Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13]C)=O.C(O)C.O.[NH2:19][NH2:20]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:19][NH2:20])=[O:13]
Reactant: COC(=O)c1ccc2ccccc2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2ccccc2c1
Yield: 88 %

Procedure:
First, 5.0 g of methyl 2-naphthoate and 20 mL of ethanol were put in a four-neck flask, and stirred. Then, 5 mL of hydrazine monohydrate (NH2NH2.H2O) was added to this mixture, and heated and stirred at 80° C. for 5 hours to be reacted. After the reaction, the solution was added to 100 mL of water, whereby a solid was precipitated. The resulting suspension was subjected to suction filtration to give a solid. This solid was recrystallized from a mixed solvent of chloroform and hexane, so that 4.4 g of 2-naphthohydrazide was prepared as a white solid with a yield of 88%. The synthetic scheme of Step 1 is shown by (a-12).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18].O>N1C=CC=CC=1>[NH2:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[NH:10][C:17]([C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)=[O:18]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: O
Solvent: c1ccncc1
Product: Nc1cc([N+](=O)[O-])ccc1NC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.1 %

Procedure:
To a stirred solution of 4-nitro-o-phenylene diamine (76.5 g, 0.5 mole) in 500 ml of pyridine, is added dropwise 2-furoyl chloride (65 g, 0.5 mole). After the addition is complete the reaction solution is stirred at room temperature for 15 minutes and then at reflux for 2 hr. The hot reaction solution is poured into 6 liters of water to give an oil, which solidifies upon standing overnight at room temperature to give 125 g (100 percent) of yellow intermediate. The solid is used in part B without further purification.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([CH2:9][C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=O.Cl>CO.O1CCCC1.C(=O)(O)[O-].[Na+]>[NH2:3][C:4]1[S:5][C:6]([CH2:9][C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cnc(NC=O)s3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cnc(N)s3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 35.3 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (4.67 g) and conc. hydrochloric acid (4.67 g) in methanol (93 ml) and tetrahydrofuran (46 ml) was stirred at 30° C. for 4 hours. After the organic solvent was removed by evaporation, to the residue was added water (70 ml), followed by adjusting to pH 6 to 7 with 10% aqueous solution of sodium hydroxide. After the insoluble substance was removed by filtration, the filtrate was adjusted to pH 3.0 with 10% hydrochloric acid under cooling, followed by stirring at the same temperature for 20 minutes. The precipitated substance was collected by filtration, washed with water and dried to give a residue, which was dissolved in an aqueous solution of sodium bicarbonate and then chromatographed on alumina (12 ml) using 5% aqueous sodium acetate as an eluant. The fractions containing the desired compound were collected and acidified to pH 3.1 with 10% hydrochloric acid, and the precipitated substance was collected by filtration and then dried to give 7-[2-(2-aminothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (1.53 g), mp>290° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[SH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(OCC)(=O)C>CN(C)C=O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:5]
Reactant: O=Cc1ccccc1F
Reactant: COC(=O)CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCSc1ccccc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
Under an argon atmosphere, 2-fluorobenzaldehyde (3 g) was dissolved in 9 ml of dimethylformamide and potassium carbonate (5.01 g) was added. Methyl 4-mercaptobutyrate (4.5 ml) was added at room temperature and-was stirred at room temperature for 14 hours. After the addition of 50 ml of ethyl acetate, the mixture was washed with 30 ml of water twice, 3 ml of a 1N hydrochloric acid, and 30 ml of water three times. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was subjected to silica gel chromatography (hexane/ethyl acetate=6/1) purification. The resulting effective fractions were concentrated to yield methyl 4-(2-formylphenylthio)butyrate (5.45 g, Yield 95%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]3[S:19][C:18]([CH2:20][OH:21])=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.[H-].[Na+].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])=[C:4]([C:11]2[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]3[S:19][C:18]([CH2:20][O:21][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=4)(=[O:38])=[O:37])=[CH:17][C:15]=3[N:16]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1cc2nc(-c3cc(F)cc4[nH]ccc34)nc(N3CCOCC3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2cc3nc(-c4cc(F)cc5c4ccn5S(=O)(=O)c4ccc(C)cc4)nc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
To a suspension of [2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-methanol (0.54 g, 1.41 mmol) in anhydrous THF (20 mL) and DMF (5 mL) was added sodium hydride (60% suspension in mineral oil, 0.34 g, 8.5 mmol). The resulting mixture was stirred at RT for 10 min, then p-toluenesulfonyl chloride (1.08 g, 5.66 mmol) was added and the reaction mixture was heated at 40° C. for 3 h. The resulting solution was partitioned between EtOAc and a saturated aqueous solution of ammonium chloride. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (0.60 g, 62%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][CH:7]([CH2:9][OH:10])[C@H:6]([OH:11])[C@@H:5]([OH:12])[C@@H:4]1[OH:13].[CH3:14][O:15][C:16]1C=CC(O)=[CH:18][CH:17]=1.[OH-:23].[Na+]>C(OCCO)(=O)C(C)=C>[C:16]([O:15][CH2:14][CH2:1][O:2][CH:3]1[O:8][C@H:7]([CH2:9][OH:10])[C@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13])(=[O:23])[CH:17]=[CH2:18]
Reactant: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: [OH-]
Reactant: COc1ccc(O)cc1
Agent: C=C(C)C(=O)OCCO
Agent: [Na+]
Product: C=CC(=O)OCCOC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
A 19.4 g quantity of methyl glucoside (STA-MEG 106, product of Horizon Chemical A. E. Staley Manufacturing Co.) was suspended in 140 ml of 2-hydroxyethyl methacrylate. To the suspension were added 2.6 g of hydroquinone monomethyl ether and 1.0 g of phosphomolybidic acid, and the mixture was stirred well and gradually heated. After heating to a temperature of 80° to 90° C., the mixture was further stirred for about 2 hours while maintaining the same temperature and was neutralized with 2N sodium hydroxide. The obtained reaction mixture was concentrated under reduced pressure and subjected to silica gel chromatography (eluent, chloroform:methanol=9:1). A fraction (Rf =0.2) of the reaction mixture was concentrated, giving 20.1 g of galactosyloxyethyl acrylate (HEMA-Glc) as an oily product (yield 68.8%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C@H:10]1([NH2:17])[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH2:16].Cl[C:19]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][CH2:41][CH2:42]Br>C(#N)C>[N:16]1([C@H:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C@@H:10]2[NH:17][C:19]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: BrCCCCBr
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)c1ccc(C(F)(F)F)nc1N[C@H]1CCCC[C@@H]1N1CCCC1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
Diisopropylethylamine and (1S,2S)-1,2-cyclohexandiamine were added to 2-chloro-6-(trifluoromethyl)nicotinic acid, followed by stirring at 100° C. for 30 minutes and at 140° C. for 10 minutes using a microwave reaction device. The reaction liquid was dissolved in acetonitrile, potassium carbonate and 1,4-dibromobutane were added, followed by stirring at 50° C. for 8 hours. By dissolving the residue extracted with chloroform in methanol and THF, adding 1 M sodium hydroxide aqueous solution thereto and carrying out the reaction at 50° C., 2-{[(1S,2S)-2-pyrrolidin-1-ylcyclohexyl]amino}-6-(trifluoromethyl)nicotinic acid was obtained.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1F)[CH2:2][CH2:3][CH3:4].[CH2:25]([OH:30])[C:26]([F:29])([F:28])[F:27].CC(C)([O-])C.[K+]>C1COCC1.O>[F:27][C:26]([F:29])([F:28])[C:25]([OH:20])=[O:30].[CH2:1]([C:5]1=[CH:6][N:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:30][CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1F
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OCC(F)(F)F
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.1 %
Yield: 0.1 %

Procedure:
A mixture of the product from Example 47A (101 mg, 0.27 mmol), trifluoroethanol (33 mg, 0.32 mmol) and potassium tert-butoxide (2 M) (340 μL, 0.68 mmol) in THF (10 mL) was stirred at rt for 12 hrs. The mixture was diluted with water, and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rate of 40 mL/minute to afford 34 mg (28%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.36 Hz, 3H) 1.37-1.48 (m, 2H) 1.65-1.75 (m, 2H) 1.68 (s, 9H) 4.50 (q, J=8.59 Hz, 2H) 7.05 (d, J=8.59 Hz, 1H) 7.34 (dd, J=8.90, 2.76 Hz, 1H) 7.97 (s, 1H) 8.11 (d, J=2.76 Hz, 1H); MS (DCI/NH4+) m/z 449 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:38][CH:35]1[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:33][CH2:34]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCN1CCC(O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN3CCC(O)CC3)ccc21
Yield: 38.2 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)ethyl]-amide (50.0 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 1-(2-amino-ethyl)-piperidin-4-ol (72.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 421. 1H NMR (DMSO-d6, 400 MHz): δ 8.00 (1H, m), 7.80-7.77 (1H, m), 7.65 (1H, m), 7.41-7.39 (1H, m), 7.26-7.24 (1H, m), 3.90 (1H, m), 3.75-3.72 (2H, t), 3.69 (3H, s), 3.37 (1H, m), 3.18 (2H, m), 2.07-2.02 (2H, m), 1.83-1.78 (2H, m), 1.32-1.29 (2H, m), 0.90-0.87 (2H, m), 2 —NH and —OH proton signals were not observed.
Reaction SMILES: ClC(O[CH2:5][C:6]1C=C[CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])=O.[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([C@@H:26]2[CH2:30][C@H:29]([S:31]CC3C=CC(OC)=CC=3)[CH2:28][N:27]2[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[O:42])=[O:25])[CH2:20][CH2:19]1.[C:54]([O:57][CH2:58][CH3:59])(=[O:56])C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[SH:31][C@@H:29]1[CH2:28][N:27]([C:41]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=2)=[O:42])[C@H:26]([C:24]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:15][C:54]([O:57][CH2:58][C:59]3[CH:9]=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=3)=[O:56])[CH2:19][CH2:20]2)=[O:25])[CH2:30]1
Reactant: O=C(Cl)OCc1ccccc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5.86 g of 4-dimethylaminopyridine and 10.35 g of o-nitrobenzyl chloroformate in 40 ml of dry methylene chloride was added, whilst ice-cooling, to a solution of 22.35 g of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine in 160 ml of dry methylene chloride, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with 300 ml of ethyl acetate and the dilute solution was washed, in turn, with water (100 ml, once), with an aqueous solution of sodium hydrogencarbonate (100 ml, once) and with an aqueous solution of sodium chloride (100 ml, once). The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through slica gel, using ethyl acetate as the eluent, to give 26.35 g of the title compound, as a colorless powder.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C@@H:7]1([NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH2:13].I[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1>[Cu]I>[CH3:23][C:18]1[CH:17]=[C:16]([NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]2[NH2:14])[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C)cc(N[C@@H]2CCCC[C@H]2N)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 40.8 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (40 mg, 0.210 mmol), K2CO3 (850 mg, 6.15 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (240 μL, 2.00 mmol) and 5-iodo-m-xylene (900 μL, 6.24 mmol) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 100° C. for 23 h. The resulting purple-blue suspension was cooled to room temperature and filtered through a 2×1 cm pad of Celite eluting with 50 mL of dichloromethane. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane saturated with aq NH3-methanol 40:1; 15 mL fractions). Fractions 9-13 provided 178 mg (41% yield) of the product as a tan solid. 1H NMR (400 MHz, CDCl3): δ 6.39 (s, 1H), 6.34 (s, 2H), 3.36 (br s, 1H), 3.03-2.92 (m, 1H), 2.56-2.46 (m, 1H), 2.25 (s, 6H), 2.20-2.10 (m, 1H), 2.08-1.95 (m, 1H), 1.83-1.70 (n, 2H), 1.55-1.20 (m, 5H), 1.10-1.00 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.C[Si]([N:26]=[N+:27]=[N-:28])(C)C.C([Sn](=O)CCCC)CCC>O1CCOCC1>[CH3:1][C:2]1([CH3:21])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]4[NH:28][N:27]=[N:26][N:17]=4)[CH:14]=3)=[CH:12][C:3]1=2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Agent: CCCC[Sn](=O)CCCC
Solvent: C1COCCO1
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc21
Yield: 25.6 %

Procedure:
A mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)benzonitrile (0.77 g, 2.8 mmol), trimethylsilyl azide (0.68 g, 5.6 mmol), and dibutyl tin oxide (0.071 g, 0.28 mmol) in dioxane (20 mL) was heated at reflux under a blanket of nitrogen. Upon completion of the reaction, the dioxane was removed, the organics taken up in ethyl acetate (100 mL), and washed with NaHCO3 (100 mL). The aqueous layer was acidified with 1 N aqueous HCl and extracted with ethyl acetate (100 mL). The organic layer was dried over MgSO4, and concentrated. Crystallization from ether (20 mL) gave 4,4-dimethyl-6-[3-(1H-tetrazol-5-yl)-phenyl]-1,4-dihydrobenzo[d][1,3]-oxazin-2-one as a light yellow solid (0.23 g, 26%): mp 238-240° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 8.3 (bs, 1H), 8.02 (d, 1H, J=7.66 Hz), 7.9 (d, 1H, J=7.91 Hz), 7.72-7.65 (m, 3H), 7.03 (d, 1H, J=8.75 Hz), 1.70 (s, 6H); MS (ESI) m/z 320 ([M−H]−, 100%); Anal. Calc. For C17H15N5O2: C, 63.54, H, 4.71, N, 21.79. Found: C, 62.16, H, 4.67, N, 21.31.
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[C:1]([NH:6][C:7](=[O:8])[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCc1ccccc1
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OCc1ccccc1

Procedure:
A solution of methacryloyl isocyanate (11.1 g; 0.1 mol) in 1,2-dichloroethane (50 ml) was dropwise added to dry benzyl alcohol (10.8 g; 0.1 mol) under nitrogen stream while cooling with ice. After completion of the addition, 1,2-dichloroethane was evaporated under reduced pressure. The residue (21.8 g) was recrystallized from a mixture of hexane and benzene to give benzyl N-methacryloylcarbamate as colorless needles. M.P., 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:17])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:24])([CH2:22]O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[O:21][CH2:20][C:19]([CH3:24])([CH3:22])[CH2:18][O:17]2)=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)COC(CCc2ccc(Cl)cc2)(Cn2ccnc2)OC1
Yield: 37.1 %

Procedure:
A mixture of 1-[4-(4-chlorophenyl)butan-2-on-1-yl]imidazole (2.0 g), 2,2-dimethylpropane-1,3-diol (0.84 g) and anhydrous p-toluenesulfonic acid (1.39 g) in toluene (20 ml) were heated under reflux through a Dean-Stark trap for 2 hours. The resulting mixture was poured into aqueous potassium carbonate solution, extracted with ether (2×100 ml) and the extracts dried (MgSO4). After removal of the solvent, the crude reaction product was chromatographed on silica gel eluting with 7% methanol in methylene chloride to give 1-[[2-(2-(4-chlorophenyl)ethyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl]imidazole (1.0 g) as a colorless oil which crystallized. The oil was dissolved in ether, the solution filtered and the hydrochloride salt formed by dropwise addition of ethereal hydrogen chloride until precipitation was almost complete. The precipitate was filtered, washed with ether and dried in vacuo to give 1-[[2-(2-(4-chlorophenyl)ethyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl]imidazole hydrochloride, m.p. 190°-191° C.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: NC1CCCCC1
Product: C(#Cc1cnc(NC2CCCCC2)nc1)c1ccccc1

Procedure:
The title compound, white solid, MS: m/e=278.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and cyclohexanamine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=O.F[C:11](F)(F)C(OC(=O)C(F)(F)F)=O.F[C:24](F)(F)[C:25]([CH:27]1[CH2:32][C:31](=[O:33])[N:30]([OH:34])[C:28]1=[O:29])=O>>[CH:2]1([N:1]=[C:28]=[N:30][CH:31]2[CH2:11][CH2:24][CH2:25][CH2:27][CH2:32]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH:34][N:30]1[C:31](=[O:33])[CH2:32][CH2:27][C:28]1=[O:29]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: NCCCCCC(=O)O
Reactant: O=C1CC(C(=O)C(F)(F)F)C(=O)N1O
Product: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C1CCC(=O)N1O

Procedure:
ε-Aminocaproic acid is reacted with trifluoroacetic anhydride or trifluoroacetyl-N-hydroxysuccinimide and then dicyclohexylcarbodiimide and N-hydroxysuccinimide, giving ε-(trifluoracetamido) caproic acid N-hydroxysuccinimide ester (TFA-CA-NHS).
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[CH2:7][CH3:8])=O.FC(F)(F)C([NH:29][C@@H:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH:42][C:43]([CH3:46])([CH3:45])[CH3:44])(=[O:41])=[O:40])[CH2:31][CH3:32])=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:5][C@@H:6]([C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]([CH3:20])([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:13][CH:14]=1)[CH2:7][CH3:8].[NH2:29][C@@H:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH:42][C:43]([CH3:44])([CH3:46])[CH3:45])(=[O:41])=[O:40])[CH2:31][CH3:32]
Reactant: CC[C@@H](NC(=O)C(F)(F)F)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Reactant: CC[C@@H](NC(=O)C(F)(F)F)c1ccccc1S(=O)(=O)NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC[C@@H](N)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Product: CC[C@@H](N)c1ccccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-4-(1-(2,2,2-trifluoroacetamido)propyl)-N-tert-butyl-benzenesulfonamide and (R)-2-(1-(2,2,2-trifluoroacetamido)propyl)-N-tert-butyl-benzenesulfonamide (0.501 g), K2CO3 (0.947 g) in MeOH/H2O (1:1, 20 ml) was stirred at room temperature overnight and then heated at 60° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated to about 3 ml. The residue was acidified with TFA to ca. pH 1. The solution was co-evaporated with acetonitrile (2×) and then purified by reverse phase HPLC (5-100% ACN/H2O+0.1% TFA) to give 0.2033 g (R)-4-(1-aminopropyl)-N-tert-butylbenzenesulfonamide as white powder after lyophilization and 63.4 mg (R)-2-(1-aminopropyl)-N-tert-butylbenzenesulfonamide as a white powder after lyophilization.