.00 (3H, d, J=7.1 Hz), 5.37 (1H, m), 6.92 (1H, m), 7.36 (1H, m).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[N:31]1([CH2:38][CH2:39][OH:40])[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][N:34]3[CH2:35][CH2:36][CH2:37][N:31]([CH2:38][CH2:39][OH:40])[CH2:32][CH2:33]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: OCCN1CCCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(CCO)CC3)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and 2-(1,4-diazepan-1-yl)ethanol.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CC(C)CN
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC(C)C)O2
Yield: 75 %

Procedure:
Following the amide coupling procedure described in protocol A, 510 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.04 mmol), 357 mg CDI (2.20 mmol) and 161 mg isobutylamine (2.2 mmol) produced 467 mg of 6-hydroxy-N-isobutyl-2,5,7,8-tetramethylchroman-2-carboxamide as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:16])[CH3:15])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:16])[CH3:15])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(N)ccc1C(=O)O

Procedure:
A reaction mixture prepared by dissolving 575 mg of 4-nitro-N-acetyl-anthranilic acid in 200 ml of ethyl acetate and by mixing the resultant solution with 100 mg of a 10% Pd-C catalyst was stirred at room temperature in a hydrogen gas atmosphere for 4 hours. Then, the reaction mixture was filtered through a Celite filter to remove the catalyst, and the catalyst was washed with ethyl acetate. The total amount of the filtrate was collected and concentrated under a reduced a silica gel column chromatography. A final product consisting of 4-amino-N-acetyl-anthranilic acid was obtained in an amount of 450 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:22][C@H:21]1[C:31]([O:33]CC1C=CC=CC=1)=[O:32])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[N:24]=[C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[S:22][C@H:21]1[C:31]([OH:33])=[O:32])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
A solution of the product from step (c) (0.26g) in ethanol (20ml) was treated with 10% palladium on charcoal (0.lg) and stirred in a pressure vessel under hydrogen at 3 atmospheres at room temperature for 3 days. The catalyst was filtered off and the filtrate evaporated. The residue was triturated with ether to give the title product (0.08g) as a white solid, m.p. 180.5°-182°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][N+:28]([O-:39])=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccncc4)CC3)n2)cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4cc[n+]([O-])cc4)CC3)n2)cc1OC
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a dichloromethane (10 ml) solution of 353 mg of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(pyridin-4-yl)piperazine was added 195 mg of m-chloroperbenzoic acid, followed by 1 hour of stirring at 50C. An aqueous sodium thiosulfate solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and then recrystallization (ethanol-ethyl acetate) was carried out to obtain 294 mg of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(1-oxidopyridin-4-yl) piperazine 1.5 hydrate as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[NH:13]1[C:17](B(O)O)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C.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>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:17]2[NH:13][N:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: OB(O)c1ccn[nH]1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1sc(-c2ccn[nH]2)nc1C
Temperature: 100 °C
Yield: 79.1 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (2.0 g, 7.99 mmol) in toluene (60 mL), water (20 mL) and ethanol (20 mL) was added 1H-pyrazole-5-boronic acid (1.79 g, 15.99 mmol), Pd(PPh3)4 (0.92 g, 0.80 mmol), and potassium carbonate (3.30 g, 23.98 mmol). The resulting mixture was degassed three times and heated to 100° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (hexanes-ethyl acetate, 1:1) to provide 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid ethyl ester as a yellow solid (1.5 g, 83% yield). MS (M+H)+=238; Rt=1.2 min.
Reaction SMILES: C(Br)(Br)(Br)Br.[C:6]1([S:12]([CH2:15][C:16]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20](O)[C:19]([C:27]3[CH:31]=[CH:30][O:29][C:28]=3[CH2:32][OH:33])=[CH:18][CH:17]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:6]1([S:12]([CH2:15][C:16]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:19]([C:27]4[CH:31]=[CH:30][O:29][C:28]=4[CH2:32][O:33]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2CO)c1O
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc2c1OCc1occc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
Carbon tetrabromide (0.116 g) was added to a solution of methyl 6-(benzenesulfonylmethyl)-2-hydroxy-3-(2-hydroxymethylfuran-3-yl)-benzoate (Intermediate 19, 0.1 g) and triphenyl phosphine (0.09 g) in DCM (3 mL) and the resultant solution was stirred at room temperature for 2 hours. The mixture was evaporated to dryness and the residue was dissolved in DMF (2 mL) and cesium carbonate (0.163 g) was added. The mixture was stirred for 1 hour at room temperature, then at 50° C. for 15 minutes. After cooling, the mixture was partitioned between ethyl acetate and water, the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (25%) to give methyl 7-(benzenesulfonylmethyl)-4H-furo[2,3-c]chromene-6-carboxylate (0.019 g).
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(OCC=C)(=O)=O)=C[CH:2]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18]>O>[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH:18][CH2:6][CH:1]=[CH2:2]
Reactant: C=CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cccc(C)c1N
Solvent: O
Product: C=CCNc1c(C)cccc1C

Procedure:
Allyl p-toluenesulphonate (10.6 g, 0.05 mole) was heated with 2,6-dimethylaniline (6.0 g, 0.05 mole) in a steam bath for 2 hours, poured into water (100 ml), extracted into methylenedichloride (50 ml), dried (MgSO4), filtered, solvent evaporated and the product distilled to give 2,6-dimethylphenyl allylamine, identical with that in Route II. Subsequent steps were the same as for Route II.
Reaction SMILES: C(Cl)Cl.C[O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=1.C[Si](C)(C)[O-].[K+]>C(OCC)(=O)C>[CH3:26][Si:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][O:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([OH:30])=[O:5])=[O:29])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(OCOCC[Si](C)(C)C)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCOc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Dry DCM (25 mL) was added to 2-[4-(2-trimethylsilanylethoxymethoxy)benzoyl]-benzoic acid methyl ester (3.8 g, 9.8 mmol) followed by potassium trimethylsilanolate (1.53 g, 10.8 mmol). The system was stirred at room temperature under nitrogen for 16 h and monitored by TLC. Removal of the solvent gave a light yellow oil that was taken up into ethyl acetate (100 mL), washed with 5% HCl solution (3×30 mL), brine (30 mL) and dried with MgSO4. The solvent was removed to give 2-[4-(2-trimethylsilanylethoxymethoxy)benzoyl]benzoic acid as a yellow oil (3.66 g, 9.8 mmol, 99%); Rf 0.1 (40:60 EtOAc:petrol). λmax (CH3OH)/nm 276, 217, Abs 1.799, 2.108 respectively. IR: 3215, 3177, 1666, 1593 cm−1. 1H NMR: (300 MHz, CDCl3) δ 0.00 (s, 9H, Si—(CH3)3), 0.96 (m, 2H, R—O—CH2—CH2—Si), 3.76 (m, 2H, O—CH2—CH2—Si), 5.27 (s, 2H, O—CH2—O), 7.04 (m, 2H, Ar—H), 7.34 (m, 1H, Ar—H), 7.52-7.68 (dtd, 2H, J=30.2, 7.6, 1.3 Hz, Ar—H), 7.69 (m, 2H, Ar—H), 8.07 (m, 1H, Ar—H), 10.31 (bs, 1H, COOH). 13C NMR: (75 MHz, CDCl3) δ −3.2, 16.1, 64.8, 90.7, 113.8, 125.7, 126, 127.4, 128.8, 129.1, 129.9, 131.2, 140.9, 159.6, 168.8, 194. LC/MS-ES+ m/z 297.1, 373.1 [MH+]. HRMS (EI) m/z Calcd. for C20H24O5Si: 372.1393. Found 372.1387