Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].CC(C)([O-])C.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([N:3]1[C:4]([Br:10])=[C:5]([Br:9])[C:6]([C:7]#[N:8])=[C:2]1[Br:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(Br)c(Br)n(Cc2ccccc2)c1Br
Reaction time: 8 h

Procedure:
To a stirred mixture of 1.00 g (3.04 mmol) of 2,4,5-tribromopyrrole-3-carbonitrile and 0.68 g (6.1 mmol) of potassium t-butoxide in 30 mL of dry THF under a nitrogen atmosphere is added 1.10 mL of benzyl bromide. The mixture is heated to reflux and stirred overnight. After dilution with 100 mL of water and 150 mL of ethyl acetate, the organic mixture is separated and washed with salt solution, dried over magnesium sulfate, and concentrated in vacuo to leave 2.34 g of orange oil. The oil is triturated under a mixture of 5:1 hexane/ether to give a white solid collected by filtration; 0.81 g, mp 100°-103° C. The filtrate yields a second crop; 0.11 g, mp 100°-103° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][C:11]([NH2:14])=[C:10]([N:15]3[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]3)[N:9]=2)[CH2:4][CH2:3]1.[C:22]([C:24]1[O:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=1)#[N:23].CCN(C(C)C)C(C)C>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[N:12][C:11]([NH:14][C:29]([C:27]3[O:28][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)=[O:30])=[C:10]([N:15]3[CH2:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH2:20]3)[N:9]=2)[CH2:6][CH2:7]1
Reactant: CC1CCN(c2nc(N3CCN(C)CC3)cnc2N)CC1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2nc(N3CCN(C)CC3)cnc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 24.4 %

Procedure:
Using a procedure similar to Example 23, step (a) 4-methyl-6′-(4-methyl-piperidin-1-yl)-5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (37 mg, 0.11 mmol) was stirred with 20 mg 5% Pd—C in 5 mL MeOH under H2 to afford 32 mg (100%) of the title compound as an oil, which was used immediately without further purification. Using a procedure similar to Example 4, step (c), 4-methyl-6′-(4-methyl-piperidin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamine (32 mg, 0.10 mmol)) was allowed to react with 5-cyano-furan-2-carbonyl chloride (44.6 mg, 0.28 mmol) in the presence of DIEA (107 μL, 0.610 mmol) to afford 10 mg (25%) of the title compound as a dark semi-solid. 1H-NMR (CDCl3; 400 MHz): δ 8.29 (s, 1H), 7.57 (s, 1H), 7.32 (d, 1H, J=3.6 Hz), 7.24-7.23 (d, 1H, J=3.6 Hz), 3.60-3.57 (m, 6H), 2.87-2.81 (m, 2H), 2.57-2.54 (m, 4H), 2.39 (s, 3H), 1.77-1.73 (m, 2H), 1.66-1.55 (m, 1H), 1.40-1.32 (m, 2H), 1.02 (d, 3H, J=6.5 Hz); Mass spectrum (ESI, m/z): Calcd. for C21H27N7O2, 410.2 (M+H), found 410.2.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=O)([OH:3])=[O:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[C:22]1(=[O:28])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:25](=[O:27])[CH:24]=[CH:23]1
Reactant: O=C(O)/C=C\C(=O)NCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCCCCCCCCCCCCCCCCN1C(=O)C=CC1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A mixture of N-(17-carboxyheptadecyl)maleamic acid (400 mg, 1.01 mmoles), 2.83 ml of acetic anhydride, and anhydrous sodium acetate (41.0 rag, 0.50 mmoles) was heated at 100° C. with stirring for 1 hour. The reaction mixture was allowed to cool, then poured onto ice and stirred for 1 hour. The resulting mixture was extracted with chloroform. The separated organic layer was washed with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and isolated and purified by silica gel column chromatography [eluent: mixture of benzene and chloroform (volume ratio: 1:1)], to give 18-maleimidooctadecanoic acid (172 mg, 45%) having the following properties.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12]CC(C1C=CC(Br)=CC=1)=O>CN(C=O)C.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: CCC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(C#N)cc1
Yield: 89 %

Procedure:
As described for the preparation of 4-cyanoacetophenone (Synth. Commun 1994, 887-890), a mixture of 4-bromopropiophenone (5.65 g, 26.4 mmol), Zn(CN)2 (1.80 g, 15.3 mmol), and Pd(PPh3)4 (2.95 g, 2.6 mmol) was refluxed at 80° C. in deoxygenated DMF (35 mL, stored over 4 Å molecular sieves, bubbled with Ar before use) for 18 h. The mixture was partitioned between toluene (100 mL) and 2N NH4OH (100 mL). The organic phase was extracted with 2N NH4OH (100 mL), washed with saturated aqueous NaCl (2×100 mL), dried, and concentrated in vacuo. A 10 mmol scale reaction was done similarly and the crude products were combined. Flash chromatography (330 g silica, 6/1 petroleum ether—EtOAc) afforded the desired compound as a white solid (5.17 g, 89%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:5]=[C:6]([Br:10])[CH:7]=[CH:8][CH:9]=2)[O:13][CH2:12][CH2:11][O:3]1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2cccc(Br)c2)OCCO1
Reaction time: 12 h
Yield: 85 %

Procedure:
5 g (25 mmol) of 3-bromoacetophenone are dissolved in 40 ml of toluene and then 15 ml of ethylene glycol and 500 mg of para-toluenesulphonic acid are added. The reaction medium is then heated under reflux equipped with a Dean-Stark distillation assembly. After 12 h, the medium is cooled and then treated with water and extracted with dichloromethane. After drying and concentrating, the residue is purified on a silica column in order to obtain the desired 3-(2-methyl-[1,3]dioxolan-2-yl)-1-bromobenzene (Y=85%). This product (4 g, 16.4 mmol) is then dissolved in anhydrous THF and the mixture is cooled to −78° C. 7.2 ml (18 mmol) of a 2.5M solution of butyllithium are then added dropwise. After stirring for 1 hour at the same temperature, 1.9 ml (18 mmol) of dimethylformamide are added. The mixture is maintained at −78° C. for 30 minutes and then brought to room temperature. The reaction medium is then treated with a saturated ammonium chloride solution and extracted with dichloromethane. After purification by chromatography on a silica column (ethyl acetate 10-heptane 90), a colourless oil is obtained (m=3.09 g; Y=98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[C:23]([CH3:24])=[N:22][S:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:41]1([CH3:50])[CH:46]=[CH:45][C:44]([C:47](Cl)=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[C:23]([CH3:24])=[N:22][S:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])[C:47](=[O:48])[C:44]1[CH:45]=[CH:46][C:41]([CH3:50])=[CH:42][CH:43]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {3-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propylamino]-propyl}-carbamic acid tert-butyl ester (method 10) (0.1 g, 0.21 mmol) and triethylamine (0.303 g, 3 mmol) in DCM (20 mL) at r.t. was added dropwise a solution of p-toluoyl chloride (0.1 g, 0.6 mmol) in DCM (10 mL). The resulting solution was stirred at r.t. for 30 min. after which the TLC showed the disappearance of the SM. The reaction mixture was diluted with DCM (60 mL) washed with satd. NaHCO3 (100 mL), water (100 mL), brine (100 mL) and dried (Na2SO4). Concentration of the organic layer provided the crude product which was purified by column (silica gel) chromatography using 20-30% EtOAc in hexanes as eluent. Yield was 0.117 g (94%). m/z 590 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34](O)=[C:33]([F:38])[CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:33]([F:38])[CH:32]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 3-fluoro-4-hydroxy benzoic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White foam (81%). MS (Turbo Spray): m/z=543.0 [M+H].
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:16]=[CH:15][N:14]=2)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:2]1.Br[C:29]1[O:30][CH:31]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:33]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>O>[C:8]([O:7][C:6]([N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[C:13]1[CH:18]=[C:17]([C:29]2[O:30][CH:31]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:33]=2)[CH:16]=[CH:15][N:14]=1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOC(=O)c1coc(Br)n1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1coc(-c2ccnc(N(CC3CC3)C(=O)OC(C)(C)C)c2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A mixture of tert-butyl (cyclopropylmethyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (48.3 g), ethyl 2-bromo-1,3-oxazole-4-carboxylate (25.8 g), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (4.79 g), potassium carbonate (32.4 g) and DME (489 mL)/water (98 mL) was stirred at 80° C. for 4 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (33.3 g).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][N:7]=1)=[O:4].CN(C)[CH:22]=[O:23]>C1COCC1>[CH:22]([C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1])=[N:7][CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2ccccc2)cn1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(-c2ccccc2)cc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
2,2-dimethyl-N-(5-phenylpyridin-2-yl)propanamide (2.5 g, 9.83 mmol) was dissolved in 80 mL of dry THF and cooled to 0° C. N-Butyl lithium (2.5 M in hexanes) (9.8 mL, 24.57 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 2 hours and then N,N-dimethylformamide (3.6 g, 49.15 mmol) was added. The reaction mixture was removed from the cold bath and allowed to warm to room temperature. After 30 minutes the reaction was quenched with water. The mixture was extracted with EtOAc and dried over MgSO4. The solvent was removed and the residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (2:1) to afford N-(3-formyl-5-phenylpyridin-2-yl)-2,2-dimethylpropanamide (1.87 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[CH:7]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]>>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[CH:7]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[N:4]1[CH:3]=[N:2][N:1]=[CH:5]1
Reactant: CC(C)(C)C(=O)C(Br)N1C(=O)c2ccccc2C1=O
Reactant: c1nc[nH]n1
Product: CC(C)(C)C(=O)C(N1C(=O)c2ccccc2C1=O)n1cnnc1
Yield: 23.4 %

Procedure:
21 g (0.3 mol) of 1,2,4-triazole were added to 32.4 g (0.1 mol) of 1-bromo-3,3-dimethyl-1-phthalimido-butan-2-one in 200 ml of acetontrile. The mixture was heated for 24 hours under reflux and was then concentrated in a waterpump vacuum. The residue was taken up in 200 ml of methylene chloride and the solution was washed three times in 100 ml of water at a time, dried over sodium sulphate and concentrated in vacuo by distilling off the solvent. The residue was taken up in 200 ml of acetone, the solution was heated with active charcoal and filtered, and 18 g of 1,5-naphthalenedisulphonic acid were added to the filtrate. The resulting precipitate (25.4 g of the naphthalenedisulphonate salt of melting point 155°-162° C., with decomposition) was neutralized with sodium hydrogen carbonate solution. The oil thereby formed was recrystallized from petroleum ether/ethanol. 7.3 g (23% of theory) of 3,3-dimethyl-1-phthalimido-1-(1,2,4-triazol-4-yl)-butan-2 -one of melting point 189°-196° C. were obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][O:19][C:20]([F:23])([F:22])[F:21])[O:12]1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:12][C@H:13]([CH2:18][O:19][C:20]([F:23])([F:22])[F:21])[C@@H:14]([OH:17])[C@H:15]2[OH:16])=[CH:26][CH:25]=1
Reactant: O[C@@H]1[C@H](O)[C@@H](COC(F)(F)F)O[C@H]1n1cnc2c(Cl)ncnc21
Reactant: NCCc1ccncc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1[C@H](O)[C@@H](COC(F)(F)F)O[C@H]1n1cnc2c(NCCc3ccncc3)ncnc21
Yield: 30.7 %

Procedure:
(2R,3R,4S,5R)-2-(6-Chloro-purin-9-yl)-5-trifluoromethoxymethyl-tetrahydro-furan-3,4-diol (42 mg), 2-pyridin-4-yl-ethylamine (58 mg), and diisopropylethylamine (0.124 ml) were heated at 80° C. in isopropanol (5 ml) in a reactivial for 17 h. The solution was evaporated under a stream of nitrogen and purified by autoprep HPLC to afford the title compound as a colourless solid (16 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH2:17][CH3:18])[C:13](SCC)=[N:12]3)[CH2:10][CH:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:28].[I-].N.CCO>>[NH2:28][C:13]1[N:14]([CH2:17][CH3:18])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10]2)[N:12]=1
Reactant: CCSC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CCN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Yield: 23.8 %

Procedure:
A solution of 6-bromo-1′-ethyl-2′-(ethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (195 mg, 0.44 mmol) and NH4I (128 mg, 0.88 mmol) in a solution of NH3/EtOH (5 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-ethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 24%). 1H-NMR (MeOD): 1.12 (m, 3H), 1.98 (m, 1H), 3.16 (m, 1H), 3.54 (m, 2H), 5.75 (m, 1H), 6.77 (m, 1H), 6.95 (m, 1H), 7.23 (m, 2H), 7.33 (m, 4H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.F[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:17][CH:18]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(F)cc1
Product: Cc1ccc(OC2CCNCC2)cc1

Procedure:
By following the manipulative procedures described in Example 1(a) and (b), 24.0 g of 1-benzyl-4-piperidinol and 24.0 g of p-fluorotoluene produces an oil of 4-(p-tolyloxy)piperidine.
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])[CH2:9][N:8]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[OH:28])[CH2:7][CH2:6]2.Cl[CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36])[CH2:7][CH2:6]2
Reactant: OCCOCCCl
Reactant: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(C)ccc1O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(C)ccc1OCCOCCO)CC2
Temperature: 25 °C
Yield: 52.7 %

Procedure:
The mixture of 4a (0.65 g, 1.6 mmol), 2-(2-chloroethoxy)ethanol (0.64 g, 5.1 mmol), potassium carbonate (0.71 g, 5.1 mmol) in of N,N-Dimethylformamide (DMF) (25 mL) was refluxed over night under an atmosphere of nitrogrn. The reaction mixture was cooled to room temperature and quenched with 100 mL water. The aqueous solution was extracted with ethyl acetate (3 X2 50 mL). The combined organic layer was washed with brine (3×30 mL) and dried over Na2SO4. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography with methanol/dichloromethane (10/90, v/v) as the mobile phase to afford compound 5a (0.41 g; 51% yield) as a viscous yellow oil. 1H NMR (300 MHz, CDCl3): 1.68-1.79 (m, 4H), 2.31 (s, 3H), 2.50-2.60 (m, 2H), 2.72-2.76 (m, 2H), 2.82-2.85 (m, 2H), 3.46-3.60 (m, 8H), 3.80-3.90 (m, 8H), 4.18-4.24 (m, 2H), 6.49 (s, 1H), 6.58 (s, 1H), 6.79-6.83 (d, 1H), 7.16-7.24 (m, 1H), 7.98-7.80 (m, 1H), 8.18-8.26 (s, 1H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH2:12])[CH:10]=[CH2:11]>C(Cl)(Cl)Cl>[O:6]=[C:5]([NH:12][CH2:9][CH:10]=[CH2:11])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: C=CCN
Reactant: O=C1CCCC(=O)O1
Solvent: ClC(Cl)Cl
Product: C=CCNC(=O)CCCC(=O)O

Procedure:
A functional monomer was prepared in the following manner, and was used in Example 15 to introduce activated ester groups on the backbone of the polymer. Glutaric anhydride, 20 g (0.175 mole),was dissolved in 100 ml chloroform. The glutaric anhydride solution was cooled to <10° C using an ice bath. Allyl amine, 10 g (0.177 mole), was dissolved in 50 ml chloroform and added to the cooled solution of glutaric anhydride with stirring. The addition rate of allyl amine was adjusted to keep the reaction temperature <10° C. After the allyl amine addition was completed, the reaction solution was allowed to come to room temperature while stirring overnight. After removing the solvent, the 5-oxo-6-aza-8-nonenoic acid isolated amounted to 31.4g (105% crude) with a dual DSC melting point of 35.1° C and 44.9° C. NMR analysis at 300 MHz was consistent with the desired product: 1H NMR (CDCl3) amide proton 6.19 (b, 1H), vinyl protons 5.13, 5.81 (m, 3H), methylene adjacent to amide N 3.85 (m, 2H), methylenes adjacent to carbonyls 2.29, 2.39 (t, 4H), and central methylene 1.9. (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:23]([C:24]([N:26]=[C:27]=[O:28])=O)=[C:22]([F:29])[C:21]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:20][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:22]([F:29])[C:23]=1[C:24]1[NH:26][C:27](=[O:28])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.050 g, 0.20 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.130 g, 0.41 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.040 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.30 (d, J=6.0 Hz, 2H), 7.24-7.47 (m, 2H), 7.52 (d, J=7.2 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 8.16 (m, 1H), 12.10 (br s, 1H); MS (m/z): 437.16 (M+).
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[Na+].[CH2:18]([S:21]([O-:23])=[O:22])[CH2:19][CH3:20].N1C=CC=CC=1.Cl>CN(C=O)C>[C:11]([C:9]1[O:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:16])([S:21]([CH2:18][CH2:19][CH3:20])(=[O:23])=[O:22])[CH3:15])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCS(=O)[O-]
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)C(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 50 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
To a solution of 160 mg (0.55 mmol) of 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide in DMF (3 mL) were added 87 mg (0.71 mmol) of 1-propanesulfinic acid sodium salt in one portion. Pyridine (48 μL) was added and the reaction was stirred at 50° C. for 18 h. The mixture was acidified with 1M aqueous HCl solution (1 mL) and extracted with diethyl ether (3×3 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica, eluent heptanes, 0-20% ethyl acetate) to afford 86 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(propane-1-sulfonyl)-propionamide.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:19][CH2:20][S:21][CH3:22])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])(=[O:3])[CH3:2].[OH:23]O>CO>[C:1]([O:4][CH:5]([CH2:19][CH2:20][S:21]([CH3:22])=[O:23])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])(=[O:3])[CH3:2]
Reactant: OO
Reactant: CCCCCCCCCCNC(=O)C(CCSC)OC(C)=O
Solvent: CO
Product: CCCCCCCCCCNC(=O)C(CCS(C)=O)OC(C)=O
Reaction time: 5.5 h
Yield: 101.7 %

Procedure:
To a solution of 1-(decylamino)-4-(methylthio)-1-oxobutan-2-yl acetate (21.1 g, 63.4 mmol) in methanol (110 mL) at 0° C. was added hydrogen peroxide (30%, 19.43 mL, 190 mmol) and the ice bath was removed. The reaction was allowed to stir for 5.5 hr. The reaction was diluted with water (400 mL) and then extracted with EtOAc (200 mL) to give an emulsion which did not separate after 18 hrs. The emulsion was treated with brine (250 mL) and the layers separated. The aqueous layer was extracted with EtOAc (200 mL) and the combined organic layers were washed with 10% sodium bisulfite. The organic layer was dried over magnesium sulfate, filtered and evaporated to give an orange oil (22.4 g, 100%). m/z 348 (MH+).