Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=4[CH3:33])[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(Cl)cc3)CCCCC2)CC1

Procedure:
Example 85 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 1H, J=1.6 Hz), 7.42–7.39 (m, 2H), 7.31–7.21 (m, 4H), 7.08 (d, 1H, J=8.0 Hz), 6.78 (br s, 1H), 3.29 (dd, 2H, J=6.0, 12.0 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.65 (m, 1H), 2.50 (m, 1H), 2.34–2.30 (m, 4H), 2.28 (s, 3H), 2.00–1.88 (m, 4H), 1.74–1.59 (m, 12H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 538.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[F:11][C:12]([F:17])([F:16])[C:13](N)=[O:14].FC(F)(F)C(OC)=O>>[F:11][C:12]([F:17])([F:16])[C:13]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])=[O:14]
Reactant: NCCOCCOCCO
Reactant: NC(=O)C(F)(F)F
Agent: COC(=O)C(F)(F)F
Product: O=C(NCCOCCOCCO)C(F)(F)F
Reaction time: 24 h
Yield: 98 %

Procedure:
The amino group of 2-(2-(2-aminoethoxy)ethoxy)ethanol was protected as the trifluoroacetamide by reaction with excess of methyl trifluoroacetate to give in 98% yield. Briefly, methyl trifluoroacetate (3.20 g, 2.52 ml, 25 mmol) was added dropwise through a septum with stirring and gentle cooling to 2-(2-(2-aminoethoxy)ethoxy)ethanol (2.98 g, 20 mmol), and the mixture was sealed and left at room temperature for 24 hours. The volatiles were evaporated under membrane pump vacuum and bath temperature of 65° C. to give trifluoro-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide as a slightly yellowish oil which crystallized when stored in the refrigerator: 4.83 g, 98% yield. 1H NMR (DMSO-d6): δ 9.41 (t, 1H, NH), 4.57 (bs, 1H, OH), 3.55-3.28 (m, 12H, CH2); 13C NMR (DMSO-d6): δ 156.60 (q, J=36.1 Hz, CO), 115.96 (q, J=116 Hz, CF3), 73.15, 70.50, 70.46, 68.67, 61.08, 39.99.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][OH:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.O>[CH3:34][S:35]([O:30][CH2:29][CH2:28][N:15]1[CH2:16][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=3)=[CH:12][CH:11]=2)[C:14]1=[O:31])(=[O:37])=[O:36]
Reactant: O=C1N(CCO)CC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of 3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (340 mg, 0.713 mmol) in DCM (3.5 mL) at 0° C. are added MsCl (111 μL, 1.43 mmol) and TEA (199 μL, 1.43 mmol). The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is taken in H2O (40 mL) and extracted with EtOAc (3×20 mL). The combined organic layer is washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography (20˜70% EtOAc/hexanes) to provide the title compound (337 mg, 85% yield) as a colorless oil-like product; HPLC-MS calculated for C25H22ClF3N2O5S (M+H+) 555.1, found 555.1.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O)CO.I[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.N>C(O)CCC.O.[Cu]I>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([NH:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(I)cc1
Reactant: NC1CCCCC1
Agent: [Cu]I
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: OCCO
Solvent: O
Solvent: CCCCO
Product: COc1ccc(NC2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 69.7 %

Procedure:
An oven-dried resealable 15 mL Schlenk tube was charged with CuI (9.5 mg, 0.0499 mmol, 5.0 mol %), K3PO4 (440 mg, 2.07 mmol), evacuated and backfilled with argon. Cyclohexylamine (144 μL, 1.26 mmol), ethylene glycol (0.11 mL, 1.97 mmol), and a solution of 4-iodoanisole (235 mg, 1.00 mmol) in 1-butanol (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred magnetically at 100° C. for 14 h. The resulting thick, green-brown suspension was allowed to reach room temperature, poured into a solution of 30% aq ammonia (1 mL) in water (20 mL), and extracted with 3×15 mL of CH2Cl2. The colorless organic phase was dried (Na2SO4), concentrated, and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 5:1; 15 mL fractions). Fractions 9-17 provided 143 mg (70% yield) of the product as white crystals. 1H NMR (400 MHz, CDC3): δ 6.79−6.72 (m, 2H), 6.60−6.53 (m, 2H), 3.74 (s, 3H), 3.22 (br s, 1H), 3.16 (tt, J=10.2, 3.6 Hz, 1H), 2.10−1.98 (m, 2H), 1.80−1.69 (m, 2H), 1.68−1.58 (m, 1H), 1.40−1.04 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 151.8, 141.6, 114.8, 114.7, 55.8, 52.7, 33.6, 25.9, 25.0. IR (neat, cm−1): 3388, 1509, 1239, 1038, 818. Anal. Calcd. for C13H19NO: C, 76.06; H, 9.33. Found: C, 76.00; H, 9.32.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:16][C:17]1([CH3:24])[CH2:20][N:19]([CH2:21][CH2:22]Cl)[CH2:18]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][N:10]([CH2:22][CH2:21][N:19]3[CH2:20][C:17]([CH3:24])([CH3:16])[CH2:18]3)[C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCN1c1cccc(Cl)c1
Reactant: CC1(C)CN(CCCl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(CCN2CCN(c3cccc(Cl)c3)C2=O)C1
Temperature: 25 °C

Procedure:
A solution of 5 g. of 1-(m-chlorophenyl)-2-imidazolidinone in 30 ml. of dimethylformamide is added at room temperature to a mixture of 1.5 g. of 50% NaH (as a mineral oil emulsion) in 30 ml. of dimethylformamide. The reaction mixture is stirred for an hour at room temperature and 4.5 g. of 3,3-dimethyl-1-(2-chloroethyl)azetidine is added thereto. The mixture is then stirred at room temperature for an additional two hours, then heated for five hours at 80°-85° C. The by-product salts are filtered off and the solvent is removed under vacuum. The residue is taken up with 8 ml. of aqueous 18% HCl and 16 ml. of water and extracted with ether. The water solution is alkalinized by adding aqueous 15% sodium carbonate and extracted with diethyl ether. By evaporation of the organic layer, a residue is obtained that is triturated in light petroleum. Yield 7.24 g., m.p. 84°-85° C. (from hexane). The hydrochloride melts at 191°- 192° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][CH:11]=[C:12]2[CH3:13]
Reactant: C=CC[Mg]Br
Reactant: O=[N+]([O-])c1ccccc1Br
Product: Cc1c[nH]c2c(Br)cccc12

Procedure:
2-Bromo nitrobenzene was reacted with allyl magnesium bromide according to the literature procedure (Dobbs A. J. Org Chem. 2001, 66, 638-641), to provide 7-bromo-3-methyl-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=NN(C)C)[CH:6]([CH3:15])[CH2:5]2.S(=O)(=O)(O)[OH:17]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:17])[CH:6]([CH3:15])[CH2:5]2
Reactant: CC1Cc2cc(Cl)ccc2C1=NN(C)C
Reactant: O=S(=O)(O)O
Product: CC1Cc2cc(Cl)ccc2C1=O

Procedure:
5.5 g of N′-(5-chloro-2-methylindan-1-ylidene)-N,N-dimethylhydrazine are emulsified in 100 ml of 2N sulfuric acid and boiled under reflux for 4 h. The cooled reaction mixture is cautiously extracted with ethyl acetate; the organic extract is extracted several times with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered, dried in vacuo and chromatographed on silica gel with ethyl acetate/hetpane ⅕. 5-Chloro-2-methylindan-1-one is obtained as an oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[Na:9].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[CH2:16]([O:15][C:13]([N:2]([CH3:1])[CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCS(=O)(=O)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: CN(CCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-methylaminoethane-1-sulfonic acid, sodium salt (16.1 g, 100 mmol), in aq. sodium hydroxide (1M, 100 mL, 100 mmol) at 0° C., benzyl chloroformate (16 mL, 112 mmol) was added over a period of 15 minutes. The resulting mixture was stirred at room temperature for 2 hours and extracted with hexane. The aqueous solution was freeze dried to provide 2-[[(benzyloxy)carbonyl](methyl)amino]-ethane-1-sulfonic acid, sodium salt.
Reaction SMILES: [Br:1][C:2]1[CH:47]=[CH:46][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]([CH2:20][C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=4)[C:24]=3[CH:40]([CH3:42])[CH3:41])=O)C(O)=O)=[C:8]2[CH:43]([CH3:45])[CH3:44])=[CH:4][CH:3]=1.C1(=O)[O:53][C:51](=[O:52])C=C1.BrC1C=CC(CN2C3C(=CC=CC=3)C=C2C(C)C)=CC=1.C(N1C2C(=CC=CC=2)C(C(CC(C2C3C(=CC=CC=3)N(CC)C=2C)=O)C(O)=O)=C1C)C>>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]([CH:21]3[CH:20]=[C:16]([C:9]4[C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:7]([CH2:6][C:5]5[CH:46]=[CH:47][C:2]([Br:1])=[CH:3][CH:4]=5)[C:8]=4[CH:43]([CH3:45])[CH3:44])[O:53][C:51]3=[O:52])=[C:24]2[CH:40]([CH3:42])[CH3:41])=[CH:34][CH:35]=1
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)c1c(C(=O)CC(C(=O)O)c2c(C(C)C)n(Cc3ccc(Br)cc3)c3ccccc23)c2ccccc2n1Cc1ccc(Br)cc1
Agent: CC(C)c1cc2ccccc2n1Cc1ccc(Br)cc1
Agent: CCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CC)c3ccccc23)c2ccccc21
Product: CC(C)c1c(C2=CC(c3c(C(C)C)n(Cc4ccc(Br)cc4)c4ccccc34)C(=O)O2)c2ccccc2n1Cc1ccc(Br)cc1

Procedure:
Following a procedure similar to that described above in part A of this example except that 2,4-bis[1-(4-bromobenzyl)-2-isopropyl-3-indolyl]-4-oxobutanoic acid (prepared by the interaction of maleic anhydride and 1-(4-bromobenzyl)-2-isopropylindole ina similar manner to that described in Example 3, part A) is used in place of 2,4-bis(1-ethyl-2-methyl-3-indolyl)-4-oxobutanoic acid, there is obtained 3,5-bis[1-(4-bromobenzyl)-2-isopropyl-3-indolyl]-2(3H)-furanone (Formula II: R=4-BrC6H4CH2 ; R1 =(CH3)2CH; Y=H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:12][C:13]1[C:18]([CH:19]=[O:20])=[C:17]([F:21])[CH:16]=[CH:15][C:14]=1[NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24].[OH-].[K+].Cl>CO>[C:10]([C:8]1[CH:9]=[C:4]2[C:3]([CH:19]([OH:20])[C:18]3[C:13]([F:12])=[C:14]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH:15]=[CH:16][C:17]=3[F:21])=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)#[N:11]
Reactant: N#Cc1cnc2[nH]ccc2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(C#N)cc23)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (13, 301 mg, 2.10 mmol), propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (12, 1.11 g, 4.20 mmol) and potassium hydroxide (354 mg, 6.31 mmol) were combined in a vial with 4.2 mL of methanol. The reaction was stirred for 3 hours at room temperature. The reaction solution was neutralized with 0.1 N aqueous hydrochloric acid and extracted 3× with ethyl acetate. The organic layers were combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. This was allowed to stir over the weekend at room temperature, then extracted with ethyl acetate and water. The organic layer was washed with brine and then dried over magnesium sulfate, filtered, and the solvents were removed from the filtrate under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound (14, 315 mg). MS(ESI) [M−H+]−=405.3.
Reaction SMILES: [C:1]([C:4]1O[C:6]([CH3:15])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)(=O)[CH3:2].[CH2:16]([NH2:19])[CH2:17][NH2:18].O.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)C>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:2][C:1]1[C:4]2[N:18]([C:6]([CH3:15])=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:8]=2)[CH2:17][CH2:16][N:19]=1
Reactant: CC(=O)c1cc(-c2ccccc2)c(C)o1
Reactant: NCCN
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CCO
Product: CC1=NCCn2c1cc(-c1ccccc1)c2C

Procedure:
2-Acetyl-5-methyl-4-phenylfuran (1.9 g) was heated to 150° C. for 1 hour under argon with 6.3 ml of 1,2-ethanediamine and 0.6 ml of water. After cooling the mixture was poured into 500 ml of water and the mixture was extracted three times with 80 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 1.9 g of brown oil, was chromatographed on 100 g of aluminium oxide (neutral, III) with methylene chloride as the eluent. 0.6 g of a total of 1.2 g (56%) of crude product were dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.4 g of 3,4-dihydro-1,6-dimethyl-7-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt: 180°-182° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29](Cl)=[O:30])[CH:22]=[N:21]2)=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:29]([C:23]1[CH:22]=[N:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[C:24]=1[C:25]([F:28])([F:26])[F:27])=[O:30]
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Reactant: Nc1cccc(C(F)(F)F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1cccc(C(F)(F)F)c1F)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Fluoro-3-trifluoromethyl-phenylamine (0.007 g; 0.039 mmol) was added to a suspension of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.010 g; 0.032 mmol) and PS-DIEA (0.1 g) in acetonitrile (2 mL). The reaction mixture was shaken at room temperature for 12 h at which time PS-TSCl (0.2 g) high loading was added to remove the excess amine. After an additional 12 h of shaking, the reaction mixture was filtered and concentrated to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2-fluoro-3-trifluoromethyl-phenyl)-amide. LCMS m/z=449.9 (M−H)−.
Reaction SMILES: [CH2:1]([S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[C:13]1([S:10]([C:1](=[CH:24][C:23]2[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=2)[C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:3])(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(CS(=O)(=O)c1ccccc1)c1ccccc1
Product: O=C(C(=Cc1ccc(F)cc1)S(=O)(=O)c1ccccc1)c1ccccc1
Yield: 62 %

Procedure:
A solution of phenacylphenyl sulfone (0.01 mol) and 4-fluorobenzaldehyde (0.01 mol) was subjected to Method 1 of Procedure 4. The title compound, melting point 142-143° C., was obtained in 62% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]3([CH2:16][C:17]([CH3:32])([CH3:31])[C:18]=2/[CH:19]=[CH:20]/[CH:21]([OH:30])[CH2:22][CH:23]([OH:29])[CH2:24][C:25]([O:27]C)=[O:26])[S:15][CH2:14][CH2:13][CH2:12][S:11]3)=[CH:4][C:3]=1[CH3:33].[OH-].[Na+]>CO>[OH:29][CH:23]([CH2:22][CH:21]([OH:30])/[CH:20]=[CH:19]/[C:18]1[C:17]([CH3:32])([CH3:31])[CH2:16][C:10]2([S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH2:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:33])[CH:4]=1)[CH2:24][C:25]([OH:27])=[O:26]
Reactant: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)c(C)c2)CC2(CC1(C)C)SCCCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C2=C(/C=C/C(O)CC(O)CC(=O)O)C(C)(C)CC3(C2)SCCCS3)ccc1F
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 11 (1.05 g, 2.12 mmol) in 10 mL of methanol at 0°-5° C. was added dropwise aqueous NaOH (2.1 mL of 1N, 2.1 mmol). The mixture was stirred for 1 h and most of the volatiles were removed in vacuo. The residue was acidified with aqueous HCl to pH 3 and extracted with ether. The combined extracts were washed with brine and dried (MgSO4). Removal of the volatiles in vacuo gave 0.90 gm of tan colored solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[Br:8][CH2:9]CO.OS([O-])(=O)=O.[Na+]>C1(C)C=CC=CC=1>[Br:8][CH2:9][CH2:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1
Reactant: COc1ccsc1
Reactant: OCCBr
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: BrCCOc1ccsc1
Yield: 67 %

Procedure:
5.00 g of 3-methoxythiophene (Aldrich) was solubilized with 11.00 g of 2-bromoethanol in 20 mL of toluene, then 2.00 g of NaHSO4 was added in one portion. The mixture was heated and methanol was distilled off. The solution was cooled and washed with water and diethylether. The organic phase was dried with magnesium sulfate. After evaporation, a brown liquid was obtained which was purified by column chromatography on silica gel using a mixture of CCl4 and CHCl3 (9:1) as the eluent. An oil was recovered which was further purified by recrystallization in methanol. White crystals were then obtained with a yield of 67%. M.P.=46° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][N:9]1[C:15]([CH3:17])([CH3:16])[C:13](=[O:14])[N:12]([CH2:18][CH2:19][OH:20])[C:10]1=[O:11].[CH3:21][C:22]1(C)NC(=O)N[C:23]1=[O:28].C1OC1>>[C:1]([O:5][CH2:7][CH2:8][N:9]1[C:15]([CH3:17])([CH3:16])[C:13](=[O:14])[N:12]([CH2:18][CH2:19][O:20][C:23](=[O:28])[CH:22]=[CH2:21])[C:10]1=[O:11])(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][N:9]1[C:15]([CH3:17])([CH3:16])[C:13](=[O:14])[N:12]([CH2:18][CH2:19][OH:20])[C:10]1=[O:11]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: C=CC(=O)O
Agent: CC1(C)C(=O)N(CCO)C(=O)N1CCO
Solvent: C1CO1
Product: C=CC(=O)OCCN1C(=O)N(CCOC(=O)C=C)C(C)(C)C1=O

Procedure:
1,3-Bis(2-acryloyloxyethyl)-5,5-dimethylhydantoin is prepared by reaction of acrylic acid and 1,3-bis(2-hydroxyethyl)-5,5-dimethylhydantoin according to Example 4 of U.S. Pat. No. 3,852,302. 1,3-Bis(2-hydroxyethyl)-5,5-dimethylhydantoin is prepared by the reaction of 5,5-dimethylhydantoin and ethylene oxide according to Example C of U.S. Pat. No. 3,629,263.
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH+]1([O-])CCOCC1.C(#N)C>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.ClCCl>[C:23]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=[O:16])[N:10]=[CH:9]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: [O-][NH+]1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C

Procedure:
A mixture of 1 g (2.72 mmol) of 1-(triphenylmethyl)-4-[3-hydroxypropyl]imidazole, 0.55 g (4.07 mmol; 1.5 equivalents) of morpholine oxide and 1.36 g of powdered 4 Å molecular sieve in an anhydrous mixture of acetonitrile and dichloromethane (10:4) is stirred at room temperature under nitrogen. 0.047 g (0.135 mmol; 5 mol %) of tetrapropylammonium perruthenate (VII) is added in a single portion and the mixture is stirred at room temperature for 48 hours. The reaction mixture is filtered through silica gel (preloaded with ethyl acetate) and the filtrate is evaporated under reduced pressure. The oil obtained is purified by chromatography on a column of silica gel with diethyl ether as eluent to yield 3-(1-triphenylmethyl-4-imidazolyl)propionaldehyde.
Reaction SMILES: [I:1][C:2]1[C:3]([CH2:11][NH:12]C(=O)C)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1>Cl>[I:1][C:2]1[C:3]([CH2:11][NH2:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CC(=O)NCc1cc2c(cc1I)OCO2
Agent: Cl
Product: NCc1cc2c(cc1I)OCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
N-((6-Iodobenzo[d][1,3]dioxol-5-yl)methyl)acetamide (2.4 g, 7.5 mmol) was added to methanolic hydrochloric acid solution (4 N) (60 mL). The mixture was stirred at 80° C. overnight. Solvent was removed and the residue was dissolved in water, adjusted to PH7 with 10% NaHCO3, filtered to obtain (6-iodobenzo[d][1,3]dioxol-5-yl)methanamine as a yellow solid (1.76 g, 85%). LC-MS: 278 [M+1]+. 1H-NMR (DMSO-d6): δ 1.88 (s, 2H), 3.57 (s, 2H), 6.02 (s, 2H), 7.13 (s, 1H), 7.33 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:45][CH2:44][C:42]1[CH:41]=[CH:40][N:39]=[C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:47])([F:30])[F:46])=[CH:33][CH:34]=2)[CH:43]=1)=[O:7])[CH3:2]
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Acid 4B (273.28 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv., 277.5 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (EtOAc 1/petroleum ether 1) afforded 100 mg of a white solid. Yield=19% 1HNMR (DMSO, 400 MHz) δ 1.09 (3H, t, J=7.2 Hz), 3.39 (2H, q, J=6.8 Hz), 4.48 (2H, d, J=6 Hz), 5.15 (1H, s), 6.14 (1H, s), 7.36 (1H, dd, J=4.8 Hz, J′=1.2 Hz), 7.47 (2H, t, J=8.8 Hz), 7.84 (4H, m), 8.01 (1H, s), 8.30 (2H, d, J=8 Hz), 8.64 (1H, dd, J=5.2 Hz, J′=0.8 Hz), 8.89 (1H, bt) [M+1] 508.7 (C24H21F4N3O3S requires 507.50).