Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](Cl)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:26][C:27]1[C:35]([OH:36])=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([CH3:37])[NH:31]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.CC(C)=O.FC1C(O)=CC=C2C=1C=C(C)N2.C(=O)([O-])[O-].[K+].[K+]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([O:36][C:35]4[C:27]([F:26])=[C:28]5[C:32](=[CH:33][CH:34]=4)[NH:31][C:30]([CH3:37])=[CH:29]5)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A mixture of 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-6-methoxyquinazoline (12.24 g, 33.5 mmol), 4-fluoro-5-hydroxy-2-methylindole (5.54 g, 33.5 mmol), (prepared as described for the starting material in Example 1), and potassium carbonate (4.64 g, 33.5 mmol) was heated in N,N-dimethylacetamide (150 ml) at 85° C. for 4 hours. 4-Fluoro-5-hydroxy-2-methylindole (33 mg, 0.2 mmol) and potassium carbonate (108 mg, 57%) were added and the mixture heated for a further 1 hour at 85° C. and then stirred at ambient temperature overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give a white solid which was suspended in acetone (150 ml) and heated at reflux for 1 hour. After cooling the mixture was filtered and the solid dried in air to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (10 g, 60%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:63][C@H:64]([C:69](O)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:63][C@H:64]([C:69]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:26])[NH:27][CH3:28])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CNC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.8 %

Procedure:
To a solution of 4-{[(1′S,2′S)-1′-hydroxy-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}-N-methylbenzamide (22, 150 mg, 0.38 mmol), DCC (94 mg, 0.45 mmol) and DMAP (5 mg, 0.038 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (134 mg, 0.38 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (180 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 75 mg (39%) of the title compound as an off white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:12]([CH3:14])[CH3:13])[CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[N:21]([CH3:22])[N:20]=[C:19]([OH:23])[C:18]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:26][C:16]([F:15])([F:25])[C:17]1[N:21]([CH3:22])[N:20]=[C:19]([O:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:12]([CH3:14])[CH3:13])[CH:3]=2)[C:18]=1[Cl:24]
Reactant: Cn1nc(O)c(Cl)c1C(F)(F)F
Reactant: CN(C)Nc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)Nc1cc(Oc2nn(C)c(C(F)(F)F)c2Cl)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 97.4 %

Procedure:
1.98 g (0.01 mol) of the product of step (a) was mixed with 2.2 g (0.011 mol) of 5-trifluoromethyl-4- chloro-3-hydroxy-1-methylpyrazole and 1.65 g of potassium carbonate in 15 ml of DMSO and heated for 24 hours at 90° C. The mixture was poured into 400 ml of H2O and extracted with ether. The organic layer was separated, washed with H2O, brine, dried over MgSO4 and solvent removed to give 3.7 g of solid, m.p. 72°-76° C.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.O.[NH2:19][NH2:20]>CCO>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([C:4]2[C:3]([CH3:17])([CH3:16])[CH2:2][NH:20][N:19]=2)[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: NN
Reactant: COc1ccc(C(=O)C(C)(C)CCl)cc1OC
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNCC2(C)C)cc1OC
Temperature: 80 °C
Yield: 100 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar, Vigreux column and nitrogen inlet was charged with 3-chloro-1-(3,4-dimethoxy-phenyl)-2,2-dimethyl-propan-1-one (1.3 g, 5 mmol), EtOH (20 mL) and hydrazine monohydrate (0.3 mL, 6 mmol). The mixture was heated at 80° C. for 2 h. LC-MS and TLC analysis showed consumption of SM. The solvent was evaporated under reduced pressure and trace hydrazine and EtOH was removed under high vacuum for 30 min. The material was used as in the next step. Amount obtained: 1170 mg, 5 mmol, 100% yield. LC-MS (ESI) m/e 235 (M+H). Step 3
Reaction SMILES: F[C:2]1[C:7](F)=[C:6](I)C=C[C:3]=1[C:10]1C=[CH:14][C:13](C2C=CC(CCC)=CC=2)=[CH:12][C:11]=1F.OCC(C)(CO)C.CC(C)=O>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:6][CH2:7][CH2:2][CH2:3][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCc1ccc(-c2ccc(-c3ccc(I)c(F)c3F)c(F)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(CO)CO
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCCCCCCCC
Yield: 68 %

Procedure:
A solution of (0.1 mmol) of 10, (0.12 mmol) of 14, 14 mg (0.13 mmol) of neopentyl glycol, 95 mg (0.3 mmol) of Ba(OH)2.8H2O, 80 μl (6.08 mmol, 5 mmol %) of a 76 mM acetone solution of Pd(OAc)2 in 2 ml of 95% i-PrOH is stirred at 80° C. for 12 hours. The solvent is subsequently removed under reduced pressure. 2 ml of 2 M HCl are added to the residue, and the mixture is extracted with dichloromethane (3×2 ml). The combined organic phases are dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, and the residue is purified by recrystallisation twice from nonane (yield: 68%).
Reaction SMILES: Cl.Cl.CN(C)[C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.C(O)(=O)/C=C/C(O)=[O:36].CN(C)C(=O)COCCN1CCN(C(C2C=CC=CC=2)C2C=CC([Cl:60])=CC=2)CC1>>[ClH:23].[ClH:60].[C:24]1([CH:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][O:7][CH2:6][C:5]([OH:30])=[O:36])[CH2:11][CH2:12]2)[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CN(C)C(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: Cl
Product: O=C(O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 77.8 %

Procedure:
The procedure described in Example 13 is followed with the difference that, instead of the (RS)-N,N-dimethyl-{2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}-acetamide dihydrochloride, 106.4 g (0.2 moles) of (RS)-N,N-dimethyl-{2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}-acetamide fumarate is used, and, after adjusting the pH of the reaction mixture to 3.8, the precipitated fumaric acid is filtered to facilitate the extraction with dichloromethane. Thus, 71.8 g (77.8%) of the title compound are obtained, m.p.: 225-228° C. The purity of the product corresponds to the quality requirements given in Eur. Pharm., 3, 1997, 1084.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: C#Cc1ccc(Cl)cc1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccc(Cl)cc1

Procedure:
Following the general method as outlined in Example 1, starting from tert-butyl(2-bromo-4-chlorophenoxy)acetate (Intermediate 1) and 4-chlorophenylacetylene (Apollo), the title compound was obtained as a beige solid after purification by preparative HPLC
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:24]Cl>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:24][C:23]2[CH:26]=[CH:27][C:28]([F:29])=[C:21]([F:20])[CH:22]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: Fc1ccc(CCl)cc1F
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(F)c(F)c3)n2)ccc1F
Yield: 66.7 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3,4-difluorobenzyl chloride were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1(7) to yield the title compound as a pale yellow solid (66.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=2[O:27][CH3:28])=[O:7])=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1.CCOC(C)=O>[C:23]([C:11]1[C:10]([O:27][CH3:28])=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][CH:4]=2)[CH:14]=[C:13]([C:15]2[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(NC(=O)c2ccc(N)cc2)c(OC)c(C(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ncccc1-c1cc(NC(=O)c2ccc(NS(C)(=O)=O)cc2)c(OC)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
step 5—To a solution of 104 (0.10 g, 0.25 mmol) in pyridine (2 mL) at 0° C. was added methanesulfonyl chloride (0.034 g, 0.30 mmol). Stirring was continued at 0° C. for two h, then at RT for an additional two h. The reaction mixture was diluted with EtOAc, washed sequentially with aqueous CuSO4 and 2N HCl, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography (EtOAc/hexane) to afford 0.12 g of N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]-4-methanesulfonylaminobenzamide (106) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:25])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: COC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl) ester (5.0 g, 10.8 mmol) in tetrahydrofuran/methanol (50 mL, 1:1) containing 3 Å molecular sieves at 0° C. was added tetra n-butylammonium fluoride (22 mL, 22 mmol, 1 M in tetrahydrofuran). After stirring at room temperature for 24 h, the mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue was partitioned between diethyl ether and saturated sodium hydrogen carbonate solution. The aqueous layer was extracted with diethyl ether. The organic extracts were combined and the solution was filtered through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with iso-hexanes/ethyl acetate 20:1 to 3:2 to afford (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (3.0 g, 82%) as a colorless oil and as a mixture of rotamers. LCMS (m/z) 345.1 [M+H], Tr=2.78 min. A solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (3.0 g, 8.72 mmol) in tetrahydrofuran (20 mL) at −78° C. was treated with lithium bis(trimethylsilyl)amide (13 mL, 13.0 mmol, 1 M in tetrahydrofuran). After stirring at −78° C. for 1 h, the mixture was treated with iodomethane (1.4 mL, 22.5 mmol). The reaction mixture was stirred at −78° C. for 1 h, then at 0° C. for 1 h and at room temperature for 1 h. The reaction mixture was re-cooled to 0° C. and quenched with water. The aqueous phase was extracted with dichloromethane (2×) and the organic solution was passed through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of iso-hexanes/ethyl acetate 4:1 to 0:1 to afford the title compound (1.62 g, 52%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.41-1.52 (m, 18H), 1.53-1.67 (m, 4H), 1.71-1.99 (m, 3H), 3.17-3.51 (m, 1H), 3.70-3.81 (m, 3H), 3.90-4.21 (m, 1H). LCMS (m/z) 359.0 [M+H], Tr=2.90 min.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:45])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([S:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:14][CH:15]=1)=[O:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSCc4ccccc4)cc2)CCO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)Cc4ccccc4)cc2)CCO3)cc1
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of N-(4—(benzylthiomethyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.12 g) in dichloromethane (25 ml) was added 70% m-chloroperbenzoic acid (0.06 g) at the temperature ranging from −20 to −10° C., and the mixture was stirred for 10 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4—(benzylsulfinylmethyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 109) (0.08 g) as colorless crystals.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]>P(=O)(O)(O)O>[CH2:9]([C:8]([C:7](=[O:12])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4])[CH2:10][CH3:11]
Reactant: O=CC(=O)O
Reactant: CCCCC(C)=O
Agent: O=P(O)(O)O
Product: CCCC(=CC(=O)O)C(C)=O

Procedure:
Prepared from glyoxylic acid (15.2 g, 0.17 mol), 2-hexanone (30 g, 0.3 mol) and orthophosphoric acid (30 ml). 1H n.m.r. δ (CDCl3) 0.88, t J 7.2 Hz, 3H, CH3; 1.44, m, 2H, CH2; 2.41, s, 3H, CH3; 2.78, t J 7.5 Hz, 2H, CH2; 6.51, s, CH 13C n.m.r. δ (CDCl3): 14.0, CH3; 22.5, 26.5, CH2; 28.6, CH3; 124.5, C2; 157.3, C3; 170.4, COOH; 199.8 C2.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10](Cl)[C:11]([CH3:13])=[CH2:12])(=[O:3])[CH3:2].[I-].[Na+].C[N+]1([O-])CC[O:22]CC1.CN(C)C=O>O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH:12]=[O:22])(=[O:3])[CH3:2]
Reactant: C=C(C)C(Cl)CCC(C)=CCOC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC=C(C)CCC=C(C)C=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
1.15 g (3.99 mmols) of 6-chloro-3,7-dimethyl-2,7-octadienyl acetate (purity: 80%), 0.91 g (6 mmols) of sodium iodide and 1.36 g (10 mmols) of N-methylmorpholine N-oxide (monohydrate) were placed in a flask, to which was added 5 ml of N,N-dimethylformamide. The mixture was agitated at 50° C. for 4 hours. After completion of the reaction, 10 ml of water was added to the reaction mixture, followed by extraction twice each with 70 ml of diethyl ether. The resulting extract was washed with each 20 ml of 3% sulfuric acid, a saturated sodium hydrogen carbonate aqueous solution and a 10% sodium sulfite aqueous solution, and dried with magnesium sulfate. After drying, the solvent was removed by distillation from the solution and the resulting residue was purified by column chromatography using silica gel [eluent: ethyl acetate/hexane (volume by ratio)=1/9-1/3], thereby obtaining 0.627 g of 8-acetoxy-2,6-dimethyl-2,6-octadienal. Yield: 75%. The results of an instrumental analysis of the 8-acetoxy-2,6-dimethyl-2,6-octadienal are as follows.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[F:28].C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:18][C:11]=2[CH:12]=1)[CH:24]=[O:25]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: OB(O)c1cc2cc(N3CCCCC3)ccc2o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cc3cc(N4CCCCC4)ccc3o2)c(F)c1
Yield: 25.2 %

Procedure:
A mixture of 5-(piperidin-1-yl)benzofuran-2-ylboronic acid (50 mg, 0.204 mmol), 4-bromo-3-fluorobenzaldehyde (37 mg, 0.184 mmol), triethylamine (0.56 mL, 4.1 mmol) and bis(triphenylphosphine)palladium(II)chloride (14 mg, 0.02 mmol) in ethanol (5 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (15 mg, 15% yield). ESI-MS: 324.2 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.19 (t, 1H), 7.75 (d, 1H), 7.67 (d, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 7.14-7.11 (m, 2H), 3.13 (m, 4H), 1.77 (m, 4H), 1.59 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:22]([O-:24])=[O:23])[C@@H:10]([C:19]([O-:21])=[O:20])[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][CH:9]([C:22]([OH:24])=[O:23])[C@@H:10]([C:19]([OH:21])=[O:20])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)[O-])C(OCc1ccccc1)C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: N[C@H](C(=O)O)C(OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
To a solution of 65 mg (0.14 mmol) of the compound (14) in chloroform (2 ml) was added 2 ml of trifluoroacetic acid, and then the mixture was stirred at room temperature for 20 hours. The solvent was distilled off and the residue was subjected to column chromatography on ion exchange resin (Dowex 50Wx4) and washed with water, then eluted with 1N aqueous ammonia to give 23 mg of the title compound (15) (yield 65%).
Reaction SMILES: [CH2:1]([CH:4]1[C@:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[F:20])([CH3:10])[N:8]=[C:7]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]([CH3:37])([CH3:36])[S:5]1(=[O:39])=[O:38])[CH:2]=C.C(=O)(O)[O-:41].[Na+].C(Cl)Cl.[BH4-].[Na+]>CO>[C:24]([O:23][C:22]([N:21]([C:7]1[C:6]([CH3:37])([CH3:36])[S:5](=[O:38])(=[O:39])[CH:4]([CH2:1][CH2:2][OH:41])[C@:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[F:20])([CH3:10])[N:8]=1)[C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: C=CCC1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)C(CCO)S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
A 3-necked round bottom flask equipped with a mechanical stirrer, Claisen adapter with thermocouple and a nitrogen inlet was charged with tert-butyl N-[(3R)-2-allyl-3-(2-fluoro-5-nitro-phenyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (4.00 g, 7.02 mmol, 2.85:1 ratio of diastereomers), sodium bicarbonate (1.180 g, 14.04 mmol), DCM (30 mL) and MeOH (10.00 mL), and the resulting solution was cooled to Tinternal<−65+/−1° C. Ozone was bubbled through the reaction mixture until starting material was consumed according to LCMS (˜1.5 h). The solution was purged with oxygen and then nitrogen, and sodium borohydride (0.531 g, 14.04 mmol) added in one portion. The cooling bath was removed, and the reaction mixture was allowed to warm to RT overnight. 2 mL acetone was added, followed by 10 mL sat. aq.NH4Cl. After stirring for 10 min, 5 mL water was added and the layers were separated. The organic portion was dried over magnesium sulfate, filtered and concentrated in vacuo to provide tert-butyl N-tert-butoxycarbonyl-N-[(3R)-3-(2-fluoro-5-nitro-phenyl)-2-(2-hydroxyethyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (4.04 g, 2.85:1 ratio of diastereomers) as a white solid that was used without further purification. LC/MS (ESI+) m/z=596.2 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.C([O:13][B:14](OC(C)C)[O:15]C(C)C)(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[B:14]([OH:15])[OH:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc(Cl)c(I)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(Cl)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold (-78° C.) solution of 2,5-dichloroiodobenzene (50 g) and triisopropoxyborane (46.5 ml) in tetrahydrofuran (500 ml) was added dropwise n-butyllithium in hexane (1.69 M, 119 ml). The mixture was stirred at -78° C. for 30 minutes. The reaction mixture was poured into 2M hydrochloric acid solution (180 ml) and stirred for 10 minutes. The product was extracted with ether (200 ml) 2 times, and the organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo. To the residue was added n-hexane (60 ml) and the crystalline was collected, washed with n-hexane and dried to give 2,5-dichlorophenyl-dihydroxyborane (21.0 g).