Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:28])[CH3:29])[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([F:36])[CH:38]=[CH:39][C:40]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Yield: 13.7 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-6-Chloro-3-[2-(1-ethoxycarbonyl-1-methyl-ethoxy)-5-fluoro-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 10 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (40 mmol) in toluene to give the title compound as a white solid (800 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:22]([CH2:29][CH2:30][CH2:31][C:32]([NH2:44])([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:33]([OH:35])=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl.Cl.[N:47]1([C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][N:54]=2)[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C=O)C.O>[C:22]([CH2:29][CH2:30][CH2:31][C:32]([NH2:44])([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:33]([N:50]1[CH2:51][CH2:52][N:47]([C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][N:54]=2)[CH2:48][CH2:49]1)=[O:35])([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Reactant: CC(C)(C)OC(=O)CCCC(N)(Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCCC(N)(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of EDCI (100 mg, 0.54 mmol), HOBt.H20 (82 mg, 0.54 mmol), 5-Boc-amino-2-(4-chlorobenzyl)-pentanoic acid (170 mg, 0.50 mmol), and TEA (190 μL, 1.4 mmol) in 3 mL DMF was stirred 10 minutes, and solid 4-piperazin-1-yl-quinazoline dihydrochloride (130 mg, 0.45 mmol) was added. The reaction mixture was stirred at room temperature 15 hours, after which water was added. The reaction mixture was extracted with DCM, and combined extracts washed with sat NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (1:1 to 1:9 DCM:EtOAc) to give 5-Boc-amino-2-(4-chlorobenzyl)-1-(4-quinazolin-4-yl-piperazin-1-yl)-pentan-1-one. LCMS (APCI+) m/z 538 [M+H]+; Rt: 3.12 min.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:52]=[CH:51][C:18]([CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[C:36]([F:41])[CH:37]=5)[N:32]=4)=[CH:28][C:23]=3[N:22]=[C:21]2[CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]2[C:48]([OH:50])=[O:49])=[CH:17][CH:16]=1.CC1(C)C(C)(C)OB(C2N=CSC=2)O1>>[F:41][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[N:32]=[C:31]([CH2:30][O:29][C:27]1[CH:26]=[CH:25][C:24]3[N:20]([CH2:19][C:18]4[CH:17]=[CH:16][C:15]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=5)=[CH:52][CH:51]=4)[C:21]([C@H:42]4[CH2:47][CH2:46][CH2:45][CH2:44][C@H:43]4[C:48]([OH:50])=[O:49])=[N:22][C:23]=3[CH:28]=1)[CH:40]=[CH:39]2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C1CCCCC1c1nc2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(Br)cc1
Agent: CC1(C)OB(c2cscn2)OC1(C)C
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared using similar methods to those in Example 97 using (4-(trifluoromethyl)phenyl)boronic acid and racemic (1R,2S)-2-(1-(4-bromobenzyl)-5-((6-fluoroquinolin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole in Step A. MS (ESI): mass calcd. for C38H31F4N3O3, 653.23; m/z found, 654.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.33 (d, J=8.4, 1H), 8.11-8.05 (m, 1H), 7.81-7.74 (m, 3H), 7.70 (d, J=8.3, 2H), 7.66-7.56 (m, 4H), 7.30 (d, J=2.4, 1H), 7.27-7.22 (m, 3H), 7.02 (dd, J=8.8, 2.4, 1H), 5.60 (d, J=17.1, 1H), 5.54 (d, J=17.2, 1H), 5.39 (s, 2H), 3.65-3.55 (m, 1H), 2.90-2.80 (m, 1H), 2.42-2.31 (m, 1H), 2.08-1.98 (m, 1H), 1.92-1.73 (m, 4H), 1.54-1.38 (m, 2H).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH:7][CH3:8])[CH3:6].[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([O:22]CC)=O)[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10].Cl>ClCCl>[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:7]([CH2:5][CH3:6])[CH3:8])=[O:22])[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]=1[CH3:32])#[N:10]
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CCNC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reaction time: 1.33 h
Yield: 87.2 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution) (2.40 ml, 2.47 mmol) was dropwise added at room temperature to a dichloromethane (8 ml) solution of N-ethylmethylamine (146 mg, 2.47 mmol), followed by stirring for 80 minutes. Subsequently, a dichloromethane (4 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (400 mg, 1.23 mmol) was dropwise added, followed by stirring for 19 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, then the reaction liquid was extracted with chloroform. Next, the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (362 mg, 87%) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:9][C:10]([C:12]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[C:26](=[O:32])[NH:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[O:20])[N:14]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:13]=1)=[O:11])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:28]1([NH:27][C:26]([C@@H:22]2[CH2:23][CH2:24][CH2:25][N:21]2[C:19](=[O:20])[CH2:18][O:17][C:15]2[N:14]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:13]=[C:12]([C:10]([NH:9][C@@H:7]([CH3:8])[C:6]([OH:39])=[O:5])=[O:11])[CH:16]=2)=[O:32])[CH2:29][CH2:30][CH2:31]1
Reactant: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reaction time: 6 h

Procedure:
To a solution of 634 mg (S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionic acid tert-butyl ester in 5 ml dichloromethane were added 0.8 ml TFA. After stirring for 6 h it was concentrated and codistilled twice with toluene to give the crude product. Yield: 905 mg
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3(Cl)[CH:23]([Cl:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3[Cl:24])=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)C(Cl)(C2CCC(c3ccc(Cl)cc3)CC2)C1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21

Procedure:
115.8 g of 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-1,4-naphthoquinone (Formula III) obtained in Example 6 was suspended in glacial acetic acid (926 ml). 33.77 g anhydrous sodium acetate was then added to the mixture and heated to reflux for 1 hour. After which, the mixture was cooled. Water was then added. The precipitated product was filtered of and recrystallized from acetonitrile to obtain 94.5 g (89.34% yield) of the trans-isomer of the compound of Formula IV.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[C:41]1[CH:45]=[CH:44][S:43][CH:42]=1>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([C:41]4[CH:45]=[CH:44][S:43][CH:42]=4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:22][CH:23]=2)[NH:34]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccsc2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccsc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-[(5-oxo-7-propyl-4-thiophen-3-yl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.52 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4].N1C=CC=CC=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])#[N:20]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:12][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:19]#[N:20])[CH:22]=2)[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1ccc(N)c(NC(=O)c2cccc(C#N)c2)c1
Reaction time: 12 h
Yield: 56.4 %

Procedure:
To a solution of 4-methoxycarbonyl-1,2-benzenediamine (8 g, 48 mmol) and pyridine (4 mL, 48 mmol) in acetonitrile (300 mL) at 0° C. was added 3-cyanobenzoyl chloride (8 g, 48 mmol). After 12 h, the reaction was concentrated and the residue was suspended with vigorous stirring in ethyl acetate (500 mL) and 1 M citric acid (200 mL). The solid was filtered, washed with diethyl ether and vacuum dried to give the title compound as an off-white solid (8 g, 56%); MS(FD): 295.1 (M+).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1>C1COCC1.C(OCC)C>[CH:1]1([C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=2)([OH:15])[CH3:14])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CC(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C(C)(O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
27 ml (26.8 mmol) of 1N cyclopropylmagnesium bromide solution in THF were added to 3.00 g (22.4 mmol) of 1-(4-methylphenyl)ethanone in 60 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. Then a further 11 ml (11.2 mmol) of 1N cyclopropylmagnesium bromide solution in THF were added, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient with addition of 0.1% triethylamine) to result in 491 mg (13% of theory) of the title compound.
Reaction SMILES: [C:1]12([C:14]([OH:16])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([C:11]([OH:13])=[O:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:17]N1C(=O)C2=CC=CC=C2C1=O>[Co+2].C(O)(=O)C>[OH:17][C:5]12[CH2:4][C:3]3([C:11]([OH:13])=[O:12])[CH2:9][CH:7]([CH2:8][C:1]([C:14]([OH:16])=[O:15])([CH2:2]3)[CH2:10]1)[CH2:6]2
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [Co+2]
Solvent: CC(=O)O
Product: O=C(O)C12CC3CC(O)(C1)CC(C(=O)O)(C3)C2
Temperature: 80 °C
Reaction time: 24 h
Yield: 52.5 %

Procedure:
A mixture of 1.92 mol of 1,3-adamantanedicarboxylic acid, 192 mmol of N-hydroxyphthalimide, 1.83 mmol of cobalt (II) acetylacetonato and 1290 ml of acetic acid was stirred at 80° C. under an oxygen atmosphere (1 atm) for 24 hours. The reaction mixture was concentrated and then separated by the addition of ethyl acetate and water. Sodium chloride was added to the aqueous layer and the layer was extracted with ethyl acetate; the organic layer was dried on anhydrous magnesium sulfate and was concentrated. The caked crude purified product was washed with ethyl acetate to give 5-hydroxy-1,3-adamantanedicarboxylic acid (yield: 52.5%) at a conversion rate from 1,3-adamantanedicarboxylic acid of 75%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C:19]2[NH:20][CH:21]=[CH:22][C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:15]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:9])[C:19]3[NH:20][CH:21]=[CH:22][C:18]=3[C:17]=2[CH:16]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Reactant: O=C1CCC(=O)N1Br
Agent: CCC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
434 mg (2.44 mmol) of N-bromosuccinimide is added to 500 mg (1.95 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 1) dissolved in 10 ml of anhydrous dimethylformamide and the reaction mixture is stirred for 1 h at room temperature. The mixture is then diluted in 10 mL of ethyl acetate, the solid is filtered, rinsed with diethyl ether then recrystallized from acetic acid to give 360 mg (55%) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with one equivalent of acetic acid in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:11]=[C:10]([CH3:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:28]1CCCC1.[OH-].[Li+].P(=O)(O)(O)O>C(OCC)(=O)C>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])/[CH:11]=[C:10](/[CH3:26])\[C:9]([OH:28])=[O:27])=[CH:15][CH:16]=1
Reactant: CC1=C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Reactant: C1CCOC1
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C/C(=C/[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.7 g (R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) is added to tetrahydrofuran (20 ml). Aqueous lithium hydroxide solution (10 ml, 3 M) is added and the mixture is stirred for 20 h at ambient temperature. The mixture is acidified by addition of phosphoric acid and subsequently diluted by addition of ethyl acetate. The phases are separated and the organic phase is washed with water and then concentrated under reduced pressure. Isopropyl acetate is added to the residue and the mixture is filtered to afford (Z)—(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (5a, R1=Boc, R2=H, R3=CO2H). 1H NMR (DMSO): 1.28 (9H), 1.85 (3H), 2.78 (2H), 5.07 (1H), 5.92 (1H), 6.96 (1H), 7.30 (2H), 7.35 (1H), 7.46 (2H), 7.56 (2H), 7.63 (2H), 12.65 (1H).
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:23][O:24][CH2:25]Cl.O>CN(C)C=O.C(OCC)(=O)C>[CH3:23][O:24][CH2:25][N:9]1[C:8]2[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:7]=2[S:6][C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:10]1=2
Reactant: CCOC(=O)c1ccc2c(c1)Sc1nccnc1N2
Reactant: ClCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)Sc1nccnc1N2COC
Reaction time: 1 h

Procedure:
100 ml of a solution of 7.0 g of ethyl 10H-pyrazino[2,3-b][1,4]benzothiazine-7-carboxylate in N,N-dimethylformamide was ice-cooled in a nitrogen atmosphere and 1.3 g of sodium hydride (60% oily) was added thereto. Then the resulting mixture was brought back to room temperature and stirred for 1 hour. Next, it was ice-cooled again and 2.5 ml of chloromethyl ether was dropped thereinto. After the completion of the reaction, the reaction mixture was distributed into water and ethyl acetate. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate/hexane) to thereby give 5.0 g of ethyl 10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine-7-carboxylate as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C@@H:11]2[C@:20]3([CH3:21])[C@H:15]([C:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][CH2:19]3)[CH2:14][CH2:13][C@@:12]2([CH3:25])O)[CH:6]=[CH:7][CH:8]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C@@:12]3([CH3:25])[C@H:11]([CH2:10][S:9]2)[C@:20]2([CH3:21])[C@H:15]([C:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][CH2:19]2)[CH2:14][CH2:13]3)=[CH:7][CH:8]=1
Reactant: COc1cccc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: -78 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A solution of (1R,2R,4aS,8aS)-1-{[(3-methoxyphenyl)sulfanyl]-methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (13-1) (1.2 g, 3.2 mmol) in CH2Cl2 (85 mL) was cooled to −78° C. under N2. To the mixture, a solution of SnCl4 (1.5 mL) in CH2Cl2 (15 mL) was added dropwise. The mixture was stirred at −78° C. for 3 h. The dry ice bath was removed and stirring at room temperature continued for 2 h. The reaction mixture was quenched with water and the organic layer was separated and concentrated to dryness. The crude product was purified by flash chromatography on silica gel (Hexanes/Toluene, 2:1) to yield (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo-[8.8.0.02,7.011,16]octadeca-2,4,6-triene (51) (1.0 g, 93% yield) as a white solid. Regioisomer (52) was also obtained as shown in Example 26.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Cl:11])=[N:4][CH:3]=1.[CH3:12][NH2:13].[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[C:28]([O:34][CH3:35])[CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:11][C:5]1[N:4]=[CH:3][C:2]2[N:1]=[C:30]([C:29]3[CH:32]=[CH:33][C:26]([O:25][CH:22]4[CH2:23][CH2:24][N:19]([CH:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:20][CH2:21]4)=[CH:27][C:28]=3[O:34][CH3:35])[N:13]([CH3:12])[C:8](=[O:10])[C:7]=2[CH:6]=1
Reactant: CN
Reactant: COc1cc(OC2CCN(C3CCCC3)CC2)ccc1C=O
Reactant: Nc1cnc(Cl)cc1C(=O)O
Product: COc1cc(OC2CCN(C3CCCC3)CC2)ccc1-c1nc2cnc(Cl)cc2c(=O)n1C

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 5-amino-2-chloroisonicotinic acid, methylamine and 4-[(1-cyclopentylpiperidin-4-yl)oxy]-2-methoxybenzaldehyde.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[N+:18]([O-:38])[CH:19]=[CH:20][CH:21]=2)=[C:7]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[S:6]1(=[O:28])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)N1C(=O)C(NCCCOc2cccnc2)=C(c2ccccc2)S1(=O)=O
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccc[n+]([O-])c2)=C(c2ccccc2)S1(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
2-tert-Butyl-5-phenyl-4-{[3-(pyridin-3-yloxy)propyl]amino}isothiazol-3(2H)-one 1,1-dioxide (Example 5) (0.202 g, 0.49 mmol) was dissolved in dry DCM (15 ml) and cooled to 0° C. with an icebath. mCPBA (70%) (0.120 g, 0.53 mmol) was added and the icebath was removed and the reaction mixture was allowed to reach rt. After stirring for 2 h the reaction mixture was extracted with saturated aqueous NaHCO3 solution (20 ml) and brine (20 ml). The organic phase was dried (Na2SO4), filtered and evaporated. The residue was purified by silica gel column chromatography using a 10:90 mixture of heptane and EtOAc and then DCM:MeOH 97:3 as eluant, to give the title compound (0.160 g, 76%). 1H NMR (500 MHz, CDCl3): δ 7.90-7.83 (m, 2H), 7.51-7.37 (m, 5H), 7.16-7.09 (m, 1H), 6.80-6.74 (m, 1H), 5.68-5.57 (m, 1H), 3.85-3.76 (m, 2H), 3.09-3.02 (m, 2H), 1.85-1.76 (m, 2H), 1.70 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.8, 157.0, 135.1, 133.0, 131.8, 129.9, 128.9, 128.2, 125.7, 125.2, 113.5, 107.6, 67.0, 61.8, 60.6, 41.7, 32.1, 28.8, 27.8, 22.9; Mass Spectrum: M−H+ 432.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:15][O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20].C(N(CC)CC)C.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][O:16][C:17](=[O:21])[CH2:18][N:19]([C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:20]
Reactant: CNCC(=O)OC
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a stirred solution of 3-nitrophenylacetic acid (25 g, 0.14 mol), sarcosine methyl ester hydrochloride (20.2 g, 0.15 mol), triethylamine (20 ml, 0.15 mol) and 4-dimethylaminopyridine (17.7 g, 0.15 mol) in dichloromethane (300 ml) was added, under nitrogen, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (27.8 g, 0.15 mol). The mixture was stirred at room temperature for 18 h then the solvent removed in vacuo. Ethyl acetate (300 ml) was added to the residue and the mixture partitioned with 1M HCl (2×200 ml), saturated sodium bicarbonate solution (2×200 ml), water (200 ml) and brine (200 ml). The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, using petrol:ethyl acetate (1:1) as the eluant, to afford the title amide (25 g, 68%) as a yellow oil. 1H NMR (360MHz, CDCl3) δ3.13 (3H, s), 3.75 (3H, s), 3.88 (2H, s), 4.16 (2H, s), 7.26-7.65 (2H, m), 8.09-8.14 (2H, m). MS (CI, NH3), 284 (M+NH4+).