Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.[N:15]([CH2:18][CH2:19][OH:20])=[N+:16]=[N-:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:15]([CH2:18][CH2:19][O:20][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[N+:16]=[N-:17]
Reactant: O=C1CCC(=O)O1
Reactant: [N-]=[N+]=NCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCOC(=O)CCC(=O)O
Temperature: 40 °C

Procedure:
Succinic anhydride (23.0 g, 0.230 mol) was added into a three-neck round-bottom flask equipped with a condenser and a dropping funnel. Under nitrogen atmosphere and magnetic stirring, freshly distilled methylene chloride (150 mL), DMAP (2.3 g, 19 mmol) and freshly distilled Et3N (46.46 g, 0.460 mol) was sequentially added. After the flask was immersed into an ice—water bath, 2-azidoethanol (20.0 g, 0.230 mol) was added dropwise into the previous solution. The solution was later heated at 40° C. for 48 h, and the reaction mixture was washed successively with 1 M HCl solution (5×100 mL) and deionized water (2×100 mL). The organic phase was dried over anhydrous MgSO4 overnight. After filtering and removal of methylene chloride under reduced pressure, the final product was obtained as a yellow viscous liquid. The yield was: 38.4 g, 90%. 1H NMR (CDCl3, δ, ppm): 4.20 (t, 2H, N3CH2CH2), 3.42 (t, 2H, N3CH2), and 2.61 (m, 4H, CH2CH2COOH).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)=[CH:14][C:13]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1ccc(Cl)c(-n2cccc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Cl)c(-n2cccc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-(1H-pyrrol-1-yl)benzaldehyde in an analogous manner to that described in Example 1 gave 9-[4-chloro-3-(1H-pyrrol-1-yl)phenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. This product was recrystallized from dimethylformamide/water and gave a yellow crystalline solid of melting point 282-283° C. (decomposition).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][C:7]1[C:15]([CH3:17])([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH+:8]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=O)=[CH:22][CH:21]=1>>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N+:8]3[C:9]4[C:14]([C:15]([CH3:17])([CH3:16])[C:7]=3[CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:22][CH:21]=1
Reactant: CC1=[NH+]c2ccccc2C1(C)C
Reactant: COc1ccc(C=CC(=O)c2ccccc2)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: COc1ccc(-c2cc(-c3ccccc3)[n+]3c(c2)C(C)(C)c2ccccc2-3)cc1

Procedure:
2,3,3-Trimethyl-3H-indolium perchlorate (5 g.) and 3-(4-methoxyphenyl)-1-phenyl-prop-2-ene-1-one (10 g.) were heated together on a steam bath for three hours. The cooled mixture was purified by recrystallization from acetonitrile. The melting point is 258°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]([C:10]1[S:11][C:12]([S:35][CH3:36])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([NH2:30])=[CH:28][C:27]([N+:31]([O-:33])=[O:32])=[CH:26][C:25]=3[CH3:34])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C([O:50][CH2:51][C:52](Cl)=[O:53])(=O)C.[OH-].[Na+]>C(Cl)Cl.CCOC(C)=O.C(O)(=O)C>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]([C:10]1[S:11][C:12]([S:35][CH3:36])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([NH:30][C:51](=[O:50])[CH2:52][OH:53])=[CH:28][C:27]([N+:31]([O-:33])=[O:32])=[CH:26][C:25]=3[CH3:34])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2N)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2NC(=O)CO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {[4-(6′-amino-2′-methyl-4′-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (216 mg, 0.384 mmol, as prepared in Example 295, step h) in DCM (2 mL) was added DIEA (212 μL, 1.15 mmol) and acetoxyacetyl chloride (54 mL, 0.5 mmol). The solution was stirred at rt for 3 hr. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide 256 mg of a crude oil that was used without further purification. ESI-MS (m/z): Calcd. for C28H30N4O9S3: 663.1 (M+H); found: 662.7, 563.0 (M−Boc). To a solution of the crude intermediate obtained above in MeOH (2.5 mL) was added 1 N NaOH (2.5 mL) and the mixture was stirred at rt for 45 min at which time TLC was consistent with complete conversion. The reaction mixture was neutralized with acetic acid, concentrated in vacuo, and the residue partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 220 mg (92%, crude yield over two steps) of the title compound which was used without further purification. ESI-MS (m/z): Calcd. for C26H28N4O8S3: 621.1 (M+H); found: 620.7, 521.0 (M−Boc).
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)NC=3C=CC=2)C=CC=CC=1>[C:6]1([CH2:5][CH2:4][P:1]([OH:2])[OH:3])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[PH2]O
Reactant: C=Cc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2cccc3c2Oc2c(cccc2P(c2ccccc2)c2ccccc2)N3)cc1
Solvent: CC#N
Product: OP(O)CCc1ccccc1
Yield: 94.2 %

Procedure:
Example 1 is repeated with 99 g of phosphinic acid, 156 g of styrene, 8.7 mg of bis(dibenzylideneacetone)palladium and 5.7 mg of 4,6-bis(diphenylphosphino)-phenoxazine in 400 g of acetonitrile to obtain 240 g (94% of theory) of 2-phenyl-ethylphosphonous acid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][NH:14][CH3:15].CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:1][C:2]1[C:7]([C:8]([N:14]([O:13][CH3:12])[CH3:15])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cccnc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCCl
Product: CON(C)C(=O)c1cccnc1F
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
2-fluoropyridine-3-carboxylic acid (100 g, 708.7 mmol) was dissolved in THF (1.5 L). DMAP (86.58 g, 708.7 mmol) was added followed by N-methoxymethanamine hydrochloride (76.05 g, 779.6 mmol). The mixture was cooled to 10° C. then DIPEA (100.8 g, 135.8 mL, 779.6 mmol) was added followed by EDC (149.5 g, 779.6 mmol) portionwise. The mixture was stirred for 30 minutes, then warmed rapidly to ambient temp (22° C.) and stirred overnight. Lc/Ms after this time showed no acid remaining. The reaction mixture was diluted with ethyl acetate (1 L) and water (1.5 L). The mixture was stirred for 10 minutes then the organic phase was isolated. The aqueous was extracted with ethyl acetate (2×500 ml) and the combined organics washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified through a silica plug, eluting with 50-70% ethyl acetate/petrol. This afforded the title compound as a pale yellow oil (81 g, 62%); 1H NMR (CDCl3) 3.39 (3H, s), 3,68 (3H, brs), 7.29 (1H, m), 7.92 (1H, m), 8.32 (1H, m); MS ES (+) 184.9 (M+1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][CH2:33][C:34]1([C:49]([OH:51])=O)[CH2:39][CH2:38][N:37]([C:40]2[C:41]3[CH:48]=[CH:47][NH:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:36][CH2:35]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.[NH2:61][CH:62]([C:66]1[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=1)[CH2:63][CH2:64][OH:65].Cl>CN1C(=O)CCC1.O1CCOCC1>[NH2:32][CH2:33][C:34]1([C:49]([NH:61][CH:62]([C:66]2[CH:67]=[CH:68][C:69]([Cl:72])=[CH:70][CH:71]=2)[CH2:63][CH2:64][OH:65])=[O:51])[CH2:39][CH2:38][N:37]([C:40]2[C:41]3[CH:48]=[CH:47][NH:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(CCO)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: NCC1(C(=O)NC(CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added to 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 12) (100 mg, 0.27 mmol) and N,N-diisopropylethylamine (0.055 mL, 0.32 mmol) in NMP (5 mL) at 22° C. The resulting solution was stirred at 50° C. for 10 minutes then cooled to ambient temperature. 3-Amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 29) (49.5 mg, 0.27 mmol) was added as a solution in NMP (2 mL) and the mixture was stirred at 22° C. for 16 hours. 4M HCl in dioxane (1 mL) was added and the mixture was stirred at 22° C. for a further 24 hours. The mixture was concentrated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-(aminomethyl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.095 g, 81%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].Br[CH2:15][C:16]([CH3:18])=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[O:1][CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: C=C(C)CBr
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=C(C)COc1cc(C(=O)O)ccc1OC

Procedure:
The reaction of methyl 3-hydroxyl-4-methoxybenzoate and 3-Bromo-2-methyl-propene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 4-Methoxy-3-(2-methyl-allyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.63 (s, —CO2H); 7.56 (d-like, 1 arom. H); 7.43 (m, 1 arom. H); 7.04 (m, 1 arom. H); 5.04, 4.90 (2 s, —C(CH3)═CH2); 4.48 (s, CH2—C(CH3)═CH2); 3.79 (s, OCH3); 1.75 (s, C(CH3)═CH2). 13C-NMR (100 MHz, d6-DMSO): 167.02 (—C═O); 152.90; 147.18; 140.76; 123.39; 122.84; 113.76; 112.33; 111.28; 71.56; 55.75; 19.16.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[CH:6]1[C:15]2[C:16]3[C:25]([C:13]4[C:14]=2[C:9]([CH:10]=[CH:11][CH:12]=4)=[CH:8][CH:7]=1)=[N:24][C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]=3>O>[CH:6]1[C:15]2[C:16]3[C:25]([C:13]4[C:14]=2[C:9]([CH:10]=[C:11]([S:1]([OH:3])(=[O:5])=[O:4])[CH:12]=4)=[CH:8][C:7]=1[S:1]([OH:5])(=[O:4])=[O:3])=[N:24][C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]=3
Reactant: O=S(=O)(O)O
Reactant: c1cc2c3c(cccc3c1)-c1nc3ccccc3nc1-2
Solvent: O
Product: O=S(=O)(O)c1cc2c3c(cc(S(=O)(=O)O)cc3c1)-c1nc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
As represented by the following reaction formula (VII), after 30% fuming sulfuric acid (2.1 L) was added to 300 g of acenaphtho[1,2-b]quinoxaline and the mixture was stirred at room temperature for 24 hours, the resultant was heated to 130° C. and stirred for 32 hours for reaction. While keeping the obtained solution at 40° C. to 50° C., 4.5 L of ion exchange water was added for dilution, and the resultant was further stirred for 3 hours. The precipitate was filtered and recrystallized with sulfuric acid. After being washed with 1 L of acetone for three times, the resultant was filtered and subjected to vacuum drying at 60° C. for 12 hours to obtain acenaphtho[1,2-b]quinoxaline-2,5-disulfonic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13][CH:12]=1.C([SiH](CC)CC)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: COC(=O)c1sccc1N
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sccc1NCc1ccnc2ccccc12
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3-amino-thiophene-2-carboxylic acid methyl ester (5 g, 31.8 mmol) and 4-quinoline-carboxaldehyde (5.25 g, 33.4 mmol) in TFA/CH2Cl2 (75 mL, 75 mL) was heated at 50° C. for 3.5 h. The solution was cooled in an ice bath and triethylsilane (10.2 mL, 63.6 mmol) was added drop-wise over 5 min. The reaction mixture was stirred at 50° C. for 3.5 h, cooled to rt, and 500 mL of CH2Cl2 was added. The reaction mixture was basified with 10 N NaOH (pH 6-7) followed by sat. NaHCO3 (pH 8). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield the crude product, which was triturated with hexane to give pure methyl 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylate as white solid. MS (ES): m/z 298.55 (100) [MH+]; 1H-NMR (400 MHz/CDCl3): δ 3.87 (s, 3H), 5.00 (d, J=4.0 Hz, 2H), 6.48 (d, J=5.6 Hz, 1H), 7.30 (d, J=5.6 Hz, 1H), 7.36 (m, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.76 (t, J=9.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.86 (d, J=4.4 Hz, 1H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH:8]=[O:9].[CH2:10]=[O:11].[OH-].[Na+]>O>[OH:9][CH2:8][C:2]1([CH2:10][OH:11])[CH2:3][CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2
Reactant: C=O
Reactant: O=CC1CC2C=CC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC1(CO)CC2C=CC1C2
Yield: 77.6 %

Procedure:
25 gm of norborn-5-en-2-carbaldehyde were added in drops to a mixture of 42 ml of 37% formalin and 12.3 gm of sodium hydroxide, dissolved in 36.9 ml of water, under stirring under a nitrogen atmosphere and water cooling over a period of 25 minutes. The temperature of the reaction mixture rose to 30° C. Subsequently the stirring was continued for another hour at 55° C., and then the reaction mixture was extracted with 50 ml of methylisobutyl ketone. The organic phase was washed with 50 ml of water, and the aqueous phase with 50 ml of methylisobutylketone. The combined organic phases were washed neutral, dried over sodium sulfate, and the solvent was distilled off. The residue was recrystallized from petroleum-ether (60-95)/toluene (1:1). The intermediate product, 2,2-di-hydroxymethyl-norborn-5-ene, was obtained in the form of colorless crystals with a yield of 77.6% of the theory, and had the following characteristics:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: N#Cc1cccc(F)c1
Product: CN1CCN(c2cccc(C#N)c2)CC1

Procedure:
According to a similar manner to that in Reference Example 17, the title compound was synthesized from 3-fluorobenzonitrile and 1-methylpiperazine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].OS(O)(=O)=O>O>[O:3]=[C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:1]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(C=Cc1ccccc1)c1cc(Cl)ccc1O
Reaction time: 1 h
Yield: 74.8 %

Procedure:
34.1 g of 5-chloro-2-hydroxyacetophenone and 22 g of benzaldehyde were added to a mixture of 180 ml of H2O and 37 g of 50% strength sodium hydroxide solution at room temperature. The mixture was heated to 55°-60° C., with thorough stirring, and was stirred at this temperature for about 1 hour. It was then rendered weakly acid with 25% strength H2SO4 (about 100 ml), with thorough cooling, and the precipitate was filtered off with suction, washed thoroughly with H2O and recrystallized from a 9:1 mixture of methanol and acetone to give 38.7 g of 3-oxo-1-phenyl-3-(2'-hydroxy-5'-chlorophenyl)-propene of melting point 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([S:22]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:24])=[O:23])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]O)=[CH:38][CH:37]=1.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>C1COCC1.ClCCl>[Cl:30][C:27]1[S:26][C:25]([S:22]([N:10]([S:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][N:32]([CH3:31])[CH3:44])=[CH:41][CH:40]=3)[N:12]=2)(=[O:23])=[O:24])=[CH:29][CH:28]=1
Reactant: COc1cccc2[nH]nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c12
Reactant: CN(C)CCOc1ccc(CO)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(OCCN(C)C)cc1
Temperature: 65 °C

Procedure:
A mixture of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 10) (0.262 g, 0.5 mmol) and (4-{[2-(dimethylamino)ethyl]oxy}phenyl)methanol (98 mg, 0.5 mmol), triphenylphosphine (197 mg, 0.75 mmol) and di tert-butyl azodicarboxylate (230 mg, 1 mmol) in THF (30 mL) was heated to 65° C. for h. LCMS indicated complete reaction. The mixture was concentrated and the residue was dissolved in methanol and applied to an SCX-2 ion-exchange cartridge (50 g) eluting with methanol, followed by 10% aq. ammonia in methanol. The ammoniacal fractions were combined and evaporated in vacuo to give the crude product (400 mg) as a yellow gum. The mixture was loaded in dichloromethane on a silica cartridge (20 g) and purified by chromatography on Flashmaster using a gradient of 0-15% methanol (containing 1% Et3N)-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give impure product (167 mg) as a colourless gum. The sample was dissolved in 1:1 MeOH-DMSO (2 mL) and purified by MDAP on Xbridge column using acetonitrile water with an ammonium carbonate modifier Appropriate fractions were combined and the solvent was evaporated in vacuo to give the title compound (91 mg, 26%) LCMS (System C) (5 min run) RT=3.76 min, ES+ve m/z 701/703 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([CH2:14][Br:15])=[O:13])[O:8][CH2:7][C:6]=2[C:5](=[O:16])[CH:4]=[CH:3]1.C(O[CH:21]=[CH:22][CH:23]=[CH2:24])(=O)C>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([CH2:14][Br:15])=[O:13])[O:8][CH2:7][C:6]=2[C:5](=[O:16])[C:4]2[C:3]1=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: C=CC=COC(C)=O
Reactant: O=C1C=CC(=O)C2=C1C=C(C(=O)CBr)OC2
Solvent: Cc1ccccc1
Product: O=C(CBr)C1=CC2=C(CO1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution containing one equivalent of isochromandione (263 mg, 0.92 mmol) from step 1 (example 6) in 25 ml of dry toluene was added three equivalents (2.7 mmol) of acetoxybutadiene. The reaction mixture was stirred overnight under argon at room temperature and then two hours at 60° C. After removal of solvent, the crude product was flash chromatographed (toluene/EtOAc,9:1). The titled orange compound was isolated (192 mg) in 62% yield.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[C:20]([CH:23]=2)[C:21]#[N:22])=[CH:11][C:10]=1[CH2:31][CH3:32])C1C=CC=CC=1.C(O)C>[Pd].CCOCC>[CH2:31]([C:10]1[C:9](=[O:8])[NH:14][C:13]([CH3:15])=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[C:20]([CH:23]=2)[C:21]#[N:22])[CH:11]=1)[CH3:32]
Reactant: CCc1cc(-c2ccc(CN3CCOCC3)c(C#N)c2)c(C)nc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CCc1cc(-c2ccc(CN3CCOCC3)c(C#N)c2)c(C)[nH]c1=O
Reaction time: 2.5 h
Yield: 76.8 %

Procedure:
A mixture of 5-(6-benzyloxy-5-ethyl-2-methylpyridin-3-yl)-2-(morpholin-4-yl)methylbenzonitrile (460 mg, 1.08 mmol), 5% palladium on charcoal (30 mg) and ethanol (15 mL) is stirred under an atmosphere of hydrogen. After 2.5 hr, the catalyst is separated by filtration through a pad of Hi-Flo. The filtrate is concentrated and the residue is stirred with ethereal hydrochloric acid. The solvent is removed to give a foam that is dissolved in ether and the solvent removed. This procedure is repeated twice more to afford 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(morpholin-4-yl)methylbenzonitrile (280 mg, 77%) as a pale yellow solid. LC/MS: MS m/e=338 (M+H); RT 0.38 min.
Reaction SMILES: [Li+].[Br-:2].Cl[CH2:4][C:5](=[CH2:15])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1COCC1>[Br:2][CH2:4][C:5](=[CH2:15])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [Br-]
Reactant: C=C(CCl)COCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(CBr)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
LiBr (2.7 g, 31.6 mmol) was flame dried under vacuum and then cooled to room temperature. TBABr (255 mg, 0.79 mmol), (2-chloromethyl-allyloxymethyl)-benzene (3.1 g, 15.8 mmol) and THF (5 mL) were then added and the suspension was stirred at 60° C. for 2 h. The mixture was filtered through Celite and the solvent was removed in vacuo to give the title compound (3.4 g) as a colourless oil which was used in the next step without further purification. 1H NMR (CDCl3): 7.47-7.30 (5H, m), 5.47-5.33 (1H, m), 5.30 (1H, q), 4.56 (2H, s), 4.19 (2H, s), 4.08 (2H, s).
Reaction SMILES: C[C:2]([CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)(C)C)([CH3:4])C>O>[CH3:4][CH2:2][CH2:5][CH2:6][CH2:9][CH2:4][CH2:2][CH2:5][CH2:6][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:13][CH:14]=1
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCCO)cc1
Solvent: O
Product: CCCCCCCCCc1ccc(OCCO)cc1

Procedure:
TRITON X-102 (an octylphenoxy polyethoxy ethanol, HLB 14.6, available commercially from Union Carbide) in 9:1 water-emulsifier ratio did not invert the emulsion; TRITON N-101 (an nonylphenoxy polyethoxy ethanol, HLB 13.4, Union Carbide) gave similar results; TRITON X-405 (HLB 17.9) and TRITON X-305 (HLB 17.3) gave separation into two layers. Optical microscopy showed there was no flocculation with TRITON X-102 OR TRITON N-101, slight flocculation with TRITON X-405, and much more flocculation with the TRITON X-305.