Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[C:9]2=[C:10]3[C:19](=[C:20]([O:22][CH3:23])[CH:21]=[C:8]2[O:7][C:6]([CH3:31])([CH3:30])[CH:5]1[OH:32])[C:18](=[O:24])[C:17]1[CH:16]=[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]2=[CH:13][C:12]=1[N:11]3[CH3:29])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[C:9]2=[C:10]3[C:19](=[C:20]([O:22][CH3:23])[CH:21]=[C:8]2[O:7][C:6]([CH3:30])([CH3:31])[CH:5]1[OH:32])[C:18](=[O:24])[C:17]1[CH:16]=[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]2=[CH:13][C:12]=1[N:11]3[CH3:29]
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)C(N=[N+]=[N-])C(O)C(C)(C)O2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)C(N)C(O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution containing 0.2 g of the compound obtained in Step A and 0.09 g of Pd/C in 5 ml of ethanol is stirred at ambient temperature under an H2 atmosphere for 48 hours. The catalyst is then filtered off and the filtrate is concentrated in vacuo. The residue is chromatographed over silica (dichloromethane/methanol: 95/5), allowing the desired product to be isolated.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12](Cl)(=[O:16])[C:13]([Cl:15])=[O:14]>>[C:13]([Cl:15])(=[O:14])[C:12]([O:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]1)=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)C1CCC(O)CC1
Product: CC(C)(C)C1CCC(OC(=O)C(=O)Cl)CC1
Yield: 95.3 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step 4-t-butylcyclohexanol was reacted with 50% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce 4-t-butylcyclohexyl chlorooxalate having an assay of 96.9% and in a corrected yield of 95.3%. In the second step 4-t-butylcyclohexyl chlorooxalate was reacted with 2,5-dimethyl-2,5-dihydroperoxyhexane, in the presence of pyridine, to yield the product:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2C)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].NC1C=CC=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: Nc1ccccc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2)cc1
Yield: 87 %

Procedure:
(RK1-1-27A) I This compound was prepared according to the procedure described for compound 11a except using aniline to obtain required product as an off-white solid, (222 mg, 87%). Mp=154-156° C. (lit 174-176° C. (Tetrahedron 62(25), 6100-6106; 2006)); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=9.2 Hz, 2H), 7.93 (d, J=9.2 Hz, 2H), 7.31-7.26 (m, 2H), 7.22-7.18 (m, 1H), 7.08 (d, J=8.4 Hz, 2H), 6.73 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:18]1[CH2:23][CH2:22][NH:21][C@@H:20]([CH3:24])[C:19]1=[O:25])[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8].CN1CCOCC1.[Cl:34][C:35]1[CH:40]=[C:39]([N:41]=[C:42]=[O:43])[CH:38]=[CH:37][C:36]=1[O:44][C:45]([F:48])([F:47])[F:46]>>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:18]1[CH2:23][CH2:22][N:21]([C:42](=[O:43])[NH:41][C:39]2[CH:38]=[CH:37][C:36]([O:44][C:45]([F:47])([F:48])[F:46])=[C:35]([Cl:34])[CH:40]=2)[C@@H:20]([CH3:24])[C:19]1=[O:25])[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8]
Reactant: O=C=Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN[C@@H](C)C1=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(OC(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Yield: 67 %

Procedure:
In analogy to the procedure described in Example 30, (S)-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-((S)-3-methyl-2-oxo-piperazin-1-yl)-5-oxo-pentanoic acid methyl ester (intermediate 29) with 3 eq. of 4-methylmorpholine and 1.2 eq. of 2-chloro-4-isocyanato-1-trifluoromethoxy-benzene (intermediate 17) gave the titled compound in 67% yield as white foam. MS: 605.20 (MH+, Cl).
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[C:10]1=[O:34])C1C=CC=CC=1>C1COCC1.[Pd]>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:11]1[C:12]2[N:19]=[C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[C:17]([F:25])=[CH:16][C:13]=2[C:14](=[O:15])[N:9]([OH:8])[C:10]1=[O:34]
Reactant: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(F)cc2F)c(=O)n1O
Yield: 48.1 %

Procedure:
Using the method of Example 56, 20% Pd/C (40 mg), 3-benzyloxy-1-(2,4-difluorophenyl)-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example Q-4, 0.15 g, 0.33 mmol) were combined in 50 mL of THF, to give 0.06 g of the title compound as a solid, mp 189-191° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:11]3[C:12](=[O:21])[O:13][C@H:14]([CH2:15]CS([O-])(=O)=O)[C@@H:10]3[CH2:9][O:8][C:7]=2[CH:22]=1)#[N:2].[K].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>>[O:29]=[C:27]1[C:26]2[C:25](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:24](=[O:34])[N:28]1[CH2:15][C@H:14]1[C@H:10]2[N:11]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][C:7]=3[O:8][CH2:9]2)[C:12](=[O:21])[O:13]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1ccc2c(c1)OC[C@H]1[C@@H](CCS(=O)(=O)[O-])OC(=O)N21
Agent: [K]
Product: N#Cc1ccc2c(c1)OC[C@H]1[C@H](CN3C(=O)c4ccccc4C3=O)OC(=O)N21
Yield: 79.6 %

Procedure:
Using compound ((3R,3aS)-7-cyano-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methylmethanesulfonate (0.31 g, 0.957 mmol) and phthalimide potassium (0.266 g, 1.435 mmol) as starting materials, preparation following the method as described in Example 1(d) afforded white solid 0.286 g, yield: 79.71%.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[N:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])=[N:14]2)=[N:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cnc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1cnc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.92 min; [M+H]+=378.55.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[OH-].[Na+].[C:15]1([S:25](Cl)(=[O:27])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:15]1([S:25]([N:8]2[C:9]3[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:27])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cccc2c1ccn2S(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 370 mg (2.3 mmole) 4-nitro-1H-indole in 10 mL toluene was added 5 mL 4 M sodium hydroxide and 50 mg tetra-n-butyl ammonium hydrogen sulfate. Solid naphthalene-1-sulfonyl chloride (533 mg, 2.35 mmole) was added in one portion. The reaction mixture was stirred at room temperature for 0.25 hr. The mixture was diluted with 5 mL water and extracted with 25 mL ethyl ether. The organic phase was washed with 5 mL water, 5 mL saturated sodium chloride, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from ether/hexane to provide 1-(naphthalene-1-sulfonyl)-4-nitro-1H-indole as light yellow crystals, 779 mg, m.p. 156-157° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:26]CC2C=CC(OC)=CC=2OC)=[N:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[F:25])=[O:16])=[CH:10][CH:9]=1)#[N:2].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:26][C:4]1[C:3]([C:1]#[N:2])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=3[F:25])=[O:16])=[CH:10][CH:9]=2)[S:6][N:5]=1
Reactant: COc1ccc(CNc2nsc(-c3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2C#N)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(N)c3C#N)cc2)c1
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
A suspension of 1-(4-{4-cyano-3-[(2,4-dimethoxybenzyl)amino]isothiazol-5-yl}phenyl)-3-(2-fluoro-5-methylphenyl)urea (593 mg, 1.15 mmol) in 50 mL of DCM was treated with 1.5 mL of TFA. Solid was dissolved and the reaction turned to yellow and then red in color. TLC indicated the completion of the reaction in <30 min. Saturated Na2CO3 solution was added and the mixture was stirred for 30 min. Layers were separated and the aqueous layer was extracted with DCM×3. The combined organics was washed with brine and dried with MgSO4, filtered, and concentrated. The crude product was redissolved in 100 mL of EtOAc. Insoluble impurity was filtered through celite and washed with EtOAc. Filtrate was concentrated in vacuo to afford the product as a cream solid (398 mg, 94%).
Reaction SMILES: C([O:8][C:9](=[O:35])[CH:10]([NH:22][C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])C1C=CC=CC=1.[OH-].[Li+].Cl>O1CCCC1>[OH:33][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:23]([NH:22][CH:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9]([OH:35])=[O:8])=[O:34])[CH:31]=[CH:30][C:29]=1[OH:32]
Reactant: O=C(CCc1ccc(O)c(O)c1)NC(CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC(NC(=O)CCc1ccc(O)c(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
2-[3-(3,4-dihydroxyphenyl)propionylamino]-succinic acid dibenzyl ester (12 g), prepared in Example 14, was dissolved in tetrahydrofuran (100 mL) and treated with 2M lithium hydroxide (126 mL). The resulting mixture was stirred for 18 hours at room temperature. The resulting reaction was neutralized with aqueous hydrochloric acid, extracted with ethylacetate (EtOAc) (500 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: MC/MeOH (5/95)) to obtain 4.28 g of the title compound. The yield was 57%. The results of analyses of the compound are as follows:
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[C:4]2[CH2:18][CH2:17][N:16]([CH3:19])[C:5]2=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CN(C)CCN(C)C.[Li]CCCC.COB(OC)OC.[C:41]([O:44]O)(=[O:43])[CH3:42].C(N(CC)CC)C.C(OC(=O)C)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C.O>[C:41]([O:44][C:2]1[C:3]([CH3:20])=[C:4]2[CH2:18][CH2:17][N:16]([CH3:19])[C:5]2=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:43])[CH3:42]
Reactant: CC(=O)OO
Reactant: CCCCCCCCc1nc2c(c(C)c1Br)CCN2C
Agent: CN(C)CCN(C)C
Agent: CN(C)c1ccncc1
Agent: COB(OC)OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1nc2c(c(C)c1OC(C)=O)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 202 mg (0.60 mmol) of 5-Bromo-1,4-dimethyl-6-octyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 5 mL of THF was added 90 μL (69.7 mg, 0.60 mmol) of tetramethylethylenediamine (TMEDA) at −78° C. followed by 0.75 mL (1.20 mmol) of n-BuLi (1.6 M in hexanes). After 30 min, 147 μL (137 mg, 1.32 mmol) of trimethoxy boron was added and the resulting mixture was stirred for another 1 h. To the reaction mixture was added dropwise 277 μL (100 mg, 314 mg total solution mg, 1.32 mmol) of peracetic acid (32% wt) and the solution was then warmed to 0° C. The mixture was diluted by 20 mL of water and extracted with three 25-mL portions of EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The resulting oil was dissolved in 10 mL of CH2Cl2 at 0° C., followed by the addition of 485 μL (352 mg, 3.48 mmol) of triethylamine, 6.1 mg (0.05 mmol) of DMAP and 164 μL (177 mg, 1.74 mmol) of acetic anhydride. The reaction was stirred at room temperature for 1 h and quenched by the addition of 10 mL of sat aq. NH4Cl. The solution was extracted with three 30-mL portions of EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The residue was purified via flash chromatography on a silica: gel column (46×2.5 cm). Step gradient elution with 1:10→1:4 ethyl acetate-hexanes as eluent gave 1d as a yellow oil: yield 92 mg (48%); silica gel TLC Rf 0.22 (3:7 ethyl acetate-hexanes); 1H NMR (CDCl3) δ 0.76 (t, 2H, J=7.2 Hz), 1.12-1.22 (m, 10H), 1.55 (quint, 2H, J=8.0 Hz), 1.88 (s, 3H), 2.20 (s, 3H), 2.35 (t, 2H, J=8.0 Hz), 2.75 (t, 2H, J=8.4 Hz), 2.88 (s, 3H), 3.42 (t, 2H, J=8.4 Hz).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[S:11][CH:12]=2)[N:5]=[C:4]2[C:16]3[C:22]([Br:23])=[C:21]([O:24][CH3:25])[CH:20]=[CH:19][C:17]=3[O:18][C:3]=12.O=P(Cl)(Cl)[Cl:28]>>[Br:23][C:22]1[C:16]2[C:4]3[C:3]([O:18][C:17]=2[CH:19]=[CH:20][C:21]=1[O:24][CH3:25])=[C:2]([Cl:28])[CH:7]=[C:6]([C:8]1[N:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[S:11][CH:12]=1)[N:5]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2oc3c(O)cc(-c4csc(C(C)C)n4)nc3c2c1Br
Product: COc1ccc2oc3c(Cl)cc(-c4csc(C(C)C)n4)nc3c2c1Br
Temperature: 110 °C
Yield: 16 %

Procedure:
A mixture of 15C (1.2 g, 2.8 mmol) in POCl3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl3 in the reaction mixture was evaporated. The residue was added dropwise into ice-water. The precipitated solids were collected by filtration and purified by short column chromatography to give M15 (0.2 g, 16% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:8][CH2:7]2.[C:32]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH2:10][CH:9]([N:12]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:8][CH2:7]3)=[CH:42][CH:43]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)CCCCN(Cc1ccc(C(=O)OC)cc1)C1CCc2cccc(O)c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCN(Cc1ccc(C(=O)OC)cc1)C1CCc2cccc(OCc3ccc(C(C)(C)C)cc3)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
550 mg (1.29 mmol) of the compound from Example 3A were dissolved in 35 ml of DMF, 320 μl (1.6 mmol) of 4-tert-butylbenzyl bromide and 1.4 g (4.14 mmol) of cesium carbonate were added and the mixture was stirred at RT for 18 h. Water was then added, and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The crude product obtained was purified by preparative HPLC (method 1).
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:29])[CH:11]2[NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[C:8]=1[C:30]([O-:32])=[O:31])(=[O:4])[CH3:3].Cl[CH2:34][O:35][C:36](=[O:49])[C@H:37]([CH:46]([CH3:48])[CH3:47])[NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CN(C)C=O.C(OCC)(=O)C>[C:42]([O:41][C:39]([NH:38][CH:37]([CH:46]([CH3:48])[CH3:47])[C:36]([O:35][CH2:34][O:31][C:30]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22]1)[C:10]2=[O:29])=[O:32])=[O:49])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CSC12)n1cccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)=C(COC(C)=O)CSC12)n1cccc1
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-[[2-carboethoxy-2-(1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, prepared by the general procedure described in W. German Offen. No. 2,236,620 are mixed in 100 ml of dimethylformamide (DMF) and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to dryness to give 3-[(acetyloxy)methyl]-7-[[2-carboethoxy-2-(1-pyrryl)acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the protecting group can be removed by standard procedures to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[S:21])=[CH:12][CH:11]=1)([O-:9])=[O:8].IC.[C:24](OCC)(=O)C>CC(C)=O.O>[CH3:24][S:21][C:17]1[N:16]([C:13]2[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)[CH:20]=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNC2=S)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: CSc1nccn1-c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred suspension of potassium carbonate(40.07 g, 22.60 mmol) in 175 mL acetone was added 1-(4-nitrophenyl) imidazoline-2-thione(5.0 g,22.60 mmol). Dripped iodomethane (1.44 mL,23.05 mmol) into reaction mixture and heated to reflux temperature for 20 h. Concentrated reaction mixture under reduced pressure and took up resulting solid in 200 mL water. Extracted aqueous three times with ethyl acetate. Combined extracts, dried over magnesium sulfate and concentrated in vacuo to give 5.29 g of crude 4-(2'-methylthioimidazol-1-yl)nitrobenzene. 1HNMR(DMSO-d6) δ: 10.45 (s, 1 H) 8.06 (dd, 1 H, J1 =2.0 Hz, J2 =8.0 Hz), 8.38-8.33 (m, 2 H), 7.77-7.72 (m, 2 H), 7.61 (d, 1 H, J=1.5 Hz), 7.14 (d, 1 H, J=1.5 Hz), 2.52 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity) 236 (M+H,100).
Reaction SMILES: [C:1](NN)(=O)C.[Br:6][C:7]1[C:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:9][C:10]2[N:11]([C:13]([CH2:16][C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[N:14][N:15]=2)[CH:12]=1>C(O)(=O)C.FC(C1C=CC=CC=1)(F)F>[Br:6][C:7]1[C:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:9][C:10]2[N:11]([C:13]([CH2:16][C:17]3[C:18]([CH3:1])=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)=[N:14][N:15]=2)[CH:12]=1
Reactant: CC(=O)NN
Reactant: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(Br)cn23)cn1
Solvent: CC(=O)O
Solvent: FC(F)(F)c1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Yield: 60 %

Procedure:
The title compound (61 mg, 60%) as a white powder was prepared from N′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(2-methyl-6-trifluoromethyl)pyridin-3-yl)acetohydrazide (100 mg, 0.20 mmol) in glacial acetic acid (0.6 mL) and (trifluoromethyl)benzene (1.8 mL) by the procedures analogous to those described for 6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56D). LC/MS (method B): retention time 1.83 min, [M+H]+=481.0.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=[O:5].ClC1N=CC=CC=1C(NC1C=CC=C(Cl)C=1)=O.[O:41]([C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.NC1CCN(CC2C=CC=CC=2)CC1>>[O:41]([C:48]1[CH:49]=[CH:50][C:51]([NH:52][C:2]2[N:23]=[CH:22][CH:21]=[CH:20][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[O:5])=[CH:53][CH:54]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccnc1Cl
Agent: NC1CCN(Cc2ccccc2)CC1
Agent: O=C(Nc1cccc(Cl)c1)c1cccnc1Cl
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccnc1Nc1ccc(Oc2ccccc2)cc1
Yield: 77.8 %

Procedure:
The title compound was prepared in the same manner as in Example 1, with the exception that 2-chloro-(N-4-phenoxyphenyl)nicotinamide of Preparation Example 6, instead of 2-chloro-(N-3-chlorophenyl)nicotinamide, and 4-phenoxyaniline, instead of 4-amino-1-benzylpiperidine, were used in the same molar amounts (Yield: 77.8%). 1H NMR (DMSO-d6) δ 10.50 (s, 1H), 10.33 (s, 1H), 8.35 (d, 1H), 8.25 (d, 1H), 7.69˜7.82 (m, 4H), 7.30˜7.46 (m, 4H), 6.88˜7.18 (m, 11H) ppm.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH:12]([NH:14][C:15]1[C:16]([S:21]([NH2:24])(=[O:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([N:35](C2C=CC=CC=2)[C:36](=O)[O-:37])[N:28]=1.Cl>C(#N)C.O>[CH3:34][O:33][C:31]1[CH:32]=[C:27]([O:26][CH3:25])[N:28]=[C:29]([NH:35][C:36]([NH:24][S:21]([C:16]2[C:15]([NH:14][CH:12]=[O:13])=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:23])=[O:22])=[O:37])[N:30]=1
Reactant: COc1cc(OC)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1ncccc1NC=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ncccc2NC=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
0.75 g (0.0049 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is added to a solution of 0.5 g (0.0019 mol) of 3-formylamino-2-pyridinesulfonamide and 0.68 g (0.0025 mol) of N-(4,6-dimethoxypyrimidin-2-yl)phenylcarbamate in 40 ml of acetonitrile. The solution is stirred for 16 hours at room temperature, 20 ml of water are subsequently added, and the pH is brought to 4 using 2-normal hydrochloric acid. The mixture is extracted with dichloromethane, the organic phase is dried over MgSO4, and n-heptane is added. Filtration gives 0.64 g (89% of theory) of N-[(4,6-dimethoxy-pyrimidin-2-yl)-amino-carbonyl]-3-formylamino-2-pyridinesulfonamide of melting point 172° C. (decomp.).
Reaction SMILES: Cl.[NH2:2]O.[CH3:4][O:5][C:6]1[C:7]([CH3:14])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[OH-].[Na+]>C(O)=O>[CH3:4][O:5][C:6]1[C:7]([CH3:14])=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:2]
Reactant: COc1cccc(C=O)c1C
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: COc1cccc(C#N)c1C
Yield: 80 %

Procedure:
Hydroxylamine hydrochloride (0.75 g, 11 mmol) was added to 3-methoxy-2-methylbenzaldehyde (1.25 g, 8.32 mmol) in formic acid (89-91%) (10 ml), and the mixture heated to reflux for 40 min., cooled, diluted with ice-cold water, basified with 10% aqueous sodium hydroxide solution and extracted with diethyl ether. The organic extract was washed with saturated aqueous sodium chloride (50 ml), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography over silica gel eluting with 5% diethyl ether in hexane to afford the product as a white solid (0.98 g). M+ 147; 360 MHz 1H n.m.r (CDCl3) 7.26-7.17 (2H, m), 7.02 (1H, d, J 7.9 Hz), 3.86 (3H, s), 2.41 (3H, s).