Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][NH:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])O.[Na+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>O1CCCC1>[CH2:32]([O:31][C:29]([N:8]([CH2:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1cccc(CNCC(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(CN(CC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}pyridine-2-carboxylate (2.81 g) in tetrahydrofuran (30.0 mL) were added water (30.0 mL) and sodium hydrogen carbonate (962 mg), and then benzyl chloroformate (1.47 mL) was added thereto under ice-cooling. The reaction suspension was stirred at room temperature overnight and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 6-({[(benzyloxy)carbonyl](2-tert-butoxy-2-oxoethyl)amino}methyl)pyridine-2-carboxylate (3.27 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[CH:6][N:5]([CH3:9])[N:4]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:7]1[C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[N:4][N:5]([CH3:9])[CH:6]=1
Reactant: Cn1cc(Cl)c(CBr)n1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2nn(C)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 3-(bromomethyl)-4-chloro-1-methyl-1H-pyrazole (61.7 mmol) in absolute ethanol (250 mL) was added 6-methyl-2-sulfanylpyrimidin-4-ol (5.84 g, 41.1 mmol) and triethylamine (23.0 mL, 165 mmol) at 0° C. The mixture was stirred at room temperature overnight. The white solid was filtered and washed with diethyl ether (300-500 mL). The filtrate was recovered, and the solvent was evaporated. The residue triturated in water, filtered, and washed with water (3×300 mL) and then DCM (50 mL). The solid was died under vacuum overnight. 2-{[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl)sulfanyl}-6-methylpyrimidin-4-ol was obtained as a white solid (5.48 g, 49% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (bs, 3H), 3.78 (s, 3H), 4.35 (s, 2H), 6.05 (bs, 1H), 7.92 (s, 1H); LRMS (ES+) m/z 271 (100%, M+1); 273 (35%, M+3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]2.S(O)(O)(=O)=O.[CH2:20]([N:22]([CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:21].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]([N:22]([CH2:20][CH3:21])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:12]([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)=[O:14])=[CH:25][CH:24]=1)[CH3:31]
Reactant: O=C(O)C1CCc2cccc(O)c2C1
Reactant: CCN(CC)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)C2CCc3cccc(O)c3C2)cc1
Reaction time: 8 h
Yield: 62 %

Procedure:
This phenol from Example 6A was dissolved in DMF (4.0 mL) and N,N-Diethyl-benzene-1,4-diamine sulfate (602 mg, 2.3 mmol), Et3N (707 mg, 7.0 mmol), and TBTU (738 mg, 2.3 mmol) were added at ambient temperature. The mixture was stirred overnight and purified by silica gel column chromatography to provide 8-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (4-diethylamino-phenyl)-amide (480 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:13][C:14](OCC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:29][OH:30].C[O-].[Na+]>CO>[OH:30][NH:29][C:14](=[O:15])[CH2:13][N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: NO
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN(CC(=O)NO)S(=O)(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-[[4-methoxybenzenesulfonyl](4-methoxybenzyl)amino]acetate (0.90 g, 2.3 mmol) is dissolved in methanol (20 mL). To this solution is added hydroxylamine hydrochloride (0.80 g, 11.5 mmol), followed by the addition of sodium methoxide (5.2 mL of a 2.67M solution). The reaction is stirred overnight at room temperature. The reaction is worked up by partitioning between dilute hydrochloric acid (pH=~3) and ethyl acetate. The aqueous phase is extracted well with ethyl acetate, the combined organic layers are washed with brine, dried (Na2SO4), and the solvent is evaporated. The product is recrystallized from ether/ethyl acetate to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](4-methoxybenzyl)amino]acetamide, m.p. 134°-135.5° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][C:10]=1[Br:18])([CH3:8])[CH3:7].[Cl-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:18][C:10]1[C:9]([CH:6]([CH3:7])[CH3:8])=[CH:14][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:11]=1
Reactant: CC(C)c1ccc(C(C)C)c(Br)c1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc(S(=O)(=O)Cl)c(C(C)C)cc1Br
Reaction time: 0.5 h

Procedure:
4-Bromo-2,5-diisopropylbenzene sulfonyl chloride was prepared as follows: Chlorosulfonic acid, 154 g, was added over 15 minutes to 80 g of 2,5-diisopropylbromobenzene in 200 ml of carbon tetrachloride. The reactants were stirred for 30 minutes longer and then poured onto a mixture of ice and saturated sodium chloride solution. The organic layer was washed with cold water and dried over magnesium sulfate. Removal of the solvent gave 105 g of crystalline product. Recrystallization from n-hexane gave pure 4-bromo-2,5-diisopropylbenzene sulfonyl chloride, which softened at 77°C and melted at 80.5°-83°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH:10]=[CH2:11].C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Nc1ccc(/C=C/C(=O)OCc2ccccc2)cn1
Yield: 39.3 %

Procedure:
A solution of 2-amino-5-bromopyridine (2.25 g, 13.0 mmole), benzyl acrylate (3.2 g, 19.7 mmole), Pd(OAc)2 (0.31 g, 1.4 mmole), tri-ort/10-tolylphosphine (0.73 g, 2.4 mmole), and diisopropylethylamine (3.5 mL, 20.0 mmole) in propionitrile (50 mL) was heated at reflux overnight. The dark mixture was filtered through Celite®, and the filtrate was concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 39%): MS (ES) m/e 255 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][NH2:11])[N:5]=[CH:4]1.C(N(CC)CC)C.[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([NH:26][C:27]([NH:11][CH2:10][CH2:9][CH2:8][C:6]1[N:5]=[CH:4][NH:3][CH:7]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=NCc1ccccc1
Reactant: NCCCc1c[nH]cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCc1c[nH]cn1)NCc1ccccc1
Reaction time: 1 h

Procedure:
5 mmol of 3-(1H-imidazol-4-yl)propanamine dihydrochloride and 10 mmol of triethylamine are mixed in 10 ml of acetonitrile and, after addition of 5 mmol of benzyl isocyanate, the whole mixture is brought to boiling for 1 h at reflux. After evaporation under vacuum, the title compound is taken up in a small amount of water and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:23])[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[CH2:20]([O:19][C:17]1[C:16]([Br:23])=[CH:15][C:9]2[CH:10]([CH:12]([CH3:13])[CH3:14])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:18]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc2c(cc1Br)C(C(C)C)CNCC2
Reaction time: 3 h
Yield: 118.6 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.011 g, 0.026 mmol) in methanol (0.5 mL) was treated with of 15% aqueous NaOH (0.5 mL), and stirred for 3 hours at 50 C. The product mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.010 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.09 (s, 1 H), 6.62 (s, 1 H), 5.94 (m, 1 H), 5.32 (dd, 1 H), 5.12 (dd, 1 H), 4.46 (d, 2 H), 3.19 (m, 1 H), 3.05 (m, 2 H), 2.66 (m, 1 H), 2.5 (bm, 2 H), 2.3-2.1 (m, 2 H), 0.95 (d, 3 H), 0.63 (d, 3 H). MS calculated for C16H22BrNO+H: 324, observed: 324.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:64])=[C:48]([NH:52][S:53]([C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)=O)[CH:40]=[CH:39][N:38]=1.[NH2:65][C:66]([CH:68]1[CH2:73][CH2:72][N:71]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:70][CH2:69]1)=[S:67]>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:67][C:66]([CH:68]3[CH2:73][CH2:72][N:71]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:70][CH2:69]3)=[N:65][C:44]=2[C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][S:53]([C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[C:47]=2[F:64])[CH:40]=[CH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 60 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (4.80 g, 10.86 mmol) and 1,1-dimethylethyl 4-(aminocarbonothioyl)-1-piperidinecarboxylate (3.19 g, 13.04 mmol) the title compound of Step A was obtained (4.31 g, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 8.57 (d, J=5.3 Hz, 1H), 7.36-7.68 (m, 5H), 7.32 (t, J=7.8 Hz, 1H), 6.90 (d, J=5.3 Hz, 1H), 4.01 (d, J=11.4 Hz, 2H), 3.20-3.34 (m, 1H), 2.92 (d, J=12.6 Hz, 2H), 2.07 (d, J=11.3 Hz, 2H), 1.52-1.70 (m, 2H), 1.40 (s, 9H). m/z (ES+): 667 [M+H]+.
Reaction SMILES: O=S(Cl)[Cl:3].[C:5]1([CH:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]2[CH2:17][CH2:16][CH:15]([CH2:18]O)[CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[C:5]1([CH:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][Cl:3])[CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: c1ccccc1
Product: ClCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 70.1 %

Procedure:
Step 2): SOCl2 (0.6 ml, 8.2 mmol) was added dropwise to a solution of 1-diphenylmethyl-4-hydroxymethylpiperidine (1.0 g, 3.6 mmol) in benzene (7 ml) at room temperature. The mixture was refluxed for 18 hours and then concentrated. The residue was dissolved in ethyl acetate, washed with 5% NaOH solution, dried (MgSO4) and concentrated. The residue was recrystallized (ethyl acetate/ether/hexane) to give 1-diphenylmethyl-4-chloromethylpiperidine (70.1%): mp 73°-75° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C.O>[OH:16][N:15]=[C:9]([C:7](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccn1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)c1ccccn1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a stirred solution of ethyl picolinoylacetate (0.500 g, 2.6 mmol) in acetic acid (0.5 mL) was added a solution of sodium nitrite (0.238 g, 3.4 mmol) in water (0.5 mL), dropwise. The resulting solution was stirred at room temperature for 2 hours after which water (0.5 mL) was added and the reaction was stirred for a further 2 hours. The mixture was extracted with Et2O and the combined organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried over MgSO4 and the solvent removed in vacuo to afford ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate (0.353 g, 1.6 mmol, 61%) as a white solid. 1H NMR (DMSO) δ 1.17 (3H, t), 4.22 (2H, q), 7.74 (1H, m), 8.04-8.11 (2H, m), 8.74 (1H, m), 12.87 (1H, s). LCMS (2) Rt: 1.09 min; m/z (ES+) 223.
Reaction SMILES: C([N+]1(C)CCCC1)C=C.[NH2:10][C:11]1[S:15][N:14]=[C:13](/[C:16](=[N:20]/[O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)/[C:17]([O-:19])=O)[N:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:58][C@@H:59]1[C:66](=[O:67])[N:65]2[C@@H:60]1[S:61][CH2:62][C:63](/[CH:71]=[C:72]1/[C:73](=[O:96])[N:74]([CH2:77][C:78]3[CH:83]=[CH:82][N+:81]([CH2:84][C:85](=[O:95])[NH:86][C:87]4[CH:92]=[CH:91][C:90]([OH:93])=[C:89]([F:94])[CH:88]=4)=[CH:80][CH:79]=3)[CH2:75][CH2:76]/1)=[C:64]2[C:68]([O-:70])=[O:69]>CN(C=O)C>[NH2:10][C:11]1[S:15][N:14]=[C:13](/[C:16](=[N:20]/[O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)/[C:17]([NH:58][C@@H:59]2[C:66](=[O:67])[N:65]3[C@@H:60]2[S:61][CH2:62][C:63](/[CH:71]=[C:72]2/[C:73](=[O:96])[N:74]([CH2:77][C:78]4[CH:79]=[CH:80][N+:81]([CH2:84][C:85](=[O:95])[NH:86][C:87]5[CH:92]=[CH:91][C:90]([OH:93])=[C:89]([F:94])[CH:88]=5)=[CH:82][CH:83]=4)[CH2:75][CH2:76]/2)=[C:64]3[C:68]([O-:70])=[O:69])=[O:19])[N:12]=1
Reactant: Nc1nc(/C(=N/OC2CCCC2)C(=O)[O-])ns1
Reactant: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Agent: C=CC[N+]1(C)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OC2CCCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C4\CCN(Cc5cc[n+](CC(=O)Nc6ccc(O)c(F)c6)cc5)C4=O)CS[C@H]23)ns1
Reaction time: 78 h

Procedure:
A solution of (Z)-(5-amino-[1,2,4]thiadiazol-3-yl)-cyclopentyloxyimino-acetate 1-allyl-1-methyl-pyrrolidinium salt in 10 ml DMF was treated with HBTU (170 mg, 0.45 mmol) for 1.5 h at room temperature. (E)-(6R,7R)-7-Amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetic acid salt (300 mg, 0.45 mmol) was added and the mixture was stirred for 78 h before it was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with water. The organic phase was evaporated and the residue triturated with diethylether. The product was purified by gel chromatography (MCI-gel, using a gradient of water with increasing concentrations of acetonitrile). Yield: 40 mg (11%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Br-:9].[Br-:10].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CO>[Br:9][C:6]1[CH:7]=[C:8]([Br:10])[C:1]([OH:2])=[CH:3][C:4]=1[OH:5]
Reactant: [Br-]
Reactant: Oc1cccc(O)c1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: Oc1cc(O)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
This synthesis was adapted from Shoji Kajigaeshi, Takaaki Kakinami, Tsuyoshi Okamoto, Hiroko Nakamura, Masahiro Fujikawa, Bulletin of the Chemical Society of Japan, 1987, volume 60, pages 4187-4189. To a solution of resorcinol (5.00 grams, 45.4 millimoles, 1.0 equivalent), dissolved in 100 milliliters dichloromethane and 40 milliliters methanol, pyridinium tribromide (29.0 grams, 90.8 millimoles, 2.0 equivalent) was added in small portions over the course of 60-70 minutes. The reaction was stirred at room temperature overnight. The solvent was removed on the rotary evaporator, and the residue taken up in chloroform (1×50 milliliters) and reconcentrated. Addition of ethyl acetate resulted in precipitation of side product. The ethyl acetate phase was separated by decanting, and the precipitate was further washed several times (4×150 milliliters 1:1 ether/ethyl acetate, 1×150 milliliters ethyl acetate, solvent separated by decanting). The combined decanted solvents were concentrated, followed by purification via automated flash chromatography (methanol in chloroform, 0-15%). The product was obtained in the form of an off-white solid (10.9 grams, 40.7 millimoles, 90%). m.p.: 66.4° C.; 1H-NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 6.74 (s, 1H), 5.46 (s, 2H); 13C NMR (101 MHz, THF-d8) δ 155.60, 136.10, 105.13, 100.74, 67.57; FTIR: 569, 594, 659, 742, 837, 868, 993, 1053, 1138, 1193, 1282, 1326, 1440, 1462, 1494, 1577, 1598, 1711, 2918, 3089, 3379, 3451, 3504 cm−1; UV/Vis: 223, 236, 296 nm; ESI/MS/MS of m/z=267: 267 [M79Br/81Br-H]−, 188 [M81Br-HBr)]−, 186 [M79Br-HBr)]−, 160 [M81Br-HBr—CO)]−, 158 [M79Br-HBr—CO)]−, 81 [81Br]−, 79 [79Br]−; HRMS (ESI−): 374.95735 calc. for C6H3Br2O2− [M-H]−: 264.8505, found 264.8510.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]1([CH:7]2[CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:10][CH2:11][N:12]2[C:27](=[O:29])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made the following manner: 100 mg of 3-phenyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine would be dissolved in dichloromethane, 1.1 equiv. of acetylchloride and 2 equiv. of N,N-diisoproylethylamine would be added. The reaction would be stirred at room temperature under nitrogen overnight. The reaction would be diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].[C:15]1([CH3:25])[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(=O)C(C)C.C(Cl)Cl>[CH:16](=[N:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14])[CH:15]([CH3:25])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(C)c1nnc(SC)n(N)c1=O
Agent: CC(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCC(C)c1nnc(SC)n(N=CC(C)C)c1=O

Procedure:
42.8 g of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one were dissolved in 60 ml of isobutyraldehyde. 0.2 g of p-toluenesulfonic acid was added, the mixture was stirred until the slightly exothermic reaction had subsided and was diluted with 200 ml of methylene chloride, and the whole was stirred with 100 ml of water, containing 0.5 g of sodium carbonate. The organic phase was separated off, washed with water and concentrated on a rotary evaporator. The residue which remained consisted of 52.0 g (97.5%) of 4-isobutylideneamino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one, melting point 16° C (from pentane); nD 20 1.5493.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][NH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].CC(=O)CC(=O)C.[F:23][C:24]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:25]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:12]([CH3:13])=[N:11][N:10]([CH2:26][C:25]2[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:24]=2[F:23])[C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Reactant: Cc1n[nH]c(C)c1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)=O
Solvent: CC#N
Product: Cc1nn(Cc2ccc([N+](=O)[O-])cc2F)c(C)c1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (10 g, 47.6 mmol, preparation according to WO2007/141267 by using 2,4-pentanedione instead of 3,5-heptanedione) and 2-fluoro-4-nitrobenzyl bromide (11.2 g, 47.9 mmol) in acetonitrile (150 mL) is added K2CO3 (6.615 g, 47.9 mmol) and the mixture is stirred for 24 hours at room temperature. The solid is filtered off and the solvent is removed by evaporation. The residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over MgSO4 and evaporated under reduced pressure. The residue is purified by MPLC (cyclohexane/ethyl acetate 7:3, silicagel 60) to yield 13.6 g of [3,5-dimethyl-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+=364 TLC: Rf=0.23 (cyclohexan/ethyl acetate 7:3, solicagel 60 F254)). b) To a solution of [3,5-dimethyl-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (13.6 g, 37.4 mmol) in methanol (250 mL) is added Raney nickel (6 g) and the mixture is hydrogenated at 50 psi and 50° C. for 12 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 11.6 g of the title compound (ESI mass spectrum: [M+H]+=334; TLC: Rf=0.53 (dichloromethane/methanol 95:5, silicagel 60 F254)).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.P([O-])([O-])(O)=O.[Na+].[Na+].[C:17]([NH:20][C:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=1[N:28]=[N:29][C:30]1[CH:39]=[CH:38][C:37]2[C:36]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]=1[S:44]([OH:47])(=[O:46])=[O:45])(=[O:19])[CH3:18].[OH-].[Na+]>O>[C:17]([NH:20][C:21]1[CH:26]=[C:25]([NH:27][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH:24]=[CH:23][C:22]=1[N:28]=[N:29][C:30]1[CH:39]=[CH:38][C:37]2[C:36]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]=1[S:44]([OH:47])(=[O:45])=[O:46])(=[O:19])[CH3:18]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(=O)Nc1cc(N)ccc1N=Nc1ccc2c(S(=O)(=O)O)cccc2c1S(=O)(=O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(Nc2nc(Cl)nc(Cl)n2)ccc1N=Nc1ccc2c(S(=O)(=O)O)cccc2c1S(=O)(=O)O

Procedure:
19 parts of cyanuric chloride are stirred vigorously into 50 parts of water, with addition of a wetting agent and 5 parts of disodium hydrogen phosphate, at a temperature of 0° C. A neutral solution of 48 parts of 2-(2-acetylamino-4-aminophenylazo)naphthalene-1,5-disulfonic acid in 450 parts of water is added dropwise, during which the pH is kept at a value of 4.5 by addition of sodium hydroxide solution. A solution of 2-[2-acetylamino-4-(4,6-dichloro-1,3,5-triazin-2-ylamino)phenylazo]-naphthalene-1,5-disulfonic acid is obtained (solution 2).