Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][CH2:3]1.ClCC(=O)[C@@H](NC(=O)C1C=CC=CC=1)CC1C=CC=CC=1>>[O:9]=[C:8]1[N:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1C(=O)C(N)CSc2ccccc21
Agent: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)c1ccccc1
Product: CCOC(=O)CN1C(=O)CCSc2ccccc21

Procedure:
(±)-3-Amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester is reacted with (S)-N-[3-chloro-2-oxo-1-(phenylmethyl)propyl]benzamide according to the procedure of Example 1(h) to yield (±)-dihydro-3-[[3-benzoylamino)-2-oxo-4-phenylbutyl]amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>CN(C=O)C>[CH2:9]([C:2]1[C:1]([NH:5][C:4](=[O:6])[CH:3]=1)=[O:7])[CH3:10].[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: O=C1C=CC(=O)N1
Solvent: c1cc[nH]c1
Solvent: CN(C)C=O
Product: CCC1=CC(=O)NC1=O
Reaction time: 0.5 h

Procedure:
SA-SH is mixed with a 25 nmol/μl solution of maleimide-pyrrole (3.4 μl; 85 nmol) prepared by taking up 2 mg of maleimide-pyrrole in 200 μl of DMF. The reaction lasts 30 minutes.
Reaction SMILES: Br[C:2]([CH3:8])([C:4](=[O:7])[CH2:5][CH3:6])[CH3:3].[SH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][S:9][C:2]([CH3:8])([CH3:3])[C:4](=[O:7])[CH2:5][CH3:6])[CH3:15]
Reactant: CCOC(=O)CS
Reactant: CCC(=O)C(C)(C)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSC(C)(C)C(=O)CC
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-2-methyl-pentan-3-one (A1) (13.5 g, 75 mmol) in CH2Cl2 (400 ml) were added ethyl 2-mercaptoacetate (9 g, 8.2 ml, 75 mmol) and 10.42 ml triethylamine at 0° C. and stirred for 3 h. The solution was allowed to come to room temperature (12 h). The resulting suspension was filtered, the filtrate washed with water (100 ml) and brine (100 ml) and dried over Na2SO4. Removal of the solvent in vacuo gave a slightly yellow oil, which was purified by flash chromatography (ethyl acetate-petroleum ether 1:25).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:29]=[C:28]4[C:23]([CH:24]=[CH:25][CH:26]=[N:27]4)=[CH:22][CH:21]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:29]=[C:28]4[C:23]([CH:24]=[CH:25][CH:26]=[N:27]4)=[CH:22][CH:21]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31]
Reactant: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1O
Yield: 76.2 %

Procedure:
A solution of 7-benzyloxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (1.50 g, 3.70 mmol), (prepared as described in Example 196), in trifluoroacetic acid (50 ml) was heated at reflux for 150 minutes. The reaction was concentrated in vacuo and the reaction neutralised with saturated aqueous ammonium hydroxide. The resulting precipitate was filtered, washed with acetone and dried under suction to give 7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (0.90 g, 2.82 mmol, 76%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24][CH2:23]3)[CH:18]=2)[N:13]=[CH:12]1.S(Cl)(Cl)=O.[NH2:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH2:28]([N:25]1[CH2:24][CH2:23][N:22]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][N:11]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=2[CH3:1])[C:6]([NH:34][C:35]2[CH:39]=[CH:38][O:37][N:36]=2)=[O:8])[C:20]3=[O:21])[CH2:27][CH2:26]1)[CH3:29]
Reactant: CCN1CCN(c2ccc3ncn(-c4cc(C(=O)O)ccc4C)c(=O)c3c2)CC1
Reactant: Nc1ccon1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc3ncn(-c4cc(C(=O)Nc5ccon5)ccc4C)c(=O)c3c2)CC1
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
To a stirred slurry of 4-methyl-3-[6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.19 g) and DMF (0.05 ml) in methylene chloride (4 ml) at 35° C. was added thionyl chloride (0.18 ml). The resultant green solution was stirred at 35° C. for 1.5 hours. The reaction mixture was concentrated to give yellow foam. The solid was stirred in methylene chloride (4 ml) at room temperature and 3-aminoisoxazole (0.15 ml) and N,N-diisopropylethylamine (0.25 ml) was added, stirred for 1.5 hours and concentrated. The resultant oil was partitioned between ethyl acetate and a saturated NaHCO3 solution. The aqueous layer was separated and the organic layer washed with brine (5 ml). The organic phase concentrated to give an off-white solid. The solid was triturated with ethyl acetate and collected by filtration to give the title compound as an off-white solid (85 mg); NMR Spectrum: (DMSOd6) 1.05 (3H, t), 2.18 (3H, s), 2.41 (2H, m), 2.55 (4H, m), 3.29 (4H, m), 7.05 (1H, s), 7.50 (1H, s), 7.62 (3H, m), 8.07 (2H, m), 8.13 (1H, s), 8.87 (1H, s), 11.47 (1H, s); Mass Spectrum: M+H+ 459.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([NH2:22])=[O:21].[OH-].[Na+]>C(#N)C>[C:20]([C:16]1[S:17][CH:18]=[CH:19][C:15]=1[NH:14][CH:2]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:3]([OH:5])=[O:4])(=[O:21])[NH2:22]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: NC(=O)c1sccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: NC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.4 %

Procedure:
A solution of ethyl 2-bromo-2-phenylacetate (349 μl, 2.00 mmol) and 3-aminothiophene-2-carboxamide (284 mg, 2.00 mmol) in acetonitrile (2 ml) was heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile was evaporated, and the residue was dissolved in EtOH (2 ml). Sodium hydroxide (80 mg, 2.00 mmol) was added, and the reaction mixture was stirred at room temperature for 24 hours. Then ethanol was evaporated, and the residue was taken up with water and washed with EtOAc. The pH of the aqueous phase was adjusted to 3 with HCl, and product was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain 2-(2-carbamoylthiophen-3-ylamino)-2-phenylacetic acid (389 mg, 70% yield), which was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[N:18]=[C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:16](CC4C=CC(OC)=CC=4)[N:15]=3)=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([CH2:12][CH2:13][C:14]3[N:18]=[C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[NH:16][N:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2nc(CCc3cnc4ccc(Cl)cc4n3)nc2N2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Clc1ccc2ncc(CCc3n[nH]c(N4CCCC4)n3)nc2c1
Yield: 17.7 %

Procedure:
7-chloro-2-(2-(1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl)ethyl)quinoxaline (17 mg, 37.9 μmol, Eq: 1.00) was stirred in trifluoroacetic acid (173 mg, 117 μl, 1.51 mmol, Eq: 40) with anisole (81.9 mg, 82.7 μl, 757 μmol, Eq: 20) at 120° C. overnight. The mixture was made basic by addition of sodium hydroxide 2N aq. and extracted three times with 1,2-dichloromethane, dried over magnesium sulfate, filtered and evaporated. The crude material was applied on silica gel and purified by column chromatography to give 7-Chloro-2-[2-(5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-yl)-ethyl]-quinoxaline (2.2 mg, 17.7%) as off-white solid. MS: m/z=329.12 (M+H+)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O>CS(C)=O.O>[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:17][C:16]1[CH:18]=[CH:19][C:11]([CH:10]=[O:9])=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: OCCCCCCCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCOc1ccc(C=O)cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
41.45 g (300 mmol) of potassium carbonate and 27.4 g (165 mmol) of potassium iodide are added to a solution of 22.8 g (150 mmol) of vanillin and 30.7 g (225 mmol) of 6-chlorohexanol in 500 ml of dimethyl sulphoxide (DMSO) and the mixture is stirred overnight at 60° C. under nitiogen. The mixture is then cooled to room temperature, poured into 600 ml of water and extracted three times with 150 ml of ethyl acetate each time. The combined organic phases are washed twice with 200 ml of water each time, dried over magnesium sulphate, filtered and concentrated. Purification of the residue by chromatography on 400 g of silica gel using cyclohexane/ethyl acetate 1:1 yields 29.95 g of 4-(6-hexyloxy)-3-methoxybenzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 112.4 %

Procedure:
Benzoyl peroxide (0.012 g) was added to a mixture of 4-(4-methylbenzoyl)-nitrobenzene (1.20 g) and N-bromo succinimide (0.89 g) suspended in carbon tetrachloride (63 mL). The reaction mixture was refluxed under argon for 4 hours while illuminated with an incandescent lamp. The mixture was filtered, and the yellow solution containing the crude product was evaporated, chromatographed on silica gel, eluting with hexane/ethyl acetate, to give 4-(4-bromomethylbenzoyl)-nitrobenzene (1.79 g, 81%) as a white solid, m.p. 112.7-113.1° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[O:30][CH2:31][C:32]([OH:34])=O)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[O:30][CH2:31][C:32]([NH:47][CH2:46][CH2:45][C:44]([OH:48])=[O:43])=[O:34])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC(=O)O)c2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC(=O)NCCC(=O)O)c2)cc1

Procedure:
The product from Example 62C and β-alanine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 8.10 (t, 1 H), 7.24 (m, 8 H), 6.99 (m, 5 H), 6.71 (m, 1 H), 6.55 (m, 2 H), 4.43 (s, 2 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.31 (dd, 2 H), 2.88 (s, 3 H), 2.40 (t, 4 H), 2.07 (s, 2 H); MS (APCI) m/z 618 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[C:6]([N+:23]([O-])=O)[CH:5]=1)(=[O:3])[CH3:2].C(OCC)C>C(O)C.ClCCl.[Pd]>[C:1]([C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[C:6]([CH:5]=1)[NH2:23])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c(N)c1
Yield: 80.2 %

Procedure:
4-acetyl-2-nitro-N-(3-(3-pyridyl)-phenyl)-aniline (2 g, 6 mmol) is suspended in a mixture of ethanol (50 ml) and dichloromethane (10 ml) and is hydrogenated at ambient pressure using palladium (5% on activated carbon) as the catalyst. Filtration of the resulting solution through celite followed by evaporation of solvent leaves an oil which upon trituration with a mixture of diethylether and petroleumether (1:1) affords 1.46 g pure 5-acetyl-2-(3-(3-pyridyl)phenylamino)aniline (80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH2:24])=[O:13])[S:10][C:3]=12
Reactant: N
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc2nccc(Cl)c2s1
Reaction time: 3 h

Procedure:
A 250 mL flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (3.00 g, 13.7 mmol) and CH2Cl2 (100 ml) under nitrogen. DMF (cat) (0.100 ml) and oxalyl dichloride (1.49 ml, 17.1 mmol) were added dropwise, and the reaction mixture was stirred for 3 hours, and concentrated in vacuo. The brown solid was redissolved in CH2Cl2 (100 ml) and ammonia (gas) (0.233 g, 13.7 mmol) was gently bubbled through the reaction mixture for 5 minutes. The flask was then capped and stirred at room temperature overnight under closed atmosphere. The brown suspension was concentrated in vacuo and the resulting solid was taken up in water (to dissolve the starting material), then collected by filtration to give 7-chlorothieno[3,2-b]pyridine-2-carboxamide. MS m/z=213 [M+H]+. Calc'd for C8H5ClN25OS: 212.66.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][OH:16])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH3:3].[O:17]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]1[C:19]([O:21][CH3:22])=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[OH:17][CH:18]([C:23]([O:16][CH2:15][CH2:14][N:4]([CH2:1][CH2:2][CH3:3])[S:5]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCCN(CCO)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCN(CCOC(c1ccccc1)(c1ccccc1)C(O)C(=O)OC)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.3 g (30 mmol) of N-propyl-N-(2-hydroxyethyl)benzenesulfonamide and 7.6 g (30 mmol) of methyl 2,3-epoxy-3,3-diphenylpropionate were dissolved in 40 ml of methylene chloride and, with ice-cooling, 0.57 g (3 mmol) of p-toluenesulfonic acid was added. The reaction mixture was stirred at room temperature for 24 hours and then diluted with methylene chloride and extracted with 2M aqueous sodium hydroxide solution, the organic phase was separated off and dried over sodium sulfate and the solvent was distilled off. The residue (12.0 g of an oil) was directly reacted further.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:29]([O:36][C:37](=[O:42])[CH2:38][C:39](O)=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:29]([O:36][C:37](=[O:42])[CH2:38][C:39]([NH:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)CC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
(2-Amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (570 mg) was dissolved in CH2Cl2 (15 ml) and DMF (5 ml) prior to the addition of DIEA (2.3 ml) and malonic acid monobenzyl ester (400 mg). After cooling to 0° C., HATU (940 mg) was added. The resulting mixture was warmed to rt and stirred overnight before being concentrated. Flash chromatography of the resulting residue gave N-(2-tert-butoxycarbonylamino-5-trifluoromethyl-phenyl)-malonamic acid benzyl ester (570 mg), MS found: (M−H)−=451.2.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.CC([N:27]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:41]=[C:40]([CH:42]=O)[NH:39][N:38]=2)=[CH:33][CH:32]=1)C(=O)[O-])(C)C>CN(C=O)C>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]3[N:21]=[C:42]([C:40]4[NH:39][N:38]=[C:37]([C:34]5[CH:35]=[CH:36][C:31]([NH2:27])=[CH:32][CH:33]=5)[CH:41]=4)[NH:22][C:17]=3[CH:16]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(-c2cc(C=O)[nH]n2)cc1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc3nc(-c4cc(-c5ccc(N)cc5)n[nH]4)[nH]c3c2)CC1
Temperature: 65 °C
Yield: 70 %

Procedure:
Triethylamine (2.32 g, 23 mmol) was added to a solution of 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine as the tetra-hydrochloride salt in anhydrous DMF (11 mL) after five minutes, a solution of 1,1-dimethylethyl[4-(5-formyl-1H-pyrazol-3-yl)phenyl]carbamate in anhydrous DMF (2 mL) was added to the diamine. The reaction flask was left open to the air and heated to 65° C. After twelve hours the reaction was concentrated in vacuo and the residue purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the product (0.60 g, 70% yield). (Note that the BOC group was removed under the purification conditions.)
Reaction SMILES: [S:1]([O-:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH:7]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:8][S:9]([CH2:12][CH2:13][CH2:14][N+:15]([CH3:18])([CH3:17])[CH3:16])(=[O:11])=[O:10].[CH3:39][N:40]=[C:41]=[O:42].CN(C)C>C(Cl)(Cl)Cl>[S:1]([O-:5])(=[O:4])(=[O:3])[CH3:2].[CH3:39][NH:40][C:41]([O:6][CH:7]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:8][S:9]([CH2:12][CH2:13][CH2:14][N+:15]([CH3:17])([CH3:16])[CH3:18])(=[O:11])=[O:10])=[O:42]
Reactant: CN=C=O
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CS(=O)(=O)CCC[N+](C)(C)C
Agent: CN(C)C
Agent: CS(=O)(=O)[O-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCC[N+](C)(C)C)OC(=O)NC
Reaction time: 8 h

Procedure:
Into 6 ml of chloroform are added 1.4 g of 3-[(2-hydroxy-3-octadecyloxypropyl)sulfonyl]propyltrimethylammonium mesylate, 1 ml of methyl isocyanate and 1 ml of trimethylamine and the mixture is shaked overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel column chromatography to give 0.2 of the captioned
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[ClH:15].[Cl:16][CH2:17][CH2:18][N:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[Na+]>CN(C)C=O>[ClH:16].[ClH:15].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:17][CH2:18][N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: c1ccc(CN(CCOc2ccc(-n3ccnc3)cc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold suspension of 33 g (0.82 mol) 50% sodium hydride in 500 mL dimethylformamide, add 50.4 g (0.315 mol) 4-(1H-imidazol-1-yl)phenol portionwise, maintaining the temp below 10° C. After addition, stir at room temp for 1 hr. Add 93.2 (0.315 mol) 2-chloro-N,N-dibenzylethanamine hydrochloride portionwise followed by 2.35 g (0.16 mol) sodium iodide. Heat the reaction to 50° C. for 24 hr. After this time, quench with 15 mL H2O, filter, and remove the solvents. Dissolve the residue in methanolic HCl and remove the solvents to provide the title compound which can be recrystallized from isopropanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].C(=O)([O-])[O-].[K+].[K+].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CC(C)=O>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[C:9]3[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]2=[O:16])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
N-(4-Bromobutyl)phthalimide 7 (9.70 g, 34.40 mmol) was added to a suspension of potassium carbonate (8.20 g, 59.30 mmol) and piperazine-1-carboxylic acid tert-butyl ester 8 (5.00 g, 26.80 mmol) in acetone (125 mL). The mixture was heated at reflux for 14 hours. After cooling to ambient temperature, the reaction mixture was filtered and the filtrate concentrated to a waxy yellow solid. Purification by column chromatography (silica gel, gradient of 70:30 to 0:100 hexanes/ethyl acetate, v/v) gave compound 9 (8.69 g, 84%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.46-1.59 (m, 2H), 1.63-1.76 (m, 2H), 2.32-2.40 (m, 6H), 3.38-3.44 (m, 4H), 3.71 (t, J=6.9 Hz, 2H), 7.71-7.73 (m, 2H), 7.82-7.84 (m, 2H); ESI MS m/z 388 [C21H29N3O4+H]+.
Reaction SMILES: O[C:2]1([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:20]>>[ClH:20].[NH:18]1[CH:19]=[C:15]([C:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH:3]=2)[N:16]=[CH:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2c[nH]cn2)CC1
Agent: Cl
Product: C1=C(c2c[nH]cn2)CCNC1
Temperature: 120 °C

Procedure:
tert-Butyl 4-hydroxy-4-(1H-imidazol-4-yl)-piperidine-1-carboxylate (20 mg) was dissolved in 6 ml of 6M hydrochloric acid and the solution was stirred at 120° C. for one night. The solvent was evaporated in vacuo and the precipitate was filtered to give 55 mg of the title compound as a dark solid crude product.
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:14]C(=O)N(C)C)[CH:13]=1)[C:9]#[N:10])=O.[OH-].[Na+]>>[SH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([SH:14])[CH:13]=1)[C:9]#[N:10]
Reactant: CN(C)C(=O)Sc1cc(C#N)cc(SC(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(S)cc(S)c1

Procedure:
3,5-Bis(dimethylcarbamoylthio)benzonitrile was subjected to hydrolysis with aqueous sodium hydroxide according to the ordinary procedure, giving 3,5-dimercaptobenzonitile.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([OH:23])(=[O:22])=[O:21])[CH:8]=2)[N:3]=1.[CH2:24]1[S:29](=[O:31])(=[O:30])[O:28][CH2:27][CH2:26][CH2:25]1.S1(CCCC1)(=O)=O>C(OCC)C>[CH3:1][CH:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([OH:23])(=[O:21])=[O:22])[CH:8]=2)[N:3]1[CH2:27][CH2:26][CH2:25][CH2:24][S:29]([OH:31])(=[O:30])=[O:28]
Reactant: O=S1(=O)CCCCO1
Reactant: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCS(=O)(=O)O
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: CC1N(CCCCS(=O)(=O)O)c2ccc(S(=O)(=O)O)cc2C1(C)CCCCS(=O)(=O)O
Temperature: 140 °C
Yield: 86.8 %

Procedure:
To 2,3-dimethyl-3-(4-sulfobutyl)-5-sulfo-3H-indole (10 g) was added butane sultone (30 g) and the mixture heated to 140° C. overnight. On cooling to room temperature, sulfolan (20 ml) was added and the mixture poured into diethyl ether (500 ml). The resultant precipitate was removed by filtration and dried to give the desired product (12 g).