Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CN(CC(C2C=CC(CO)=C([F:52])C=2)=O)C(=O)C=1)C1C=CC=CC=1.P(Br)(Br)Br>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[C:20]([F:52])[CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)c(F)c1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Agent: BrP(Br)Br
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)c(F)c1

Procedure:
4-Benzyloxy-1-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following preparation 15c from 240 mg (0.65 mmol) 4-benzyloxy-1-[2-(3-fluoro-4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 16g) and 0.43 mL (4.57 mmol) phosphorus tribromide.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=[N:54][C:49]2C=[CH:51][CH:52]=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NC1C=NC=CC=1>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][C:48]2[CH:49]=[N:54][CH:51]=[CH:52][CH:53]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3cccnc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.3 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 3-aminopyridine (11.3 mg, 0.08 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (3.3 mg, 9%). LC-MS m/z 598 (M+H)+.
Reaction SMILES: Cl.[O:2]([C@@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[N+:29]([O-:31])=[O:30])[CH2:11]1)[Si](C(C)(C)C)(C)C>CO>[N+:29]([C@H:19]1[CH2:18][CH2:17][C@H:16]2[C@H:15]3[C@H:24]([CH2:23][CH2:22][C@:20]12[CH3:21])[C@:25]1([CH3:28])[C@H:12]([CH2:11][C@H:10]([OH:2])[CH2:27][CH2:26]1)[CH2:13][CH2:14]3)([O-:31])=[O:30]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([N+](=O)[O-])CC[C@@H]32)C1
Agent: Cl
Solvent: CO
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([N+](=O)[O-])CC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
Aqueous HCl (1 M, 20 mL) was added to a suspension of 3α-(t-butyldimethylsiloxy)-17β-nitro-5α-androstane (2.89 g, 6.6 mmol) in methanol (100 mL) and was allowed to stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure, partitioned between EtOAc (100 mL) and brine (50 mL), and the layers were separated. The aqueous fraction was then extracted with EtOAc (2×50 mL) and the organic extracts were combined, washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried over (Na2SO4), and concentrated under reduced pressure. The resulting semisolid was purified on silica using medium pressure column chromatography (hexane/EtOAc, 7:3) to provide 17β-nitro-5α-androstan-3α-ol (1.05 g, 49%) as a pale yellow solid. 1H-NMR (300 MHz, CDCl3) δ 0.73 (s, 3H), 0.79 (s, 3H), 2.05-0.86 (m, 23H), 2.70-2.52 (m, 1H), 4.05 (br s, 1H), 4.37 (dd, J=9, 9 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([NH:26][C:27]2[N:28]=[C:29]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[S:30][CH:31]=2)=[O:25])[N:18]=1)C(=O)OC(C)(C)C)[CH2:4][CH:5]([CH3:7])[CH3:6].Cl.[OH-].[Na+]>CO>[OH:1][CH2:2][CH:3]([NH:8][CH2:16][C:17]1[N:18]=[C:19]([NH:23][C:24]([NH:26][C:27]2[N:28]=[C:29]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[S:30][CH:31]=2)=[O:25])[CH:20]=[CH:21][CH:22]=1)[CH2:4][CH:5]([CH3:6])[CH3:7]
Reactant: CC(C)CC(CO)N(Cc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(CO)NCc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Temperature: 40 °C

Procedure:
tert-Butyl (1-hydroxymethyl-3-methyl-butyl)-(6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-carbamate (165 mg, 0.313 mmol, Example 62) in MeOH (5 mL) was treated with HCl (0.16 mL, 0.627 mmol, 4M in dioxane). The resulting stirred solution was heated at 40° C. in a closed system for 15 h. After cooling to RT, the pH was adjusted to 7 using 1 N NaOH. Solvent was removed and the residue was extracted with CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4, and concentrated to yield a brown liquid crude product. This crude product was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (95:5) gave the final compound as a tan solid. MS m/z: 427.2 (M+H). Calc'd. for C21H26N6O2S-426.54.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[NH2:29][C:30]1[CH:49]=[CH:48][C:33]([O:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]([C:15]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:37][CH2:36]3)=[CH:48][CH:49]=2)=[O:17])[CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CN(C(=O)OCc4ccccc4)C3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(Benzyloxycarbonyl)azetidine-3-carboxylic acid (5.10 g, 21.67 mmol), 1-hydroxybenzotriazole hydrate (4.15 g, 27.1 mmol) and tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (5.28 g, 18.06 mmol) were suspended in dimethylformamide (25 ml) followed by addition of diisopropylethylamine (9.64 ml, 54.2 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5.19 g, 27.1 mmol). The mixture was stirred at room temperature overnight and the solution was diluted with water. The resulting turbid mixture was extracted with ethyl acetate and then ethyl acetate/tetrahydrofuran. The organics were combined and dried over magnesium sulfate, filtered and concentrated to give a solid which was triturated with ether and filtered to give the title compound.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21][CH3:22])[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[OH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.[O-]CC.[Na+]>>[OH:5][C:4]([C:7]([F:8])([F:9])[F:10])([CH2:3][C:2]([CH3:11])([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21][CH3:22])[CH:13]=1)[CH3:1])[CH2:6][N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24](=[O:23])[CH:25]=[CH:26]1
Reactant: Oc1ccnc2ccccc12
Reactant: CSc1cc2c(c(C(C)(C)CC3(C(F)(F)F)CO3)c1)OCC2
Agent: CC[O-]
Agent: [Na+]
Product: CSc1cc2c(c(C(C)(C)CC(O)(Cn3ccc(=O)c4ccccc43)C(F)(F)F)c1)OCC2

Procedure:
7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methylsulfanyl-2,3-dihydrobenzofuran was reacted with 4-hydroxyquinoline and sodium ethoxide according to Example 35 to give 1-[2-hydroxy-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-trifluoromethylpentyl]-1H-quinolin-4-one.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[C:10]([C:16](=[O:17])[C:5]=2[CH:4]=1)=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=3)#[N:2].S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12](=[O:21])[NH:11][C:10]=3[C:16](=[O:17])[C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)C(=O)c1c(ccc[n+]1[O-])CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)C(=O)c1[nH]c(=O)ccc1CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.85 gram (0.0034 mole) of the N-oxide thus obtained and 0.77 gram (0.0043 mole) of tosyl chloride in 37.5 milliliters of chloroform was added a solution of 0.58 gram (0.0042 mole) of potassium carbonate in 5.8 milliliters of water and the resulting mixture was stirred vigorously at room temperature for two days and the reaction mixture washed with alkali to obtain an 11-oxo-5,6-dihydrobenzo[5,6]-cyclohepta[1,2-b]pyrid-2(1H)one product which is recovered and purified by conventional procedures.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:22]Br)=[C:15]([CH:21]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>C(O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:22][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)=[C:15]([CH:21]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cc(F)ccc1CBr
Reactant: Oc1cccc(F)c1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(F)ccc1COc1cccc(F)c1
Yield: 105.1 %

Procedure:
To a solution of 1.5 g of sodium metal in 100 ml of ethanol are added 8 g of 3-fluorophenol and 17 g of ethyl 5-fluoro-2-bromomethylbenzoate [U.S. Pat. No. 4,082,850]and the mixture is refluxed with heating for 8 hours. After cooling, 300 ml of water is added and the mixture is extracted with toluene. The extract is washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 20 g of ethyl 5-fluoro-2-[(3-fluorophenyl oxy)methyl]benzoate (oil). Mass spectrum m/z: 292(M+).
Reaction SMILES: [CH3:1][C:2]([C@:4]12[CH2:13][C@@:12]3([CH3:14])[C@:8]([CH3:15])([C@@H:9]1[CH2:10][CH2:11]3)[CH2:7][CH2:6][CH2:5]2)=[CH2:3].C(O)(=O)C1C(=CC=CC=1)[OH:19]>C(Cl)Cl>[CH3:14][C@:12]12[CH2:13][C@@:4]3([C:2]([CH2:1][OH:19])=[CH2:3])[CH:9]([C:8]1([CH3:15])[CH2:7][CH2:6][CH2:5]3)[CH2:10][CH2:11]2
Reactant: O=C(O)c1ccccc1O
Reactant: C=C(C)[C@@]12CCC[C@@]3(C)[C@@H]1CC[C@@]3(C)C2
Solvent: ClCCl
Product: C=C(CO)[C@@]12CCCC3(C)C1CC[C@@]3(C)C2
Temperature: 25 °C

Procedure:
Alloisolongifolene alcohol was prepared from alloisolongifolene via its corresponding aldehyde by SeO2, according to the protocol of Umbreit and Sharpless (1977). To a solution of 77 mg SeO2 and 68 mg salicylic acid in 30 mL CH2Cl2, 100 mg alloisolongifolene was added. Stirring at room temperature turned the reaction mixture yellow and a red solid precipitated in the first few hours. The reaction was monitored by GC-MS along with TLC and was stoppedby the addition of 60 mL demineralised water after 2.5 days. The reaction mixture was extracted with 45 mL ether, and the organic phase was subsequently washed with 30 mL brine. The red precipitate remained in the aqueous phase during extraction. After drying and evaporation, the organic phase yielded 214 mg of a crude solid that after flash chromatography on silica with pentane-CH2Cl2 (3:1) yielded 31 mg of alloisolongifolene aldehyde, a strong odorous compound (cedar-wood like). 1H NMR (200 MHz, C6D6) δ 0.71 (s, 3H, Me) δ 0.90 (s, 3H, Me), δ 0.93–2.04 (m, 13H), δ 5.42 (s, 1H, CH2═C), δ 5.73 (s, 1H, CH2═C), δ 9.35 (s, 1H, CH═O). 13C NMR (50 MHz, C6D6) δ 15.0 (q), δ 19.6 (q), δ 20.5 (t), δ 22.2 (t), δ 32.3 (t), δ 36.3 (t), δ 38.7 (t), δ 45.1 (t), δ 46.1 (s), δ 47.1 (s), δ 47.7 (s), δ 50.8 (d), δ 133.5 (t), δ 157.0 (s), δ 193.9 (d). EIMS (70 eV) m/z: 218 [M]+ (41), 203 (48), 189 (32), 185 (30), 175 (42), 161 (68), 147 (53), 145 (37), 133 (35), 119 (46), 107 (42), 105 (80), 95 (33), 93 (46), 91 (100), 81 (37), 79 (65), 77 (64), 55 (43), 53 (34), 41 (74), 39 (45). Fifteen milligrams of the aldehyde was added to a solution of 1.8 mg LiAlH4 in 0.5 mL ether. The grey suspension was stirred for 17.5 hours at room temperature and for an additional half our after the careful addition of one spatula Na2SO4.10H2O. One and a half millilitre of demineralised water was added to the mixture that was subsequently 3 times extracted with 1 mL of ether. The ether was passed through glasswool-plugged Pasteur pipette filled with silica and a spatula tip of MgSO4. The solvent was evaporated yielding 17 mg of alloisolongifolene alcohol. 1H NMR (200 MHz, C6D6) δ 0.77 (s, 3H, Me), δ 0.91 (s, 3H, Me), 0.96–1.63 (m, 13H), δ 3.96 (m, 2H), δ 4.95 (d, 1H, J=1.3 Hz) δ 5.30 (dd, 1H, J=3.26 Hz, 1.55 Hz). 13C NMR (50 MHz, C6D6) δ 15.1 (q),δ 19.7 (q), δ 20.7 (t), δ 22.3 (t), δ 32.4 (t), 37.5 (t), 38.7 (t), 44.0 (t), δ 46.1 (s), δ 47.8 (s), 6 48.2 (s), δ 51.6 (d), δ 63.4 (t), δ 107.9 (t), δ 155.9 (s). EIMS (70 eV) m/z: 220 [M]+ (5), 189 (35), 187 (36), 163 (30), 161 (56), 160 (37), 159 (30), 147 (36), 145 (38), 133 (32), 131 (37), 119 (44), 107 (61), (91), 95 (94), 93 (57), 91 (100), 81 (53), 79 (60), 77 (52), 67 (39), 55 (45), 41 (62).
Reaction SMILES: COC([C:5]1[C:6](C(OC)=O)=[CH:7][CH:8]=[C:9]2[C:18]=1[CH:17]=[C:16](OC)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1)=O.[Na+].C(=O)([O-])O>O>[CH:5]1[C:18]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(cc(OC)c3ccccc32)c1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: c1ccc2c(c1)ccc1ccccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 131.1 %

Procedure:
9-methoxy phenanthrene-1,2-dicarboxylic acid dimethyl ester 8.11 g (0.025 mol) obtained in the example I-1 was dissolved in chloride methylene 100 ml, by ice-cooling and mixing under nitrogen gas airstreams, 1M 3 bromide boron/chloride methylene solution 100 ml (0.1 mol) was dropped for 60 minutes, and further a mixing reaction was performed for 5 hours under a room temperature. Then, reactants were poured into an ice, water was added, and further hydrogen carbonate sodium 8.4 g (0.1 mol) was added and mixed sufficiently, accordingly extracted crystals were filtered. Then, they were washed twice by 500 ml ion exchange water and dried under reduced pressure at the temperature of 60° C., thus 5.84 g (yield 88.4%) objective phenanthrene compound was obtained. An infrared absorption spectrum of this phenanthrene compound is shown in FIG. 5.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:1]=[CH:12][O:13][CH3:14]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
Ninety grams of m-anisaldehyde, 250 g of (methoxymethyl)triphenylphosphonium chloride and 800 ml of tetrahydrofuran were mixed, and then 82.5 g of potassium tert-butoxide was added to this mixed suspension under ice-cooling, and the solution was stirred for 2 hours at room temperature. The reaction solution was poured in ice water, and after distilling out the THF, the mixture was extracted with ethyl acetate. The extract solution was washed with sodium bicarbonate aqueous solution and dried. The extract solution was concentrated to obtain a residue to which hexane was then added, and the resulting precipitate was filtered out. The filtrate was then concentrated, and the residue was subjected to silica gel column chromatography. Elution was then performed with a mixed solvent of hexane:ethyl acetate=20:1, to obtain 90 g of methyl (3-methoxystyryl) ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][CH2:7][C:6](=[O:9])[O:5][C:3]1=[O:4].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)(CCC(O)=O)C(O)=O.OS(O)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][C:2]([CH3:10])([CH2:8][CH2:7][C:6]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:3]([OH:5])=[O:4]
Reactant: OCc1ccccc1
Reactant: CC1(C)CCC(=O)OC1=O
Agent: CC(C)(CCC(=O)O)C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(CCC(=O)OCc1ccccc1)C(=O)O
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a mixture of 3 g (0.021 mol) of 2.2-dimethylglutaric anhydride, 2.0 ml (0.019 mol) of benzyl alcohol in 10 ml of CH2Cl2 was added 100 mg of DMAP and 3.4 ml of pyridine. The resulting solution was stired at room temperature for 4 h. After additional 2.2-dimethyl-glutaric acid (0.7 g, 4.9 mmol) was added, the mixture continued to be stirred overnight, then poured into 0.5M H2SO4 (aq.) solution and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and filtered. Concentration followed by purification by flash chromatography on silica gel using EtOAc/hexane (1:1) as the irrigant gave 3.5 g of desired product in 66% yield and 1.2 g of isomer in 23% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[O:25])[N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:3]=12.[H-].[Na+].I[CH3:29].O>O1CCCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:9]2[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:3]3[C:2](=[O:1])[CH:7]=[CH:6][N:5]([CH3:29])[C:4]=3[C:8]2=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(CN2C(=O)c3nccc(O)c3C23CCCCC3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)c3c(c(=O)ccn3C)C23CCCCC3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4′-hydroxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one (1.0 mmol, 1 eq) in tetrahydrofuran (25 mL), add sodium hydride (2.5 mmol, 2.5 eq) at 0° C. and stir for 20 min. Add iodomethane (2.5 mmol, 2.5 eq) to the above mixture and stir for 16 h. After completion add water to the reaction and extract with ethyl acetate. Remove the solvent under reduced pressure to get the crude which is purified by column chromatography to give 6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione (6).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([Cl:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][N:16]1[C:20](=[O:21])[C:19]2[C:22]([CH:28]([CH3:30])[CH3:29])=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=2[S:17]1(=[O:32])=[O:31].[F-].[K+]>CN(C=O)C>[CH:28]([C:22]1[C:19]2[C:20](=[O:21])[N:16]([CH2:15][O:12][C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([Cl:13])[CH:10]=3)[S:17](=[O:32])(=[O:31])[C:18]=2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=1)([CH3:30])[CH3:29]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: O=C1CC(Cl)=NN1c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(Cl)nn1-c1ccccc1)C2=O
Temperature: 0 °C
Yield: 31.9 %

Procedure:
A mixture 2,4-dihydro-2-phenyl-5-chloro-3H-pyrazol-3-one (350 mg; 1.8 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benziso thiazol-3(2H)-one 1,1-dioxide (686 mg, 1.98 mmol), and KF (209 mg; 3.6 mmol) in DMF (8 ml) was stirred at 20° C. for 3 hours and the mixture was diluted with ice water. The above mixture was extracted with ether (3×) and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 25-50% ethyl acetate/hexane; methylene chloride/hexane, 20-100%) and recrystallized from ethyl acetate/hexane to afford 265 mg (32%) of 4-isopropyl-6-methoxy-2-(1-phenyl-3-chloropyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1, 1-dioxide (Formula I: R1 =phenyl; R2 =Cl; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[N:7]=1.C(N(C(C)C)CC)(C)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(OCC)(=O)C>O1CCOCC1>[C:18]([N:25]1[CH2:26][CH2:27][N:28]([C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[N:4][CH:5]=2)[CH2:29][CH2:30]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cnnc(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cnnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31.1 %

Procedure:
To a solution of 3,5-dichloro[1,2,4]triazine (0.34 g, 2.28 mmol.) in anhydrous dioxane (4 mL) was add diisopropylethylamine (0.44 g, 3.41 mmol.) and N—Boc-piperazine (0.424 g, 2.28 mmol.). The reaction mixture was stirred at room temperature for 40 minutes. Ethyl acetate (200 mL) was added. The organic solution was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporation under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 5-(4-Boc-piperazin-1-yl)-3-chloro[1,2,4]triazine 151 (0.212 g, 0.71 mmol.).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[NH:9][C:8]=2[CH3:22])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[NH2:56][CH2:57][C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([NH:56][CH2:57][C:58]4[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[NH:9][C:8]=2[CH3:22])=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2[nH]c(C)c(Cc3ccc(Cl)cc3)c2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-n2[nH]c(C)c(Cc3ccc(Cl)cc3)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-(4-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazole-5-carboxylic acid (0.05 g, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.04 g, 0.20 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.28 mmol) in N,N-dimethylformamide (2 mL) was added 1-hydroxy-benzotriazole (0.05 g, 0.37 mmol). The resulting mixture was stirred at ambient temperature for 15 minutes and 3-(aminomethyl)pyridine (0.02 mL, 0.02 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 hours, diluted with ethyl acetate (30 mL), washed with water and brine. The organic solution was dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by column chromatography to the title compound as a white powder (0.03 g, 48%): mp 215-217° C.: 1H NMR (300 MHz, DMSO-d6) δ 12.31 (br s, 1H), 8.71 (t, J=5.8 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.42 (dd, J=4.8, 1.6 Hz, 1H), 7.68 (td, J=7.8 Hz, 1.9 Hz, 1H), 7.36-7.19 (m, 5H), 4.38 (d, J=5.8 Hz, 2H), 3.52 (s, 2H), 2.52 (s, 3H), 2.13 (s, 3H); MS (ES+) m/z 454.3 (M+1).