Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(-c2ccc(O)cc2)ccnc1Cl
Reactant: OB(O)c1ccccc1
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)ccnc1Cl
Yield: 90 %

Procedure:
Following conditions described in Step 1 of Example 3, 2-chloro-4-(4-hydroxyphenyl)nicotinonitrile was reacted with phenylboronic acid to give 2-chloro-4-(4-phenoxyphenyl)nicotinonitrile (60 mg, 90% yield). 1H NMR (500 MHz, CDCl3) 8 ppm 8.56 (1H, δ, J=5.22 Hz), 7.53-7.67 (2H, m), 7.37-7.49 (3H, m), 7.22 (1H, t, J=7.42 Hz), 7.09-7.16 (4H, m); MS (ES+) m/z: 307 (M+H); LC retention time: 3.863 min (analytical HPLC Method A).
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=[N:2]1.[H-].[Na+].[CH2:16](I)[CH2:17][CH2:18][CH3:19].O>CN(C)C=O>[CH2:16]([N:1]1[C:5]2[N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=[N:2]1)[CH2:17][CH2:18][CH3:19].[CH2:16]([N:2]1[CH:3]=[C:4]2[C:5]([N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9]2=[O:10])=[N:1]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: O=c1c2cn[nH]c2nc2n1CCS2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1cc2c(=O)n3c(nc2n1)SCC3
Product: CCCCn1ncc2c(=O)n3c(nc21)SCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %
Yield: 26 %

Procedure:
In 50 ml of dimethylformamide was dissolved 2.50 g (12.9 mmol) of Compound 1 prepared in Example 1, and 0.77 g (19.3 mmol) of sodium hydride (60%) and 2.20 ml (19.3 mmol) of butyl iodide were added to the solution, followed by stirring at room temperature for one hour. After addition of water and evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1). The first and second main fractions gave 2.30 g (71%) of Compound 32 and 0.84 g (26%) of Compound 33, respectively. Each compound was recrystallized from ethanol for purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[N:6]=[N:5][CH:4]=1.C1CCN2C(=NCCC2)CC1.[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:40])=[C:34](F)[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:26][CH2:25]1>C(#N)C>[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:40])=[C:34]([N:10]4[CH2:11][CH2:12][CH:8]([N:7]5[C:3]([CH3:2])=[CH:4][N:5]=[N:6]5)[CH2:9]4)[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:25][CH2:26]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: Cc1cnnn1C1CCNC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N2CCC(n3nncc3C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 6.9 %

Procedure:
3-(5-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (64 mg, 0.34 mmol) and DBU (77 mg, 0.51 mmol) was added to a suspension of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed for 18 hrs and then concentrated to dryness. The residue was triturated with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 5 mg of title product. m.p. 226°-228° C.; 1H NMR (TFA) δ: 9.35 (s, 1H), 8.32 (s, 1H), 8.08 (d, 1H), 5.72 (m, 1H), 4.30-4.80 (m, 4H), 4.10 (m, 1H), 3.80 (s, 3H), 2.90 (m, 2H), 2.72 (s, 3H), 1.12-1.64 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[N:25]1([C:31]2[N:32]=[C:33]([CH2:38][C:39]([O-])=[O:40])[NH:34][C:35](=[O:37])[CH:36]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[Na+].O>CN(C)C=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][N:6]2[C:39](=[O:40])[CH2:38][C:33]1[NH:34][C:35](=[O:37])[CH:36]=[C:31]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:32]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1(C)CNc2cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.3 %

Procedure:
130 mg of 4-chloro-3,3-dimethyl-2,3-dihydro-1H-indole [which can be prepared according to Tet. Let. (1987) (28), 5291-5294] and 220 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 187 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2c of example 1c) in 3 ml of N,N-dimethylformamide and 3 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours and then 15 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05: v/v), so as to give 24 mg of 2-[2-(4-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one, the characteristics of which are the following:
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:32]1(=[O:42])[N:36]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12
Reactant: C=CCCCCCCCCCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCCCCCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 10-undecene-1-ol (5.00 g, 29.36 mmol, 1 equiv), triphenylphosphine (7.70 g, 29.36 mmol, 1 equiv) and phthalimide (4.32 g, 29.36 mmol, 1 equiv) in dry tetrahydrofuran (THF, 30 mL) was stirred vigorously under argon. Diethyl azodicarboxylate (DEAD, 5.11 g, 29.36 mmol, 1 equiv) was diluted with THF (12 mL) and added dropwise by syringe. After the addition, the reaction was stirred at room temperature for 4 hours. The solvent was evaporated under vacuum and ether (30 mL) was added to precipitate the triphenylphosphine oxide and hydrazine dicarboxylate which were removed by filtration. The precipitate was rinsed with ether (2×30 mL) and the combined filtrates were evaporated to afford a yellow solid. The yellow solid was triturated with warm hexanes (3×50 mL) and filtered. The combined hexanes were evaporated to give 1-phthalimidylundec-10-ene as a yellow wax.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13](OC3C=CC=CC=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC([Cl:29])=C(Cl)C=1>ClC1C=C(C)C=CC=1Cl.ClC1C=CC(Cl)=CC=1Cl.ClC1C(Cl)=C(Cl)C=CC=1>[C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13]([Cl:29])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccccc1Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc(Oc2ccccc2)cc1
Agent: Cc1ccc(Cl)c(Cl)c1
Agent: Clc1cccc(Cl)c1Cl
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=S(=O)(c1ccccc1)c1ccc(Cl)cc1

Procedure:
FIGS. 1 and 2 illustrate the behavior of the new phase transfer catalysts in the formation of 1,1′-(1-methylethylidene)bis[4-[4-(phenylsulfonyl)phenoxy]benzene (CAS No. 90139-53-0). When the P2-EthylMethyl mesylate was used as a PTC at 1.0 mole % in the model reaction in refluxing o-DCB at 180° C. (See 4 (FIG. 1)), the reaction exhibited pseudo-first order kinetics. This indicates that no catalyst decomposition nor diminution in rate was occurring during the reaction. In order to further test the stability of the phosphazenium salt, similar reactions were carried out at higher temperatures, in 3,4-dichlorotoluene (bp=200° C.) (See 6 (FIG. 1)) and in 1,2,4-trichlorobenzene (bp=214° C.) (See 2 (FIG. 1)). As shown in FIG. 1, even at 200° C., essentially linear reaction kinetics were observed, indicating no decomposition of the P2-EthylMethyl mesylate phase transfer catalyst. In trichlorobenzene, only a small amount of decomposition was observed, after 60 minutes (See 2 (FIG. 1)). In this instance only 0.5 mole % catalyst was used, since after initial range-finding experiments it was determined that reaction using 1.0 mole % would be too fast to follow accurately at 214° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:13][CH:14]([NH2:16])[CH3:15].S1C=CC=C1.[H][H]>CO.[Pd]>[CH3:13][CH:14]([NH:16][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1)[CH3:15]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: [H][H]
Reactant: CC(C)N
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CCOC(=O)N1CCC(NC(C)C)CC1
Yield: 94 %

Procedure:
A mixture of 100 parts of ethyl 4-oxo-1-piperidinecarboxylate, 42 parts of 2-propanamine, 2 parts of a solution of thiophene in methanol 4% and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 118 parts (94%) of ethyl 4-[(1-methylethyl)amino]-1-piperidinecarboxylate (1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19].[C:22]([Si](C)(C)C)#[N:23].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(#N)C>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:22]#[N:23])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=1
Reactant: C[Si](C)(C)C#N
Reactant: FC(F)(F)c1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-[4-(bromomethyl)-3-(trifluoromethyl)phenyl]-1,3-benzoxazole (528 mg, 1.5 mmol) and cyanotrimethylsilane (0.30 mL, 2.2 mmol) in acetonitrile (19 mL) was added TBAF (1.0M in THF, 2.2 mL, 2.2 mmol) and the mixture was stirred at rt for 2 h. The solvent was removed in vacuo and the crude was purified by flash chromatography eluting with EtOAc:hexanes (1:9) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-(trifluoromethyl)phenyl]acetonitrile as a colorless solid. 1H NMR (CDCl3, 300 MHz) δ 8.60 (s, 1H), 8.48 (d, 1H), 7.88 (d, 1H), 7.82 (m, 1H), 7.63 (m, 1H), 7.43 (m, 2H), 4.05 (s, 2H). MS (ESI) 303 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][C:75]([NH2:79])([C:77]#[CH:78])[CH3:76]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:79][C:75]([CH3:76])([C:77]#[CH:78])[CH3:74])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: C#CC(C)(C)N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CC(C)(C)NC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 2-methylbut-3-yn-2-amine (7.6 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2-methylbut-3-yn-2-amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (20-45—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methylbut-3-yn-2-yl)acetamide. (22 mg, 0.046 mmol, 33%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:18]([NH:20][C:21]2([C:24]#[N:25])[CH2:23][CH2:22]2)=[O:19])[CH2:15][CH2:16][CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:24]([C:21]1([NH:20][C:18](=[O:19])[C@H:14]([CH2:15][CH2:16][CH3:17])[NH:13][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)[C:9]([F:12])([F:11])[F:10])[CH2:23][CH2:22]1)#[N:25]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Temperature: 82.5 °C

Procedure:
A mixture of N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide (6.46 g, 15.44 mmol), 4-methanesulfonylphenyl-boronic acid (3.40 g, 16.98 mmol), and 2M K2CO3 (19.3 mL) was dissolved in DMF (75 mL) in a thick-walled flask. The reaction mixture was degassed, and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II), dichloromethane complex (0.678 g, 0.926 mmol) was added. The flask was sealed, heated at 80-85° C. for 3 hours, cooled, and diluted with ethyl acetate (300 mL). The solution was washed with 1:1 water/brine (200 mL), brine (200 mL), filtered through a three-layered plug of silica (bottom) DARCO, and MgSO4 (top), concentrated in vacuo, and purified on a plug of silica gel (50-70% ethyl acetate/hexane elution). The product was then further purified by recrystallization from ethyl acetate/hexanes to yield the title compound.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1>CC(O)=O.[Zn]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCCO2
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A solution of 4-chromanone (19.6 mmol) in HOAc (30 mL) is added to a suspension of zinc powder (445 mmol) in HOAc (60 mL). The mixture is stirred at 100° C. for 4 h, cooled to RT, filtered through celite and concentrated in vacuo. EtOAc and aq. NaOH solution (1.0 M) are added, the layers are separated and the aq. layer is extracted twice with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification.
Reaction SMILES: ClC1C=C(Cl)C=CC=1SC(C)(C)C(N1CCN(C(C2C=C(C=CC=2F)C[C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[NH:27][N:26]=2)=O)CC1)=O.OOS([O-])=O.[K+].C(OCC)(=O)C>CO.O>[C:28]1(=[O:35])[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[N:26][NH:27]1
Reactant: CC(C)(Sc1ccc(Cl)cc1Cl)C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=c1[nH]ncc2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 4-(3-(4-(2-((2,4-dichlorophenyl)thio)-2-methylpropanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (2.5 g, 15 mmol) in MeOH (25 mL) was added dropwise a solution of Oxone (9.98 g, 30 mmol) in water (25 mL) at 0° C. after addition reaction mixture stirred at 0° C. for 4 h. The progress of reaction was checked by TLC using mobile phase 50% ethyl acetate in pet ether. The reaction mixture was evaporated on a rotatory evaporator under reduced pressure to afford the semisolid off-white compound. The suspension was diluted with water and then extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and solvents were evaporated on a rotatory evaporator under reduced pressure to afford 4-(3-(4-(2-(2,4-dichlorophenyl)sulfinyl)-2-methylpropanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (39) as off-white crystals compound (1.4 g, 32%)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8])(=[O:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:36]=[CH:35][C:28]2[C:29](=[O:34])[CH:30]=[C:31]([CH3:33])[O:32][C:27]=2[CH:26]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:36]=[CH:35][C:28]3[C:29](=[O:34])[CH:30]=[C:31]([CH3:33])[O:32][C:27]=3[CH:26]=2)[CH2:12][CH2:11]1)=[O:8])(=[O:3])[CH3:2]
Reactant: Cc1cc(=O)c2ccc(OCCCBr)cc2o1
Reactant: CC(=O)Oc1ccccc1C(=O)NC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)NC1CCN(CCCOc2ccc3c(=O)cc(C)oc3c2)CC1

Procedure:
A mixture of 4.9 g. (0.02 mol) 4-(2-acetoxybenzamido)-piperidine, 5.6 g. (0.02 mol) 7-(3-bromopropoxy)-2-methyl-4H-1-benzopyran-4-one, 13.9 ml. (0.10 mol) triethylamine and 100 ml. tetrahydrofuran is heated under reflux for 10 hours and then evaporated. The 7-{3-[4-(2-acetoxybenzamido)-piperidino]-propoxy}-2-methyl-4H-1-benzopyran-4-one obtained as a crude product is mixed with 100 ml. 1 N aqueous sodium hydroxide solution, stirred for 1 hour, filtered, washed with ethyl acetate and the aqueous phase then neutralised. The precipitate obtained is taken up in acetone, mixed with excess ethereal hydrochloric acid and the dihydrochloride of the desired end product isolated; m.p. 169°-170° C. The yield is 4.6 g. (45% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[CH3:16]C1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:29][N+:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[C:31]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:30][N:29]3[C:14]([CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=23)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Reactant: CCCCC#CC(=O)c1ccc(Br)cc1
Reactant: Cc1cccc[n+]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nn2c(C)cccc2c1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 11.4 g of the product of Stage A of Example 1, 250 ml of dimethylformamide and 9.81 g of 1-amino 2-methylpyridinium 2,4,6-trimethyl-benzene sulfonate (Synthesis, 1977, page 1, TAMURA, et al.) and 5.11 g of potassium carbonate were stirred for 5 hours at ambient temperature.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13](O)(=[O:15])=[O:14])[CH:8]=1.S(Cl)([Cl:20])=O>CN(C)C=O>[CH3:2][O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([Cl:20])(=[O:15])=[O:14])[CH:8]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)O)c1
Reactant: O=S(Cl)Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Yield: 97 %

Procedure:
To the sodium salt of 3-(3-sulfophenyl)acrylic acid methyl ester (2) (0.670 g, 2.53 mmol) benzene (2 mL), thionyl chloride (1.508 g, 0.9 mL, 12.67 mmol) and 3 drops of dimethylformamide were added and the resultant suspension was stirred at reflux for one hour. The reaction mixture was evaporated, the residue was dissolved in benzene (3 mL), filtered and the filtrate was evaporated to give the title compound (0.640 g, 97%).
Reaction SMILES: [CH3:1][C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:13]/[CH:14]=[CH:15]/[CH3:16])[C:3]([O:5]CC1C=CC=CC=1)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH2:13][CH2:14][CH2:15][CH3:16])[C:3]([OH:5])=[O:4]
Reactant: C/C=C/CC(C)(C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC(C)(C(=O)O)c1ccccc1
Reaction time: 72 h
Yield: 99.6 %

Procedure:
A solution of Example 27A (2.45 g, 8.32 mmol) in ethyl acetate (20 mL) was treated with 10% palladium on carbon (0.245 g, 10 weight percent) and stirred under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (1.71 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 0.87 (m, 3 H) 1.24 (m, 4 H) 1.57 (m, 3 H) 1.98 (m, 2 H) 7.32 (m, 5 H). MS (DCI NH3+) m/z 224 (M+NH4)+.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([O:35][C@H:36]([C:47]4[CH:56]=[CH:55]N=C5[C:48]=4[CH:49]=[C:50]([O:57][CH3:58])[CH:51]=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[C:59]([OH:63])(C)(C)C.C(C1C=CC([O:73]C)=CC=1OCC1C=CC=CC=1)C=C>O>[CH2:28]([O:35][C:36]1[CH:51]=[C:50]([O:57][CH3:58])[CH:49]=[CH:48][C:47]=1[CH2:56][CH:55]([OH:73])[CH2:59][OH:63])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=CCc1ccc(OC)cc1OCc1ccccc1
Reactant: CC(C)(C)O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: O
Product: COc1ccc(CC(O)CO)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a suspension of AD-mix-α (156.55 g) in water:tert-butyl alcohol (1:1,800 mL) cooled to 0° C. was slowly added via an addition funnel a solution of 1-allyl-2-(benzyloxy)-4-methoxybenzene (28.44 g, 0.112 mol) in water:tert-butyl alcohol (1:1,200 mL) and the reaction mixture was allowed to stir at 0° C. for 12 h. The reaction mixture was quenched by the addition of sodium sulfite. The reaction mixture was diluted with water (500 mL) and ethyl acetate (500 mL). The aqueous phase was separated and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:2) gave 30.50 g (95%, 27% ee) of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]propane-1,2-diol as a white crystalline solid. mp 82-86° C.; Anal. calcd. for C17H20O4: C, 70.81; H, 6.99. Found: C, 70.78; H, 7.16.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:11])=O.[S:14](=[O:18])(=O)(O)[OH:15]>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([S:14]([Cl:11])(=[O:18])=[O:15])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)O
Product: COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 17 °C
Reaction time: 1 h

Procedure:
To a mixture of 54.0 g (0.5 m) of anisole, 46.0 ml (0.5 m) of phosphorus oxychloride cooled to about 17° C., there was added slowly 51 g (0.525 m) of 100 percent sulfuric acid allowing the temperature to rise to approximately 29° C. at which temperature an external water bath was applied lowering the temperature to approximately 17° C. When the addition was complete, the water bath was removed and the temperature of the reaction mixture gradually rose to about 27° C. over approximately one hour and forty-five minutes. The reaction mixture was stirred overnight at ambient temperature. To the reaction mixture, 6.02 g of sodium chloride was added and the resulting mixture was heated to approximately 90° C. After approximately three and one half hours at about 90° C., the reaction mixture was cooled and poured slowly into a slurry of 500.0 g ice, 250.0 ml water and 41.6 g of sodium chloride. The solid which formed was collected by filtration, washed three times, each with 50.0 ml ice water and dried on the filter to obtain 94.9 g of 4-methoxybenzenesulfonyl chloride, a pink-white solid. The nuclear magnetic resonance spectrum was concordant with the assigned structure.