Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[NH:17]C(=O)C(C)(C)C)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(O)CC.[OH-].[Na+]>[NH2:17][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[CH:9]([CH3:10])[NH:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(NCc1ccccc1)c1cnccc1NC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: CC(NCc1ccccc1)c1cnccc1N
Yield: 89.8 %

Procedure:
A solution of N-[3-[1-(phenylmethylamino)ethyl]-4-pyridinyl]-2,2-dimethylpropanamide (12.2 g) in 200 ml n-propanol and 25 ml 10% aqueous sodium hydroxide was stirred at reflux for sixteen hours and thereafter cooled, stirred with water and extracted with ethyl acetate/ether. The organic extract was washed with water and saturated sodium chloride solution and thereafter dried (anhydrous magnesium sulfate), filtered and concentrated to 8.7 g oil. This oil was eluted with 20% methanol in dichloromethane through silica via flash column chromatography to yield 8 g oil. This oil was eluted with 10% methanol in dichloromethane through silica via HPLC to yield 7 g oil. Following unseccessful attempts to purify this oil as salts, the reconverted free base was again eluted with 20% methanol in dichloromethane through silica via HPLC to yield 5.5 g oil. A 3.5 g portion was converted to the dimaleate salt in methanol/ether to yield 4.5 g solid, d 78°-80°. This salt was reconverted to the free base to afford a solid which was recrystallized from 50% ether/hexane to yield 1.9 g crystals, m.p. 107°-109°.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH:12]([CH3:15])[CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].COC1C(OC)=NS(=O)N=1.N(C1SC=C(CSC(C)C[NH:39][C:40]2[C:44](OC)=[N:43][S:42](=[O:47])[N:41]=2)N=1)C(N)=N.N>>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH:12]([CH3:15])[CH2:13][NH:14][C:44]2[C:40]([NH2:39])=[N:41][S:42](=[O:47])[N:43]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COC1=NS(=O)N=C1NCC(C)SCc1csc(NC(=N)N)n1
Reactant: CC(CN)SCc1csc(NC(=N)N)n1
Agent: COC1=NS(=O)N=C1OC
Agent: N
Product: CC(CNC1=NS(=O)N=C1N)SCc1csc(NC(=N)N)n1

Procedure:
When a methanolic solution of 2-[(guanidinothiazol-4-yl)methylthio]propylamine is reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, Step A], and the resultant 3-{2-[(2-guanidinothiazol-4-yl)methylthio]propylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with excess ammonia by the procedure in Example 35, the title compound is thereby produced.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[BH4-].[Na+]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH3:12]
Reactant: CCCc1cc(C=O)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCCc1cc(CO)cc(OC)c1OC
Yield: 72 %

Procedure:
A solution of 3,4-dimethoxy-5-propylbenzaldehyde (11 g) and sodium borohydride (2 g) in 2-propanol (100 ml) was stirred at room temperature for 2 hours. The mixture was quenched with 2 N HCl (200 ml) and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over MgSO4, filtered and evaporated to leave a yellow oil which was purified by Kugelrohr bulb to bulb distillation at 1 mm Hg air bath temperature 150° to give the sub-title compound as a colourless oil (8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NCC(F)(F)F)n(C)n1
Yield: 90 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 2-amino-2-methyl-1-propanol, to the title compound (112 mg, 90%) which was obtained as a white solid. MS: m/e=413.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH2:17][O:18][CH3:19])[C:3]=1[CH:4]=[O:5].CCN(CC)CC.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>ClCCl.O>[CH:4]([C:3]1[C:6]([CH2:17][O:18][CH3:19])=[CH:7][C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:9][C:2]=1[O:1][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[O:5]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COCc1cc(OC2CCCCO2)cc(O)c1C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of 2-hydroxy-6-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (3.09 g, 11.62 mmol) and Et3N (6.47 mL, 46.48 mmol) in dichloromethane (50 mL) was added Tf2O (4.30 mL, 25.56 mmol) at −78° C. The mixture was stirred at −78° C. for 1 hour. The mixture was diluted with H2O and extracted with dichloromethane. The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was dissolved in Hexane-EtOAc(4:1), filtered through a plug of silica gel and filtrate was concentrated to give trifluoro-methanesulfonic acid 2-formyl-3-methoxymethyl-5-(tetrahydro-pyran-2-yloxy)-phenyl ester (2.60 g, 72%). 1H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 7.44 (s, 1H), 7.00 (s, 1H), 5.60 (s, 1H), 4.80 (s, 2H), 3.80 (m, 1H), 3.65 (m, 1H), 3.50 (s, 3H), 2.00-1.50 (m, 6H).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[C:10]([OH:15])=[N:9][CH:8]=1.[OH-:16].[Na+]>O>[F:6][C:7]1[N:12]=[C:11]([C:13]([NH2:14])=[O:16])[C:10]([OH:15])=[N:9][CH:8]=1
Reactant: [OH-]
Reactant: N#Cc1nc(F)cnc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1nc(F)cnc1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
14.39 g of concentrated sulfuric acid was added to 3.45 g of the oily 6-fluoro-3-hydroxypyrazine-2-carbonitrile, and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was then added dropwise over a period of 20 minutes to 44.5 ml of water that had been cooled to 3° C. Following completion of the dropwise addition, the resulting mixture was stirred for 20 minutes at a temperature of not more than 10° C. Subsequently, 10.17 g of a 28% aqueous solution of sodium hydroxide was added dropwise to the reaction mixture over a period of 15 minutes. Following completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes. The solid product was then filtered off, and washed with 18 ml of water, yielding 2.22 g (yield: 92.3%) of 6-fluoro-3-hydroxypyrazine-2-carboxamide.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:4]([CH3:18])[C:3]=1[CH3:19].CC([O-])=[O:22].[Na+]>C(O)(=O)C>[CH3:18][C:4]1[C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=2)[C:14]#[N:15])=[N:6][NH:7][C:2](=[O:22])[C:3]=1[CH3:19]
Reactant: CC(=O)[O-]
Reactant: Cc1c(Cl)nnc(Cc2ccc(F)c(C#N)c2)c1C
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(Cc2ccc(F)c(C#N)c2)n[nH]c(=O)c1C
Temperature: 25 °C

Procedure:
To a solution of intermediate B2 in acetic acid (0.16 M) was added NaOAc (2 eq.) and the mixture was stirred and heated to reflux for 1 h. The solution was cooled to RT and the solvent was removed under reduced pressure. The residue was suspended in water and triturated until a fine suspension was obtained. The solid material was filtered off, washed with water, dried by air stream and then under high vacuum. MS (ES) C14H12FN3O required: 257, found: 258 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH2:20]([O:22][CH2:23]OCC)[CH3:21].CN(C)C=O.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:5]([CH2:23][O:22][CH2:20][CH3:21])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Reactant: CCOCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Temperature: 35 °C
Yield: 94.6 %

Procedure:
A stirred mixture of 4-bromo-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (17.4 g, 0.05 mole), diethoxymethane (10.4 g, 0.10 mole) and dimethylformamide (DMF) (4.6 g, 0.0625 mole) in toluene, under N2, is treated portion-wise with phosphorous oxychloride (9.6 g, 0.0625 mole) at 35°-45° C. over a 10 minute period, heated at 45°-53° C. for about 0.5 hour, cooled to 35° C. and treated dropwise with triethylamine (7.25 g, 0.0715 mole) over a 2 hour period at 35°-45° C. The reaction mixture is treated with water and the toluene is removed via azeotropic distillation. The remaining residue is treated with water, filtered and the filtercake is dried in vacuo at 60° C. to give the title product, 20.8 g, 92.7% pure, 94.6% yield, identified by HPLC analysis.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=[N:17][C:10]=2[N:9]([CH3:36])[C:8]1=[O:37])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[F:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:37])[N:9]([CH3:36])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]([CH3:26])[CH3:27])=[CH:34][CH:33]=1
Reactant: CC(C)c1ccccc1Oc1cnc2c(c1Cc1ccc(F)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1ccccc1Oc1cnc2c(c1Cc1ccc(F)cc1)c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
To a solution of 3-(5-(4-fluorobenzyl)-6-(2-isopropylphenoxy)-1-methyl-2,4-dioxo-1,2-dihydro pyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (68 mg, 0.135 mmol) in THF (1 ml) and water (1 mL) was added LiOH.H2O (14 mg, 0.33 mmol). The reaction was stirred at RT for 15 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-fluorobenzyl)-3-(3-hydroxypropyl)-6-(2-isopropylphenoxy)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (55 mg, 85.4% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.23 (s, 1H), 7.38-7.35 (m, 1H), 7.23-7.18 (m, 2H), 7.14-7.10 (m, 2H), 7.03 (t, J=8.8 Hz, 2H), 6.61-6.58 (m, 1H), 4.71 (s, 2H), 4.49 (t, J=5.2 Hz, 1H), 3.98 (t, J=7.2 Hz, 2H), 3.56 (s, 3H), 3.49-3.43 (m, 2H), 3.11-3.07 (m, 1H), 1.75-1.71 (m, 2H), 1.12 (d, J=6.4 Hz, 6H). LCMS: MH+ 478 and TR=3.356 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH3:11][C:12]1([CH3:43])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16](/[CH:30]=[CH:31]/[C:32]3[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]1=2.[NH4+].[Cl-]>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:43][C:12]1([CH3:11])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[C:18]2[CH:17]=[C:16](/[CH:30]=[CH:31]/[C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: c1cscn1
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a cold (-78° C.) solution of thiazole (0.38 g (0.10 mL, 1.4 mmol) in THF (2.0 mL) was added n-butyl lithium (1.6M solution in hexanes, 0.5 mL, 0.8 mmol) and stirred for 30 min. To this solution was added 0.176 g (1.3 mmol) of zinc chloride in 3.0 mL of tetrahydrofuran and stirred for 45 min. The resulting turbid solution was transferred, via cannula, to a flask containing a mixture of 0.17 g (0.35 mmol) of ethyl (E)-4-[2-(5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-5,6-dihydronaphthalen-2-yl)ethenyl]benzoate (Compound A9) and 15 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium(O) in 3.0 mL of tetrahydrofuran. The reaction mixture was stirred for 1 h at ambient temperature and 1.5 h at 55° C. The reaction mixture was treated with aqueous NH4Cl, and extracted with EtOAc (2×). The combined organic layer was washed with brine and dried (MgSO4). The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, 20% ethyl acetate in hexane) to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:22])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([OH:5])=[O:4].[H][H]>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[Cl:1][C:2]([Cl:22])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(Cl)(Cl)CCCCCCCCC=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCc1ccccc1
Yield: 86.5 %

Procedure:
1.09 g (3.18 mmol) 13 was dissolved in 300 ml THF and hydrogenated for 40 minutes at -40° C. at a hydrogen overpressure of 42 mbar after addition of 200 mg 10% Pd/BaSO4. The catalyst is sucked off and 0.95 g (90%) 14 was obtained as a colourless oil after evaporating the remaining solution. 100 mg (0.29 mmol) 14 was dissolved in 1 ml ethanol, cooled in an ice-bath and admixed with a solution of 12 mg (0.29 mmol) sodium hydroxide in 1 ml ethanol. The sodium salt was precipitated by addition of ether and it was allowed to stand for 12 hours in a refrigerator. The precipitate was suction filtered, washed with cold ether and dried in a vacuum. 100 mg (94%) sodium salt of 14, melting point 157-159° C.
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][CH:8]=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:19](OCC)=[O:20].[Li+].[BH4-].Cl>C1COCC1>[CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][CH:8]=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:19][OH:20]
Reactant: CCOC(=O)c1ccc2c(ccc3c4ccccc4ccc23)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(ccc3c4ccccc4ccc23)c1
Yield: 94.7 %

Procedure:
Ethyl chrysene-2-carboxylate (20B, 10.1 g, 0.034 mol) in THF (500 mL) was treated with LiBH4 (Alfa, 4×0.5 g, 0.092 mol) under gentle reflux for 4 days. The reaction mixture was poured into ice and acidified carefully to pH 1 with 1M HCl. The precipitate was filtered and recrystallized from THF/hexane to afford 8.32 g (95%) of 2-chrysenemethanol mp 261°-262°, (C,H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=O)=[O:4].[CH3:23][NH:24][NH2:25]>CO>[CH3:1][O:2][C:3]([C:5]1[N:25]([NH:24][CH3:23])[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: COC(=O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Reactant: CNN
Solvent: CO
Product: CNn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of 6-chloro-4-phenylisocoumarin-3-carboxylic acid methyl ester (1.3 g) in methanol (15 ml) was added methylhydrazine (3.0 g) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was dissolved in methanol (15 ml). Sulfuric acid (1.5 ml) was added and the mixture was refluxed for 2 hrs. The reaction mixture was concentrated, and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) and crystallized from isopropyl ether to give the title compound (980 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[C:13]([S-:15])#[N:14].[K+].CC(C)=O>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:14]=[C:13]=[S:15])=[O:8]
Reactant: N#C[S-]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1C(=O)N=C=S

Procedure:
The product of Example 1B (˜60 mmol) and KSCN (5.83 g, 60 mmol) were mixed in anhydrous tetrahydrofuran (25 mL) and anhydrous acetone (40 mL) and stirred at room temperature for 2 hrs. The reaction was diluted with diethyl ether (100 mL), filtered through celite and solvents evaporated in vacuo to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 3.95 (s, 3H), 6.95 (d, 1H), 7.52 (dd, 1H), 7.84 (d, 1H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:7]1[CH:12]=CC=C[CH:8]=1.C1C=CC=CC=1>>[C:1]1([CH:7]([CH3:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Product: CC(C)c1ccccc1

Procedure:
An embodiment of the present disclosure is depicted in FIG. 1. Referring to FIG. 1, naphtha is introduced via line 1 into reactor zone 3 where the naphtha is reformed or steam cracked into aromatic products including benzene. Although only one reactor zone is shown, there can be more than one reactor zone. In reactor zone 3, C4− hydrocarbons are removed from the reformate via line 4 and the remaining reformate is withdrawn from reactor zone 3 via line 5 and introduced into column 7 where the feed is fractionated to form a light reformate fraction, a heavy reformate fraction, and a benzene/benzene coboiler fraction. The light reformate fraction is withdrawn from column 7 through line 9, the heavy reformate fraction is withdrawn from column 7 through line 11, and the benzene/benzene coboiler fraction is withdrawn from column 7 through line 13 and introduced into zone 15. In zone 15, catalyst poisons, e.g., sulfur, nitrogen, olefins, dienes, or combinations thereof are at least partially removed from the benzene/benzene coboiler fraction. The resulting fraction is withdrawn from zone 15 via line 17 and introduced into propylation zone 18. In propylation zone 18, propylene is introduced via line 19 and benzene is reacted with the propylene to form cumene. Low molecular weight molecules, such as propane and propylene, are withdrawn from propylation zone 18 via line 20. The cumene-containing product is withdrawn from propylation zone 18 via line 21 and introduced into column 23. In column 23, the cumene-containing product is fractionated to form a C8− fraction and a C9+ fraction comprised of cumene and polypropylbenzenes. The C8− fraction is withdrawn from column 23 via line 25 and either removed from the unit via line 26 or recycled via line 17 to propylation zone 18. The C9+ fraction is withdrawn from column 23 via line 27 and introduced into column 29. In Column 29, the C9+ fraction is fractionated to form a high purity cumene product fraction and a C10+ fraction comprised of polypropylbenzenes and C16+ hydrocarbons. The C10+ fraction is withdrawn from column 29 via line 33. Recovered polypropylbenzenes have a high octane rating and are available for upgrading the value of mogas pool (can be blended into gasoline to increase its octane). The high purity cumene product fraction is withdrawn from column 29 via line 31 and recovered without need of further purification. The cumene product will usually have a purity that exceeds 99.50 percent by weight based on the total weight of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12]>O=S(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12])[C:15](=[O:17])[CH2:14][CH2:13]2
Reactant: COCCOc1ccc(CCC(=O)O)cc1F
Solvent: O=S(Cl)Cl
Product: COCCOc1cc2c(cc1F)CCC2=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
The mixture of 3-[3-Fluoro-4-(2-methoxy-ethoxy)-phenyl]-propionic acid (16 g) in SOCl2 (50 ml) was refluxed for 4 hours. The mixture was evaporated, the residue was dissolved in CS2 (100 ml), and then AlCl3 (20 g) was added. The mixture was heated at 45° C. for 4 hours. 200 ml of ice-water was added to the cooled mixture and the mixture was stirred for another 1 hour. The mixture was extracted by ethyl acetate (300 ml×3). The product was purified by flash column chromatography using ethyl acetate:PE=5:1 as eluent. LC-MS: m/e 225 (MH+).
Reaction SMILES: O.[NH2:2][NH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][C@@H:29]3[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][S:46]([CH2:49][CH2:50][CH2:51][C:52]([F:58])([F:57])[C:53]([F:56])([F:55])[F:54])(=[O:48])=[O:47])=[CH:36][CH:35]=3)([CH3:27])[C:25](=O)[CH2:24][CH2:23]4)[CH2:20][CH2:19][C:18]=2[CH:17]=1.C(=O)(O)[O-].[Na+]>CO>[OH:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][C@@H:29]3[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][S:46]([CH2:49][CH2:50][CH2:51][C:52]([F:58])([F:57])[C:53]([F:56])([F:55])[F:54])(=[O:48])=[O:47])=[CH:36][CH:35]=3)([CH3:27])[C:25](=[N:2][NH2:3])[CH2:24][CH2:23]4)[CH2:20][CH2:19][C:18]=2[CH:17]=1
Reactant: NN
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=NN
Reaction time: 16 h

Procedure:
100 μl of hydrazine hydrate and 3 mg of paratoluenesulphonic acid are added to 300 mg of the product obtained in Example 73 in 3 cm3 of methanol. Agitation is carried out for 16 hours at ambient temperature, 50 cm3 of an aqueous solution of sodium bicarbonate is added, extraction is carried out with methylene chloride, the solvent is evaporated off, the residue is chromatographed on silica (eluant: ethyl acetate) and 190 mg of expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4](P(OCC)(OCC)=O)[CH2:5][CH:6]([CH3:8])[CH3:7].[H-].[Na+].[CH:20](=O)[CH:21]([CH3:23])[CH3:22].O>O1CCCC1.CCOCC>[CH3:1][O:2][C:3](=[O:17])[C:4]([CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C=O
Reactant: CCOP(=O)(OCC)C(CC(C)C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(=CC(C)C)CC(C)C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
4-Methyl-2-(diethylphosphono)pentanoic acid methyl ester (28 g, 0.1M) prepared as in Example (1) in dry tetrahydrofuran (200 ml) was stirred under nitrogen whilst sodium hydride (2.2 g, 80% dispersion in oil; 0.11M) was added portion wise at 23° C. The reaction was stirred for 30 minutes and isobutyraldehyde (72 g, 1M) added with cooling to maintain the temperature below 30° C. The reaction was stirred for 16 h at 20° C. and water (20 ml) added. The organic phase was diluted with ether and then washed successively with aqueous sodium hydrogen carbonate, water and aqueous citric acid (1M), dried over sodium sulphate and concentrated in vacuo. Vacuum distillation of the resulting oil afforded E and Z 2-(2-methylpropyl)-4-methyl-pent-2-enoic acid methyl ester (12.5 g) b.p. 60°-70° C. at 0.5 mm Hg as a colourless oil δ(CDCl3) 0.86 and 0.88 (6H, each d, each J=7 Hz CH2CH(CH3)2); 1.0-1.02 (6H, each d, each J=7 Hz, CHCH(CH3)2); 1.6-1.85 (1H, m, CH2CH) 2.1 and 2.2 (2H, each d, each J=7 Hz, CH2) 2.55 and 2.75 (1H, each m, C=CHCH); 3.74 (3H, s, OCH3); 5.58 and 6.59 (1H, each d, each J=9 Hz, C=CH).