Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH3:9])=[C:4]([CH2:10][O:11][CH3:12])[N:3]=1.Cl.N([O-])=[O:15].[Na+]>O>[OH:15][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH3:9])=[C:4]([CH2:10][O:11][CH3:12])[N:3]=1
Reactant: O=N[O-]
Reactant: COCc1nc(N)nc(O)c1C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COCc1nc(O)nc(O)c1C
Temperature: 70 °C
Yield: 55.1 %

Procedure:
2-amino-4-hydroxy-6-methoxymethyl-5-methylpyrimidine (2.7 g, 16 mmol) was added to 20% aqueous hydrochloric acid solution (7 ml), and heated to 70° C. A solution of sodium nitrite (2.3 g, 33.3 mmol) in water was added dropwise to a reaction mixture while maintaining the reaction temperature under 70° C. The reaction mixture was cooled to a room temperature. The resulting solid was filtered and dried to give 1.5 g of the titled compound.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[CH2:3][CH2:4][N:5]([CH3:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1>CO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:12])[C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[CH:14][CH:15]=1
Reactant: CN(CCN(C)c1ccc([N+](=O)[O-])cc1)c1ccncc1
Solvent: CO
Product: CN(CCN(C)c1ccc(N)cc1)c1ccncc1
Yield: 100.5 %

Procedure:
A solution of the product of part (ii) (0.50 g) in methanol (50 ml) was hydrogenated at room temperature and 3.5 bar in the presence of 5% palladium on carbon (50 mg) until the required amount of hydrogen had been absorbed. The catalyst was filtered off and the filtrate was evaporated to give the title compound (0.45 g) as a gum which was used without further purification.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[OH:28][C:6]1[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10](=[O:21])[N:11]2[CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2nccs2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2nccs2)c1O
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A mixture of 5-hydroxy-2-oxo-3-phenyl-1-thiazol-2-ylmethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (16 mg, 0.041 mmol), β-alanine (472 mg, 5.3 mmol) and NaOMe solution (8 mL, 4.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 6.8 mg of the title compound as a light brown solid. MS: (+) m/z 451.18 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.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>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:13][CH:14]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccc(O)cc1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Oc1ccc(-c2ccc(Br)cn2)cc1
Yield: 23.7 %

Procedure:
4-(5-Bromo-2-pyridinyl)phenol (0.25 g, 24%) was prepared as a white solid from (4-hydroxyphenyl)boronic acid (0.60 g, 4.22 mmol), 2,5-dibromopyridine (1.0 g, 4.22 mmol), 2M Na2CO3 (6 mL), EtOH (2 mL) and Pd(PPh3)4 (0.15 g, 0.13 mmol) in toluene (4 mL) in a manner similar to Example 1, Step 1, except the reaction was heated overnight. 1H NMR (400 MHz, CDCl3): δ 8.68 (d, 1H, J=2.2 Hz), 7.90-7.80 (m, 3H), 7.56 (d, 1H, J=8.5 Hz), 6.92 (d, 2H, J=8.5 Hz), 5.18 (bs, 1H); LRMS (ESI), m/z 250/252 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:34][CH3:35])[C:12]([NH:17][C@H:18]2[C@H:22]([OH:23])[CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].[N+:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:34][CH3:35])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][C:43](=[O:44])[C:42]3[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:47][CH:46]=3)[CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Yield: 84.4 %

Procedure:
To a solution of benzyl (trans)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate (2.93 g) in tetrahydrofuran (100 ml) was added p-nitrobenzoic acid (1.89 g), triphenyl phosphine (2.23 g) and di-tert-butyl azodicarboxylate (1.95 g). The reaction mixture was heated at 40° C. for 18 h and was poured into saturated sodium bicarbonate (200 ml). The aqueous layer was extracted with ethyl acetate (2×200 ml), dried MgSO4, filtered and concentrated. MPLC chromatography on a biotage 40 M column with 15-20% ethyl acetate/heptane provided the title compound as an oil (3.19 g, 84%): 1H NMR (400 MHz, CDCl3) δ) 8.35, 8.20, 7.49-7.22, 6.23, 5.81, 5.32, 5.20, 5.05, 4.83, 4.27, 3.95-3.85, 3.51, 2.58-2.41, 1.63, 1.32-1.14; (MS/CI) calcd for C33H31Cl2N5O3+H 664.5, found 664.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.[OH-].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[N:2]1
Reactant: COC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Yield: 104.3 %

Procedure:
Methyl (E)-4-[2-(H-indazol-3-yl)vinyl]benzoate (0.71 g, 2.54 mmol) obtained in Step 5 was dissolved in methanol (2.6 mL), and the solution was added with an aqueous sodium hydroxide solution (1 mol/L, 5.00 mL), followed by heating under reflux for 1.5 hours. Methanol was evaporated under reduced pressure, the pH of the residue was adjusted to 3 or below with 6 mol/L hydrochloric acid under ice-cooling. The resulting precipitates were collected by filtration to obtain (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.70 g, quantitative yield).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:21])[C:18]([Cl:20])=[O:19]>CCOCC>[O:21]=[C:17]([C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[NH:13][CH:12]=1)[C:18]([Cl:20])=[O:19]
Reactant: c1ccc(Oc2ccc3[nH]ccc3c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: O=C(Cl)C(=O)c1c[nH]c2ccc(Oc3ccccc3)cc12

Procedure:
Combine 5-phenoxy-indole (1.57 g, 7.5 mmol) and anhydrous ether (35 mL) and add oxalyl chloride (1.07 g, 8.25 mmol) in 8 mL ether. A precipitate forms. Stir the reaction over night. Collect the precipitate, dry in vacuo, to give the title compound: 1H NMR (300 MHz, DMSO-d6) 6.99–7.15 (m, 4H), 7.37–7.42 (m, 2H), 7.60 (d, 1H, J=8.7 Hz), 7.75 (d, 1H, J=2.4 Hz), 8.47 (d, 1H, J=3.2 Hz), 12.49, (br, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:17]=3)[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C(COC)OC.O1CCCC1.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>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:17]=4)[CH:12]=3)=[O:10])=[CH:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: CN(C)Cc1ccc2cc(C(=O)Nc3ccc(Br)cc3)ccc2c1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Cl-]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CN(C)Cc1ccc2cc(C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)ccc2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 30.3 %

Procedure:
N-(4-Bromophenyl)-6-[(dimethylamino)methyl]-2-naphthamide (128 mg, 0.334 mmol) obtained in Example 4, 4-chlorophenylboronic acid (62.7 mg, 401 mmol) and a 2N aqueous sodium carbonate solution (0.668 ml, 1.34 mmol) were dissolved in a mixed solution of dimethoxyethane (3 ml) and tetrahydrofuran (0.3 ml), tetrakistriphenylphosphinepalladium (11.6 mg, 0.01 mol) was added thereto under the nitrogen atmosphere, and the mixture was stirred at 90° C. for 4 hours. To the reaction solution was added an aqueous saturated sodium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and the insolubles were crystallized from a mixed solution of ethyl acetate and diisopropyl ether (1:3) to obtain the titled compound (42 mg) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)[O:6][CH:7]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[F:17][C:12]1[CH:11]=[C:10](/[CH:9]=[CH:8]/[C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:38][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]4[CH:25]=[CH:26][N:27]=[C:23]4[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=3)[N:4]=2)[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1F
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)c(F)c3)n2)cc1
Yield: 61 %

Procedure:
Using 4-(chloromethyl)-2-[(E)-2-(3,4-difluorophenyl)ethenyl]-1,3-oxazole (228 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (261 mg) as colorless flaky crystals.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[O:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>>[OH:28][C:24]([CH:20]1[CH2:21][CH2:22][CH2:23][O:19]1)([CH3:25])[C:26]#[C:27][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1
Reactant: C#CC(C)(O)C1CCCO1
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Product: CC(O)(C#Cc1ccc2c(c1)-n1nc(C(N)=O)cc1CCO2)C1CCCO1

Procedure:
Similar to as described in General Procedure G, 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with 2-(tetrahydrofuran-2-yl)but-3-yn-2-ol to give a mixture of titled compounds after purification by HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].[C:22]([F:37])([O:26][C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[C:23]([F:25])[F:24]>O1CCCC1>[F:25][C:23]([F:24])([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:22]([F:37])[O:26][C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)cc(C(=O)OC)c1

Procedure:
In a dry box, dimethyl 5-hydroxyisophthalate (63.0 g, 0.300 mol) was added to an oven-dried multiple neck reaction flask equipped with a stirring bar and a pressure equaling (PE) addition funnel. Tetrahydrofuran (THF, 1500 mL) was then added to the reaction flask, and the reaction mixture was stirred until a homogeneous solution resulted. Potassium t-butoxide (9.24 g, 0.0825 mol) was added to the reaction mixture, resulting in a heterogeneous mixture. Via the PE funnel, heptafluoropropyltrifluorovinyl ether (199.2 g, 0.075 mol) was added to the reaction flask to form a reaction mixture. The reaction mixture was allowed to stir at room temperature for ˜24 hours. The reaction was quenched by the addition for 80 mL of 10% HCl to the reaction flask to form a reaction material. The resulting material was concentrated at reduced pressure. The material was then dissolved in dichloromethane (˜150 mL) and then washed with 10% HCl (2×100 mL) and then with water (˜100 mL) to form an organic phase and an aqueous phase. The separated organic phase was then dried over anhydrous sodium sulfate. The sodium sulfate was then filtered off and the resulting material containing a crude product was concentrated at reduced pressure. The crude product was purified by column chromatography resulting in 100.87 g (70.63%) yield of the desired material, dimethyl 5-(1,1,2-trifluoro-2-(perfluoropropoxy)ethoxy)isophthalate.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH2:13][CH2:12][C@H:11]2[C:6](=[CH:7][CH2:8][C@H:9]3[C@@:17]([C:19]([OH:21])=[O:20])([CH3:18])[CH2:16][CH2:15][CH2:14][C@@:10]32[CH3:22])[CH:5]=1)[CH3:3]>[Pd].C(O)C>[CH3:3][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C@@:10]3([CH3:22])[CH2:14][CH2:15][CH2:16][C@:17]([C:19]([OH:21])=[O:20])([CH3:18])[C@@H:9]3[CH2:8][CH2:7][C:6]=2[CH:5]=1)[CH3:1]
Reactant: CC(C)C1=CC2=CC[C@@H]3[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccc2c(c1)CC[C@H]1[C@](C)(C(=O)O)CCC[C@]21C
Temperature: 250 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
115 g of abietic acid was put into a 1000 ml three-neck bottle , and then 2.3 g of 5% palladium/carbon catalyst was added in. The mixture was stirred at 250° C. (oil bath) for 2 hours, after slightly cooled down, 200 ml of 95% ethanol was added. The mixture was refluxed until completely dissolved, filtered when it was warm, allowed to stand still and to be crystallized to give 70 g of dehydroabietic acid after filtered and dried.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:5]([CH2:9][O:10][CH3:11])[CH2:6][O:7][CH3:8].[Li+].[OH-]>C1COCC1.CO.O>[CH2:16]([O:15][C:13]([NH:12][C@@H:4]([CH:5]([CH2:9][O:10][CH3:11])[CH2:6][O:7][CH3:8])[C:3]([OH:23])=[O:2])=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCC(COC)[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCC(COC)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-Benzyloxycarbonylamino-4-methoxy-3-methoxymethyl-butyric acid methyl ester (100 mg, 0.30 mmol, 1.0 equiv) in THF/MeOH/water (0.5 mL/0.5 mL/0.5 mL) was added LiOH*H2O (38.7 mg, 0.92 mmol, 3.0 equiv). After stirring at 0° C. for 1 hour, the reaction was quenched by addition of 1.0 N aq. HCl solution until the pH of the solution was approximately 4. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. MS m/z (M+1) 312.2
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5](=[O:21])[CH2:6][C:7]([CH3:20])=[CH:8][CH2:9][CH2:10][C:11]([CH3:19])=[CH:12][CH2:13][CH2:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.O.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:19][C:11]1=[CH:12][CH2:13][CH2:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:4]([CH:2]([CH3:1])[CH3:3])[C@@H:5]([OH:21])[CH2:6][C:7]([CH3:20])=[CH:8][CH2:9][CH2:10]1
Reactant: CC1=CC=C(C(C)C)C(=O)CC(C)=CCCC(C)=CCC1
Agent: C/C1=C\C=C(\C(C)C)[C@@H](O)C/C(C)=C/CC/C(C)=C/CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=CC=C(C(C)C)[C@@H](O)CC(C)=CCCC(C)=CCC1

Procedure:
To the above ketone compound, 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraen-1-one (137 mg, 0.48 mmol) in dry toluene (2.5 ml) was dropwise added with stirring on a cooling bath at -70° C. a solution of 1M diisobutyl aluminium hydride in toluene (0.6 ml). One hour later, disappearance of the starting material was confirmed. After addition of water (0.25 ml) and removal of the cooling bath, the reaction mixture was stirred, followed by drying over MgSO4, filtration, and concentration to give a residue, which was subjected to silica gel column chromatography (solvent: n-hexane/ethyl acetate=12:1) to obtain the aimed sarcophytol A (125 mg, 88%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[C:9]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:8][N:7]=1)=[O:5].Cl>CC(O)C>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[C:9]([C:23]([OH:25])=[O:24])=[CH:8][N:7]=1)=[O:5]
Reactant: CCOC(=O)c1ncc(C(=O)OC(C)(C)C)n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1ncc(C(=O)O)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To 24 mg of 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester was added a 5 M solution of HCl in 2-propanol (2 mL). The mixture was stirred for 24 h at RT, concentrated in vacuo and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated to provide 14 mg of the title compound as a pale yellow solid. Yield: 14 mg; MS (ESI+): m/e=381, chloro pattern.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1

Procedure:
1B, in tetrahydrofuran, was treated with hydrogen (40 psi pressure in a Parr-shaker, 10% palladium-on-carbon catalyst), to give ethyl 2-(4-(2-amino-4-(trifluoromethyl)phenylamino)phenoxy)propionate (1C), as a solid, m.p.: 78° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][C:20]1([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C(Cl)Cl>[Si:11]([O:18][CH2:19][C:20]1([CH:24]=[O:25])[CH2:21][CH2:22][CH2:23]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO)CCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1(C=O)CCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
To a round bottom flask was added DCM (5.0 mL) and oxalyl chloride (2.0 M solution in DCM, 1.36 mL, 2.71 mmol). The reaction mixture was cooled to about −78° C. To the solution was added a solution of DMSO (0.385 mL, 5.42 mmol) in DCM (1.0 mL). The mixture was stirred for about 15 min at about −78° C. and then a solution of (1-((tert-butyldimethylsilyloxy)methyl)cyclobutyl)methanol (0.500 g, 2.17 mmol, prepared using General Procedure AL with diethyl cyclobutane-1,1-dicarboxylate [Fluka], General Procedure AK with tert-butylchlorodimethylsilane) in DCM (1.0 mL) was added. The reaction mixture was allowed to stir for about 15 min and then TEA (1.82 mL, 13.0 mmol) was added. The reaction mixture was allowed to stir for about 15 min and then warmed to ambient temperature. The reaction mixture was quenched with water (25 mL) and was extracted with DCM (3×25 mL). The organics were combined, dried with MgSO4, filtered and concentrated in vacuo to give the title compound as a colorless oil (0.486 g, 98%): 1H-NMR (DMSO-d6) δ 9.71 (s, 1H), 3.87 (s, 2H), 2.27 (m, 2H), 1.93 (m, 4H), 0.90 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([CH:21]=[O:22])[CH2:19][CH2:20]1)=[O:14]
Reactant: COC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)N1CCC(C=O)CC1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
To a solution of oxalyl chloride (4.1 mL, 8.2 mmol) in dichloromethane (4 mL) at −78° C. was added dropwise a solution of dimethylsulfoxide (1.2 mL, 16.4 mmol) in dichloromethane (4 mL). After stirring for 5 min, a solution of 4-hydroxymethyl-piperidine-1-carboxylic acid methyl ester (1.3 g, 7.5 mmol) in dichloromethane (5 mL) was added. The resulting solution was stirred for another 5 min, then triethylamine (5.2 mL, 37.3 mmol) was added and the mixture allowed to warm to −10° C. After stirring for 1 h, dichloromethane (100 mL) was added, and the organic layer was washed with 1M aqueous phosphoric acid, 1M aqueous sodium hydroxide, and brine. The solution was dried over sodium sulfate then evaporated to afford the title intermediate as a wheat colored oil (1.0 g, 5.8 mmol, 78%). 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.36 (m, 2H), 1.83 (m, 2H), 2.48 (br m, 1H), 2.93 (br t, 2H), 3.56 (s, 3H), 3.80 (br d, 2H), 9.56 (s, 1H).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:40])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])=[CH:18][C:17]=1[O:38][CH3:39])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])=[O:40])=[C:17]([O:38][CH3:39])[CH:18]=1)([OH:33])=[O:32]
Reactant: COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)ccc1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)ccc1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of 250 mg (0.44 mmol) (R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methoxy-phenoxy]-acetyl]-pyrrolidine-2- carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 188 mg (94%) of the title compound as a white powder. MS m/e (%): 473 (M+Na+, 45), 468 (M+NH4+, 24), 451 (M+H+, 100).