Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:6]=2[CH:23]=1.Cl[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][O:29][C:28]1=[O:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][N:20]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:19][CH2:18]3)[C:6]=2[CH:23]=1
Reactant: Cc1ccc2c(c1)CC(N1CCNCC1)c1cc(Cl)ccc1S2
Reactant: O=C1OCCN1CCCl
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(Cl)ccc1S2

Procedure:
In a similar manner to that described in Example 1, from 1-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine and N-(betachloroethyl)oxazolidinone, there is obtained 3-{2-[4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone, which after recrystallization from ethyl acetate/petroleum ether, has a melting point of 184°-186°. The maleate salt melts after recrystallization from methanol/ether at 174°-175°.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[N:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>C(O)C.C(Cl)(Cl)Cl.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])=[CH:16][CH:17]=1
Reactant: C[C@@H](N=Cc1ccc(O)cc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: C[C@@H](NCc1ccc(O)cc1)c1ccccc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
11.26 g (0.05 mole) of (R)-(-)-N-(p-hydroxybenzylidene)-1-phenylethylamine were dissolved in 150 ml of ethyl alcohol. The resulting solution was admixed with 0.95 g (0.025 mole) of sodium borohydride at room temperature, stirred at a temperature of from 30° to 35° C. for 2 hours, and then stirred at a temperature of from 55° to 60° C. for 2 hours. After the completion of the reaction, 28 ml of a 10% hydrochloric acid were added at room temperature to the reaction mixture, which was then concentrated under reduced pressure. The residue thus obtained was admixed with 50 ml of water, and thereafter neutralized or weakly alkalized with a 20% aqueous sodium hydroxide solution. Then an extraction operation was carried out twice with 100 ml of chloroform, and the chloroform layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give 11.34 g of crude (R)-(+)-N-(p-hydroxybenzyl)- 1-phenylethylamine. The crude product was refined by a column chromatography employing silica gel, so that 10.64 g of a refined product were obtained as viscous oil. Yield: 93.6%.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[N:11]=[C:5]2[N:4]=1.[F:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:19][CH2:20][O:18][C:14]1[CH:13]=[C:12]([C:10]2[N:11]=[C:5]3[N:4]=[C:3]([NH2:2])[CH:8]=[CH:7][N:6]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Reactant: Nc1ccn2cc(-c3cccc(O)c3)nc2n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccn2cc(-c3cccc(OCF)c3)nc2n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
In a sealed tube 3-(7-aminoimidazo[1,2-a]pyrimidin-2-yl)phenol hydrobromide (260 mg, 0.85 mmol) was combined in DMF (3 ml) to give a brown solution. Toluene-4-sulfonic acid fluoromethyl ester (249 mg, 1.22 mmol; CAS Nr. 114435-86-8) was dissolved in DMF and added. Cs2CO3 (527 mg, 1.62 mmol) was added. The reaction mixture was heated under argon to 70° C. for 9 h, then stirring was continued overnight at RT. The reaction mixture was diluted with H2O (30 ml) and extracted with EtOAc (3×30 ml). The combined organic layers were dried (MgSO4) and concentrated under vacuum and the crude product was purified by flash chromatography (50 g SiO2, DCM/MeOH/NH3aq. 140:10:1). The title compound (105 mg, 48%) was obtained as a yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:38])=[C:11]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.CO>Cl.O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:38])=[C:11]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2c1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCNCC3)cc2c1=O
Yield: 96.7 %

Procedure:
tert-Butyl 4-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]piperidine-1-carboxylate (3.42 g) was stirred in 4N HCl in dioxane (20 ml) and methanol (3 ml) at room temperature for 18 hours and then concentrated. The residue was purified by column chromatography on an ion exchange column (isolute SCX-2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) washing with methanol initially and then eluting with a 99:1 mixture of methanol and aqueous ammonia solution to give N-cyclopropyl-4-methyl-3-[4-oxo-6-(piperidin-4-yloxy)quinazolin-3(4H)-yl]benzamide (2.67 g) as a light brown solid; NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.69 (m, 2H), 1.50 (m, 2H), 1.95 (m, 2H), 2.15 (s, 3H), 2.60 (m, 2H), 2.85 (m, 1H), 2.95 (m, 2H), 4.59 (m, 1H), 7.51 (d, 1H), 7.52 (d, 1H), 7.59 (s, 1H), 7.71 (d, 1H), 7.82 (s, 1H), 7.90 (d, 1H), 8.18 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[S:13][C:14]([NH:18]C(=O)C)=[N:15][C:16]=4[CH2:17][C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O>[C:1]1([N:7]2[C:11]3[C:12]4[S:13][C:14]([NH2:18])=[N:15][C:16]=4[CH2:17][C:10]=3[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccccc1)C2
Agent: Cl
Solvent: O
Product: Nc1nc2c(s1)-c1c(cnn1-c1ccccc1)C2
Temperature: 25 °C

Procedure:
2.9 g (8.71 mmol) N-(4-phenyl-4,7-dihydro-3-thia-1,4,5-triaza-cyclopenta[A]pentalen-2-yl)-acetamide (prepared analogously to Example 58 from intermediate compound 22) are suspended in 20 ml of water and 20 ml 32% hydrochloric acid and refluxed for 2 hours with stirring. After cooling to ambient temperature the mixture is extracted with diethyl ether and the aqueous phase is made basic. The precipitate formed is stirred for 0.25 hours at 5° C., suction filtered and dried. The crude product is suspended in 150 ml of tetrahydrofuran and combined with 5 ml of conc. hydrochloric acid, then stirred for 16 hours at 60° C. After cooling to 5° C. the precipitate is suction filtered and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[C:11](=[C:12]4[CH:20]=[C:19]5[O:21][CH2:22][O:23][C:18]5=[CH:17][C:13]4=[N:14][CH:15]=3)[N:10]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:9](=[O:29])[C:8]=2[CH:30]=1)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[C:11](=[C:12]4[CH:20]=[C:19]5[O:21][CH2:22][O:23][C:18]5=[CH:17][C:13]4=[N:14][CH:15]=3)[N:10]([CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[C:9](=[O:29])[C:8]=2[CH:30]=1
Reactant: CN(C)CCn1c(=O)c2cc([N+](=O)[O-])ccc2c2cnc3cc4c(cc3c21)OCO4
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCn1c(=O)c2cc(N)ccc2c2cnc3cc4c(cc3c21)OCO4
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
To a solution of compound 4a (40 mg, 0.1 mmol) in ethanol (10 mL), Ra—Ni (˜50 mg) then hydrazine hydrate (0.2 mL) were added and the reaction stirred at room temperature for 3 h. The catalyst was filtered through the Celite and filtrate was concentrated in vacuo to provide 26 mg of a solid (69.1% yield); mp 245–246° C.; 1H NMR (CDCl3) δ 2.36 (s, 6H), 3.01 (t, 2H, J=7.4), 4.11(s, 2H), 4.68 (t, 2H, J=7.4), 6.17(s, 2H,), 7.18 (dd, 1H, J=2.8, 11.4), 7.46 (s, 1H) 7.71 (d, 1H, J=3), 7.80 (s, 1H) 8.20 (d, 1H, J=8.8), 9.40 (s, 1H); HRMS m/z calcd for C21H20N4O3H: 377.1614. found 377.1604.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20](O)=[O:21])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:21])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CCC(=O)O)CC1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CCC(=O)NS(C)(=O)=O)CC1
Yield: 41.6 %

Procedure:
To a stirred solution of 4-(4-(2-tert-butylphenyl)piperazin-1-yl)-4-oxobutanoic acid obtained in Example 53 (0.100 g, 0.31 mmol), EDCI (0.090 g, 0.47 mmol), HOBt (0.064 g, 0.47 mmol) and diisopropylethylamine (0.163 g, 1.26 mmol) in methylene chloride (2.0 mL) was added methane-sulfonamide (0.031 g, 0.31 mmol) at room temperature. After 18 h the reaction mixture was diluted with ethyl acetate, washed with 1.0 M hydrochloric acid (5.0 mL), water (5.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 95:5 methylene chloride/MeOH) to provide 4-(4-(2-tert-butylphenyl)piperazin-1-yl)-N-(methylsulfonyl)-4-oxobutanamide (0.051 g, 41%) as an off-white solid, mp: 89-90° C.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[C:8]([O:15]COC)=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])([CH3:6])([CH3:5])[CH3:4]>CO>[Br:1][C:13]1[CH:14]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]([OH:15])=[C:9]([CH:12]=1)[CH:10]=[O:11]
Reactant: COCOc1c(C=O)cccc1C(C)(C)C
Reactant: BrBr
Solvent: CO
Product: CC(C)(C)c1cc(Br)cc(C=O)c1O
Temperature: 20 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
Bromine (747 g) was gradually added to a solution of the 3-(tert-butyl)-2-(methoxymethoxy)benzaldehyde (1247 g, 4.67 mol) in methanol (4000 ml) while cooling on ice. After stirring at 20° C. for 1 hour, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, the mixture was washed with water, saturated sodium aqueous hydrogencarbonate and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to yield a crude product of the title compound (1333 g) as a red oil.
Reaction SMILES: C1(=O)N([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]2=[O:18])C(=O)C=C1>CN(C)C=O.O>[C:13]1(=[O:18])[N:12]([CH:11]([N:12]2[C:13](=[O:18])[CH:14]=[CH:15][C:16]2=[O:17])[CH2:10][CH2:9][CH2:8][CH2:7][CH3:6])[C:16](=[O:17])[CH:15]=[CH:14]1
Reactant: O=C1C=CC(=O)N1CCCCCCN1C(=O)C=CC1=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(N1C(=O)C=CC1=O)N1C(=O)C=CC1=O

Procedure:
The experiment was repeated using 1,6-bismaleimidohexane in dry dimethylformamide in place of the lysine bismaleimide in water to yield antibody material cross-linked with bismaleimidohexane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1C(=O)C(I)=C(C1C=CC=CC=1)O2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:20])[C:47]4[C:46](=[CH:45][CH:44]=[CH:39][C:38]=4[F:37])[O:28][C:27]=3[C:26]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1c(I)c(-c2ccccc2)oc2cccc(F)c12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cccc(F)c4c3=O)cc2)CCC1
Yield: 26 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 5-fluoro-3-iodo-2-phenyl-chromen-4-one (55 mg, 0.15 mmol) was reacted to give the title compound (19 mg, 26%). 1H NMR (400 MHz, CDCl3): δ 7.65-7.57 (m, 1H), 7.41-7.29 (m, 6H), 7.28-7.22 (m, 2H), 7.21-7.16 (m, 2H), 7.09-7.03 (m, 1H), 5.03 (s, 1H), 2.61-2.29 (m, 4H), 2.21-2.00 (m, 1H), 1.88-1.74 (m, 1H), 1.48-1.18 (m, 9H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[N:10]([O-])=[O:11].[Na+].N>CCCCCCC.O.CO>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:10]=[O:11])=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: CNc1ccccc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: CO
Product: CNc1ccc(N=O)cc1
Temperature: 0 °C
Yield: 51 %

Procedure:
Initially, 107 g (1.0 mol) of N-methylaniline was added dropwise to a methyl alcohol solution containing 40% HCl with stirring at a temperature between 5° and 10° C. for one and a half hours. Thereafter, 80 g (1.12 mol) of sodium nitrite, of a purity of 97%, was added to the solution obtained at 5° C. After stirring at a temperature between 15° and 25° C. for 15 hours, the solution was poured in 2 l of ice water and the water solution was neutralized to pH 8 with aqueous ammonia after stirring for 15 minutes. Thereafter, 500 ml of heptane was added to the solution. After stirring at a temperature between 10° and 20° C. for 2 hours, the crystals obtained were filtered, washed sufficiently on the filter paper and thereafter dried with hot-air at 50° C. for 48 hours. 69.5 g of N-methyl-p-nitrosoaniline of a melting point of 115°~117° C. was obtained. The yield was 51.1%.
Reaction SMILES: [OH-].[Na+].C1(C[O:10][C:11]([C:13]2([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])C=CC=CC=1.Cl.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(Cl)Cl>[N:29]1([CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:20]3[O:10][C:11](=[O:12])[C:13]4([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[N:19]=3)=[CH:27][CH:26]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(CN2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC(c2ccc(CN3CCOCC3)cc2)=NC12CCCCC2
Reaction time: 1 h
Yield: 84.3 %

Procedure:
2 ml of 2N aqueous sodium hydroxide solution was added to a solution of 300 mg (0.69 mmol) of 1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester in 2 ml of tetrahydrofuran, and the mixture was heated under reflux overnight. After the mixture was neutralized by concentrated hydrochloric acid, the reaction solution was distilled off under reduced pressure. 3 ml of methylene chloride, 698 mg (6.9 mmol) of triethylamine and 264 mg (1.38 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to the residue, and the mixture was stirred for 1 hour. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 191 mg (80%) of the title compound.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([C:15]3([CH3:28])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.Cl>CO>[NH:4]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([C:15]3([CH3:28])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(-c3nnn[nH]3)c2)CC1
Agent: Cl
Solvent: CO
Product: CC1(C(=O)Nc2cccc(-c3nnn[nH]3)c2)CCNCC1
Temperature: 50 °C

Procedure:
tert-Butyl 4-(3-(1H-tetrazol-5-yl)phenylcarbamoyl)-4-methylpiperidine-1-carboxylate from step A (0.11 g, 0.29 mmol) was treated with HCl (4.0 N in dioxane, 0.36 mL, 1.45 mmol) in methanol (2.0 mL) and heated at 50° C. for 30 minutes. The mixture was concentrated to give the title compound as the hydrochloride salt in quantitative yield. MS (ES+) [M+H]+=287.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-])=O.[CH3:13][NH:14][CH3:15]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N:14]([CH3:15])[CH3:13])[C:3]=1[NH2:10]
Reactant: CNC
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Solvent: C1CCOC1
Product: CN(C)c1cc(F)cc(F)c1N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
To a solution of 2,4,6-trifluoronitrobenzene (2.58 g, 0.0145 mol) in THF (20.0 ml) was added a solution of N,N-dimethylamine in THF (8.5 mL of 2M soln) and stirred for 45 min at 0° C. It was then stirred at room temperature for 30 min and concentrated to dryness. The resulting material was dissolved in EtOH (25 mL), added Pd/C (10%, 0.6 g) and hydrogenated at 50 psi for 4 h. The catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was partitioned between sod. bicarbonate (10%, 25 mL) and EtOAc (30 mL). The organic phase was washed with water, dried (Na2SO4), and concentrated to dryness to afford the title compound (1.3 g, 50%) as a dark colored solid: 1H NMR (CDCl3/400 MHz) δ6.52 (m, 2H), 3.64 (br, 2H), and 2.65 (s, 6H); ES-HRMS m/z 172.0772 (M+C8H10N2F2 requires 172.0810).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:18]=[C:17]([NH:19][N:20]=[C:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:21]1(=[N:20][NH:19][C:17]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([S:6](=[O:7])(=[O:8])[NH2:5])[CH:18]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(NN=C2CCCC2)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NN=C2CCCC2)cc1S(N)(=O)=O
Yield: 90.9 %

Procedure:
3.9 g (10.6 mmol) of methyl 2-(N-tert-butylsulfamoyl)-4-cyclopentylidenehydrazinobenzoate are stirred in 40 ml of trifluoroacetic acid at 25° C. for 2 hours. The mixture is evaporated and the residue is triturated with diethyl ether. After filtering off with suchion and drying, 3.0 g (91% of theory) of methyl 4-cyclopentylidenehydrazino-2-sulfamoylbenzoate of melting point: 227-229° C. (decomposition) are obtained.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([NH2:20])[C:9]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[C:21]([CH2:25][C:26](Cl)=O)([CH3:24])([CH3:23])[CH3:22]>C(OCC)(=O)C>[CH3:22][C:21]([CH3:24])([CH3:23])[CH2:25][C:26]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=2[N:20]=1
Reactant: CCS(=O)(=O)c1ccc(NCC2CCOCC2)c(N)c1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CCOCC1
Reaction time: 2 h
Yield: 34 %

Procedure:
To a solution of 4-(ethylsulfonyl)-N′-(tetrahydro-2H-pyran-4-ylmethyl)benzene-1,2-diamine (Step B) in ethyl acetate (16 mL) was added tert-butylacetyl chloride (0.1 mL, 0.8 mmol) at room temperature. After stirring for 2 h, the mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethanol and 2N sodium hydroxide solution. The mixture was microwaved for 30 min at 130° C. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by amine coated silica gel column chromatography (hexane:ethyl acetate=2:1 as eluent) to afford the title compound (103 mg, 34%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CO>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC1CO1
Solvent: CO
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Yield: 33 %

Procedure:
A solution of methyl 3-[5-acetamido-2-(2,3-epoxypropoxy)benzoyl]propionate (0.52 g, 0.0016 mole), t-butylamine (20 ml) and methanol (10 ml) was heated under reflux for 16 hours. Evaporation of the reaction mixture left an oil which was dissolved in ethanol and treated with ether to give crystalline methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21 g, 33%; m.p. 127°-128°).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:8][C:6](=[O:7])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[B:13](O)([OH:15])[OH:14]>O>[B:13]1([OH:15])[O:11][CH:3]([CH:4]([OH:10])[CH:5]([OH:9])[C:6]([OH:8])=[O:7])[CH:2]([CH2:1][OH:12])[O:14]1
Reactant: OB(O)O
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: O
Product: O=C(O)C(O)C(O)C1OB(O)OC1CO
Temperature: 50 °C

Procedure:
35.6 grams of gluconolactone and 12.2 grams of technical grade boric acid were added to 50 ml. of water at room temperature. The resultant mixture was stirred and heated at about 50° C. for about 4 hours and the water allowed to evaporate to reduce the mixture volume to about 45 ml. The mixture was then cooled to room temperature and 28 grams of triethanolamine were added with stirring.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:27])=[O:26])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl.O.[O-:30][Mn](=O)(=O)=O.[K+].[O-]S([O-])=O.[Na+].[Na+].Cl.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:27])(=[O:30])=[O:26])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reaction time: 1 h
Yield: 16.3 %

Procedure:
To a solution of 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (3.7 g, 9.8 mmol) [See Ex. 20 below] in 1:10 3N HCl/H2O (88 mL) was added a solution of KMnO4 (1.5 g, 9.8 mmol) in H2O (15 mL). After sting at rt for 1 h, additional KMnO4 (0.15 g, 0.9 mmol) was added, and sting was continued for 15 min. The mixture was then poured into saturated aqueous Na2SO3 (200 mL), and the pH was adjusted to slightly acidic by the addition of 3N HCl, then to neutral by the addition of 2.5N NaOH. The solid which formed was collected by filtration, washed successively with H2O and MeOH and recrystallized three times from MeOH to afford the title compound (0.63 g, 16%): mp 148°-149° C.