Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[F:5][CH:6]([C:12]([CH3:14])=[O:13])[C:7]([O:9]CC)=O>>[F:5][CH:6]([C:12](=[O:13])[CH3:14])[C:7]([NH:4][CH2:1][CH2:2][CH3:3])=[O:9]
Reactant: CCOC(=O)C(F)C(C)=O
Reactant: CCCN
Product: CCCNC(=O)C(F)C(C)=O
Reaction time: 2 h

Procedure:
0.8 mol (65.8 ml) of n-propylamine were added dropwise within 0.5 h to 0.2 mol (25 ml) of ethyl 2-fluoroacetoacetat. The reaction mixture was heated and then held for 2 h at 60° C. Then it was evaporated to dryness, dissolved in 50 ml water and 60 ml ethanol and adjusted with 32% HCl to pH 3. It was again evaporated, dissolved in 300 ml ethyl acetate, filtered and again evaporated to dryness. 17 g of crude product was chromatographed over 800 g silica gel with ethyl acetate/hexane 1/1. After drying, 14 g of the title compound were obtained.
Reaction SMILES: [CH:1]1([C:7]2[CH:21]=[CH:20][C:10]([C:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl>CO.[OH-].[K+]>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:20][CH:21]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCC(=O)c1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCC(=O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To a solution of ethyl 3-(4-cyclohexylbenzoyl)propionate (19.6 g) in methanol (150 ml), 2N KOH (102 ml) was added, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into water (200 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was evaporated off, to yield 3-(4-cyclohexylbenzoyl)propionic acid (10.8 g, 61%), which was then recrystallized from isopropyl ether to yield colorless prisms having a melting point of 140°-141° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(CC)C.Br[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:11][CH2:12][CH2:13][CH2:14][S:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CCCC2SCCCS2)cc1
Reactant: BrCCCc1ccccc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: c1ccc(CCCC2(CCCc3ccccc3)SCCCS2)cc1
Temperature: -25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.0 g (4.2 mmol) of 2-(3-phenylpropyl)-1,3-dithiane in 25 ml of dry tetrahydrofuran was cooled to -78° C. and treated with 3.23 ml (4.2 mmol) of sec-butyllithium. The resulting solution was stirred at -25° C. for 20 min, recooled to -78° C., and treated with 0.64 ml (4.2 mmol) of 1-bromo-3-phenylpropane. After being stirred at -78° C. for 15 min, the solution was allowed to stir overnight at ambient temperature. The solution was partitioned between ether and aqueous ammonium chloride, and the organic layer was washed sequentially with water, 1M sodium bisulfite, and saturated brine, dried over MgSO4, and concentrated in vacuo to give the desired compound. 1H NMR (CDCl3) δ 1.65-1.9 (m, 9H), 2.18 (m, 1H), 2.55-2.75 (m, 6H), 2.78 (t, J=8 Hz, 1H), 3.40 (t, J=6 Hz, 1H), 7.1-7.35 (m, 10H). Mass spectrum (M+H)+ =357.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH3:12].C(O)(=O)C>CCO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:11][CH3:12]
Reactant: CNc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1c(N)cccc1Cl
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
2-Chloro-N-methyl-6-nitrobenzenamine (1.5 g, 8.0 mmol) was dissolved in a mixture of EtOH (15 mL) and H2O (15 ml). Iron powder (2.2 g, 40 mmol) was added followed by Acetic acid (0.55 mL, 9.6 mmol). The reaction was monitored by TLC, after 30 min, the reaction was completed. The reaction mixture was filtered over celite pad and the filtrate was neutralized by saturated NaHCO3 (10 mL). The product was extracted by EtOAc (2*10 mL), the organic layer was washed with brine (10 mL), dried over MgSO4 and concentrated to dryness to afford 920 mg of 6-chloro-N1-methylbenzene-1,2-diamine (Yield: 73%) as dark brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3cccc(Br)c3)c2)CC1
Yield: 29.2 %

Procedure:
N-(3-Bromobenzyl)-5-fluoro-2-nitrobenzenamine (624 mg, 2.2 mmol), t-butyl piperazine-1-carboxylate (414 mg, 2.2 mmol), N,N-diisopropylethylamine (287 mg, 2.2 mmol) were stirred at 80° C. in dry acetonitrile (10 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (316 mg, 32% yield). 1H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.05 (d, 1H), 7.32-7.21 (m, 4H), 6.18 (d, 1H), 5.72 (s, 1H), 4.46 (d, 2H), 3.49 (m, 4H), 3.27 (m, 4H), 1.45 (s, 9H); MS (ESI) m/z: Calculated for C22H27ClN4O4Na 469.16; Observed: 469.4 (M++Na).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:25][Mg+].[Br-].Cl>C1COCC1.O>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([OH:24])[CH3:25])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[Mg+]
Reactant: O=Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Yield: 886.4 %

Procedure:
A mixture of 3-(naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.15 g, 0.44 mmoles) and MeMgBr (0.36 ml of 3M solution in ether, 1.1 mmoles) was stirred in THF at −20° C. to 0° C. for 30 minutes. Reaction mixture was diluted with water, acidified to pH=3 with 2N HCl, then extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to afford the title compound (0.13 g, 3.9 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 49 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinazoline (81 mg) was dissolved in toluene (5 ml) with heat, 4-methoxyphenyl isocyanate (0.29 ml) was added, and the admixture was refluxed with heat for 40 minutes. The separated solid was filtered and washed with toluene to obtain 60 mg of the title compound (yield: 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:6]([CH3:22])[C:3]=1[C:4]#[N:5].[ClH:23].Cl[C:25]([NH2:27])=[NH:26]>COCCOCCOC.C(OCC)C>[NH2:27][C:25]1[N:26]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([C:10]([Cl:23])=[CH:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=3)[C:6]=2[CH3:22])[N:1]=1
Reactant: Cl
Reactant: N=C(N)Cl
Reactant: Cc1c(C#Cc2ccc(C(F)(F)F)cc2)ccc(N)c1C#N
Solvent: COCCOCCOC
Solvent: CCOCC
Product: Cc1c(C(Cl)=Cc2ccc(C(F)(F)F)cc2)ccc2nc(N)nc(N)c12
Yield: 46.9 %

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 1, using 2.7 grams (0.009 mole) of 2-amino-6-methyl-5-[(4-trifluoromethylphenyl)ethynyl]benzonitrile and 1.2 grams (0.011 mole) of chloroformamidine hydrochloride in 10 mL of 2-methoxyethyl ether. Upon completion of the reaction, the reaction mixture was diluted with 200 mL of diethyl ether. The resultant solid was collected by filtration, and was dissolved in a hot mixture of 300 mL of water and 100 mL of n-propanol. The solution was filtered hot through a sintered glass funnel to remove some insoluble material. The filtrate was then made basic with 100 mL of concentrated ammonium hydroxide. The resultant solid was collected by filtration, and dried at 60° C. under vacuum. The solid was then dissolved in a solution of 10% methanol in methylene chloride, and the solution was subjected to column chromatography on silica gel. Elution was accomplished using 10% methanol in methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of 2,4-diamino-5-methyl-6-[1-chloro-2-(4-trifluoromethylphenyl)ethenyl]quinazoline, mp >300° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([CH2:25][CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32](Cl)=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[CH:23][CH:22]=1>CS(C)=O.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH2:26][NH:27][C:28]([C:29]2[CH:34]=[CH:33][C:32]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][C:2]=3[F:1])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[O:39])=[CH:40][CH:41]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2[N+](=O)[O-])c(F)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 46.4 %

Procedure:
Methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (prepared in Step A; 163 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K2CO3 (122 mg, 0.885 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (prepared in Step B; 300 mg, 0.885 mmol). The reaction was stirred at 80° C. for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified by silica gel chromatography, eluting with hexane:acetone (2:1) to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3-fluorophenyl)acetate (200 mg, 46.4% yield).
Reaction SMILES: [H-].[Na+].CO.[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:16]([O:18]C)=[O:17].[H][H].Cl>O>[CH3:24][O:23][C:21](=[O:22])[C:20](=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([F:5])=[CH:7][CH:8]=1)[CH:15]([CH3:14])[C:16]([OH:18])=[O:17]
Reactant: O=Cc1ccc(F)cc1
Reactant: [H][H]
Reactant: COC(=O)CC(C)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Reaction time: 1.5 h

Procedure:
A 2 L three-neck flask fitted with a drop-wise addition funnel and a mechanical stirrer was charged with 18.63 g (0.466 mol) of sodium hydride (60% suspension in mineral oil) under a stream of argon gas. The sodium hydride was washed twice with 100 mL portions of hexane and once with a 100 mL portion of toluene in order to remove the mineral oil. The reaction flask was then charged with toluene (220 mL) followed by a catalytic amount of methanol (0.5 mL, 12.3 mmol). A mixture of 4-fluorobenzaldehyde (21 mL, 0.196 mol) and dimethyl methylsuccinate (87.61 g, 0.547 mol) was added drop-wise to the mechanically stirred solution. Drop-wise addition occurred slowly over 1.5 hours such that the reaction temperature did not exceed 35° C. and evolution of hydrogen gas occurred at a steady, moderate rate. After the drop-wise addition was complete, the reaction mixture was stirred for 3 hours. The reaction mixture was cooled in an ice-water bath. Concentrated HCl (100 mL) was added slowly drop-wise at a rate such that the reaction temperature did not exceed 20° C. Water (100 mL) was added, and the biphasic mixture was poured into a separatory funnel. The organic layer was separated, then extracted twice with 1 M aqueous potassium carbonate. The combined aqueous extracts were carefully acidified to pH 2 with concentrated HCl. The resultant cloudy suspension was extracted three times with 500 mL portions of diethyl ether. The combined organic extracts were dried over Na2SO4, filtered, and evaporated to yield 2-(4-fluoro-benzylidene)-3-methyl-succinic acid 1-methyl ester as an orange oil which contained excess dimethyl methylsuccinate as a major impurity and minor amounts of other impurities. This crude product was used in the next reaction without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][N:13]=2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:43][O:44][C:45](=[O:60])[C:46]([CH3:59])([CH3:58])[CH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[C:51]([CH:55]=O)=[C:50]([CH3:57])[CH:49]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:43][O:44][C:45](=[O:60])[C:46]([CH3:58])([CH3:59])[CH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[C:51](/[CH:55]=[CH:2]/[C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:10][C:11]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)=[N:12][N:13]=3)=[CH:5][C:4]=2[N+:21]([O-:23])=[O:22])=[C:50]([CH3:57])[CH:49]=1
Reactant: O=[N+]([O-])c1cc(-c2nnc(-c3ccc(Cl)cc3)o2)ccc1CBr
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1cc(C)c(/C=C/c2ccc(-c3nnc(-c4ccc(Cl)cc4)o3)cc2[N+](=O)[O-])c(C)c1
Temperature: 25 °C

Procedure:
Combine 2-(4-bromomethyl-3-nitro-phenyl)-5-(4-chloro-phenyl)-[1,3,4]oxadiazole (894 mg, 2.27 mmol) and PPh3 (656 mg, 2.50 mmol) in DMF (13 mL) and heat to 95° C. under N2 for 4.5 h. Add 3-(4-formyl-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (intermediate A in Example 1-62, 675 mg, 2.72 mmol) and K2CO3 (627 mg, 4.54 mmol), continue heating at 95° C. for 6.5 h. Allow the reaction to cool to room temperature. Dilute the cooled reaction with EtOAc (150 mL) and extract with water (50 mL). Dry the organic layer over Na2SO4 and evaporate the solvent. Purify the resulting oil by silica gel chromatography (10-45% EtOAc/HEP) to afford a yellow solid: (M+H)+ 546.1.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([NH:15][C:16]2[C:17]([C:26]([OH:28])=O)=[CH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:7]2[C:12]=1[O:11][C:10]([CH3:14])([CH3:13])[CH:9]=[CH:8]2.FC(F)(F)[C:31](OC(=O)C(F)(F)F)=[O:32]>ClCCl>[CH3:31][O:32][C:4]1[CH:3]=[C:12]2[O:11][C:10]([CH3:13])([CH3:14])[CH:9]=[CH:8][C:7]2=[C:6]2[C:5]=1[C:26](=[O:28])[C:17]1[CH:18]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]3=[CH:25][C:16]=1[NH:15]2
Reactant: COc1ccc(Nc2cc3ccccc3cc2C(=O)O)c2c1OC(C)(C)C=C2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(c3[nH]c4cc5ccccc5cc4c(=O)c13)C=CC(C)(C)O2
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a solution containing 1.94 mmol of the compound obtained in Step 1 in 20 ml of anhydrous dichloromethane, maintained at 0° C. under argon, there are added 9.71 mmol of trifluoroacetic anhydride. After reacting for 3 days at ambient temperature, the reaction mixture is concentrated under reduced pressure. The residue is taken up in a mixture of dichloromethane and aqueous NaHCO3 solution. After extraction with dichloromethane, the combined organic phases are treated in conventional manner. Chromatography of the residue over silica gel (dichloromethane) allows the expected product to be isolated, the latter being subsequently recrystallised from ethyl ether.
Reaction SMILES: [C-]#[N:2].[Na+].S(=O)(=O)(O)O.[C-]#N.[Na+].C[C:13]([OH:15])=O.[CH3:16][C:17](O)([CH3:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:16][C:17]([NH:2][CH:13]=[O:15])([CH3:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [C-]#N
Reactant: CC(=O)O
Reactant: CC(C)(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(Cc1ccccc1)NC=O
Temperature: 25 °C

Procedure:
11.3 g (230 mmol) NaCN are added to 60 mL AcOH. A combination of 30 mL AcOH and 60 mL concentrated sulfuric acid is carefully dropped into the NaCN/AcOH mixture while maintaining the temperature below 20° C. Then 30 mL (195 mmol) 2-methyl-1-phenyl-2-propanol, in 30 mL acetic acid, are added dropwise to the reaction mixture, again keeping the temperature below 20° C. After having finished the addition, the reaction mixture is stirred for an additional hour at r.t., poured onto ice water and is finally neutralised with an aq. Na2CO3 solution. The resulting mixture is extracted with diethylether. The organic layer is dried with MgSO4, filtered and the solvent is removed under reduced pressure. The crude product is used without further purification.
Reaction SMILES: CC(C)(O)[C:3]#[N:4].[C-]#N.[K+].[CH3:10][C@:11]12[CH2:28][CH:27]=[C:26]3[C@@H:16]([CH2:17][CH2:18][C:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21](=[O:29])[CH:20]=4)[C@@H:15]1[CH2:14][CH2:13][C:12]2=[O:30].CO>O>[C:3]([C@@:12]1([OH:30])[CH2:13][CH2:14][C@H:15]2[C@H:16]3[C:26](=[CH:27][CH2:28][C@:11]12[CH3:10])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)#[N:4]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C#N
Reaction time: 3.5 h

Procedure:
Acetone cyanohydrin (5 ml) and sufficient potassium cyanide to adjust the pH to 9.9 is added to a slurry of androst-4,9(11)-dien-3,17-dione (0,5 g), methanol (40 ml) and water (2.5 g) at 40°. The reaction becomes homogeneous followed by precipitation of the product. After 3.5 hours, water (7.5 ml) is added dropwise and the reaction is allowed slowly to stir at 20°-25° overnight. The slurry is cooled on in ice bath, filtered, the solids washed with methanol/water (1/1) and dried under reduced pressure to give the title compound (4.54 g); [α]D (c=1, CHCl3)=+118°; MS=311, 296 and 284 m/e; NMR (CDCl3)=0.97, 1.37, 2.9, 5.5 and 5.70 δ
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[C:10]1([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2C=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].[CH3:27]O>>[Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])/[CH:8]=[CH:27]/[C:20]2[CH:19]=[CH:18][C:17]([S:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)s1
Reactant: O=Cc1ccccc1Sc1ccccc1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: O=C(/C=C/c1ccc(Sc2ccccc2)cc1)c1ccc(Br)s1

Procedure:
In FIG. 4, the synthesis scheme for PAG 16 is carried out as follows: A brominated acetylthiophene derivative, 1-(5-bromothiophen-2-yl)ethanone (14) is reacted with 4-(phenylthio)benzaldehyde (1) in the presence of methanol and potassium hydroxide at room temperature to form a precursor compound, (E)-1-(5-bromothiophen-2-yl)-3-(4-(phenylthio)phenyl)prop-2-en-1-one (15). The precursor compound (15) is exposed to microwave heating at 125° C. in the presence of diphenyliodonium hexafluoro phosphate (V) (6) to form a photoacid generator, (E)-(4-(3-(5-bromothiophen-2-yl)-3-oxoprop-1-enyl)phenyl)diphenylsulfonium hexafluorophosphate(V), identified herein as PAG 16. The reactions are carried out by conventional heating (Δ) and microwave heating (MW) and the Quantum yield per molecule of PAG 16 is 71% for conventional heating (Δ) and 83% for microwave heating (MW).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23](Cl)=[O:24])(C(C)(C)C)(C)C.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1.[CH2:46](N(CC)CC)C.CI.[H-].[Na+]>C1COCC1.CN(C=O)C>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:32]([CH3:46])[CH:33]2[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]2)=[O:24])[C:10]([CH2:9][OH:8])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 mg (0.22 mmol) of chloroformate 6-1 in THF was added 130 mg (0.65 mmol) of (+/−)-3-amino-1-N-Boc-piperidine (9-1) and 90 μL (0.65 mmol) of triethylamine. After stirring overnight at room temperature, the mixture was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide both diastereomers in pure form. To 35 mg (0.057 mmol) of the first eluting diastereomer in DMF at 0° C. was added 18 μL (0.29 mmol) of MeI and 11 mg (0.29 mmol) of NaH (60% dispersion in oil). After stirring for 3 h at 0° C., the reaction was quenched with saturated NH4Cl, poured into EtOAc, and the layers were separated. The organic phase was washed with brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was then dissolved in CH2Cl2 and 1 mL of trifluoroacetic acid was added. After stirring for 3 h at room temperature, the solvents were removed, the residue was partitioned between EtOAc and saturated NaHCO3, the organic phase was washed with brine, dried over MgSO4 and concentrated by rotary evaporation. The residue was then purified by silica gel chromatography with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 9-2 as a white solid. Data for 9-2: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.25 (s, 1H), 4.8 (m, 1H), 4.65 (m, 1H), 4.45 (m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.1 (m, 2H) 2.9 (s, 3H), 2.6 (m, 2H), 2.1-0.9 (m, 6H) ppm. HRMS (ES) calc'd M+H for C24H27F2N3O2: 428.2144. Found: 428.2132.
Reaction SMILES: [CH3:1][NH2:2].Br[CH:4]([CH3:21])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[CH3:20])=[O:6]>C1C=CC=CC=1>[CH3:1][NH:2][CH:4]([CH3:21])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[CH3:20])=[O:6]
Reactant: CCCCOc1cc(C)c(NC(=O)C(C)Br)c(C)c1
Reactant: CN
Solvent: c1ccccc1
Product: CCCCOc1cc(C)c(NC(=O)C(C)NC)c(C)c1

Procedure:
To a cold stirred solution of 14.8 g. of monomethyl amine in 250 ml dry benzene was added (portionwise, keeping temperature below 10° ) 19.5 g (0.0594 mole) of 2-bromo-4'-butoxy-2',6'-dimethyl propionanilide (made according to the procedure in the first part of this example); this dissolved readily forming a clear solution. The mixture was heated to 70° for ca 1 hr. with stirring, at which point a white precipitate had separated and reflux became so vigorous that the reaction had to be controlled by external cooling.