Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]=[CH2:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.B1C2CCCC1CCC2>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:12]([OH:13])[C:11]3[CH:14]=[C:15]([CH2:18][CH3:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: C=Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)C(O)c1cc(Cl)cnc1C=C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (20 mg, 0.075 mmol) was dissolved in 1 mL of tetrahydrofuran. RH(COD)2BF4 (3 mg, 0.007 mmol) was added followed by a dropwise addition of 9-BBN (0.44 mL of 0.5 M in THF, 0.22 mmol) and the reaction was stirred overnight. The reaction was cooled to 0° C. and quenched by the simultaneous addition of 1M sodium hydroxide (2.5 ml) and 30% aqueous hydrogen peroxide (0.75 mL) and stirred for 5 hours. The resulting solution was poured into ethyl acetate and brine and extracted three times with ethyl acetate. The combined organics were dried over magnesium sulfate, dried over magnesium sulfate, concentrated in vacuo, and purified via flash chromatography (0-60% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H); 8.03 (s, 1H); 7.54 (s, 1H); 7.28 (m, 2H); 7.17-7.14 (m, 2H); 5.31 (s, 1H); 2.70 (q, 2H); 1.25 (t, 3H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for (C16H15ClNO) [M+H]+, 272.1; found 272.1.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][Br:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:24](SCC(COS(C)(=O)=O)OCC)CCCCCCCCCCCCCCC.[Br-].[Li+]>>[CH2:1]([S:17][CH2:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][Br:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)OCC
Reactant: CCCCCCCCCCCCCCCCSCC(CBr)OC
Agent: [Br-]
Agent: [Li+]
Product: CCCCCCCCCCCCCCCCSCC(CBr)OCC
Yield: 93 %

Procedure:
This compound was prepared in an analogous manner to that (±)-1-hexadecylthio-2-methoxy-3-bromopropane with 6.0 grams (0.014 mole) of (±)-1-S-hexadecyl-2-O-ethyl-3-O-mesylthioglycerol and 20.0 grams (0.07 mole) of lithium bromide. Silica gel column chromatography as before gave 5.5 grams (93%) of product as an oil. 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 31H, (CH2)14, CH3 --CH2 --O], 2.58(m, 2H, S--CH2), 2.62(m, 2H, CH--CH2 --S), 3.3-3.5(m, 5H, CH, CH3 --CH2 --O, CH2 --Br).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[CH:11][N:12]=[C:2]([C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[CH3:13])[CH:3]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: Cc1cc(F)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1ccnc(-c2ccc(F)cc2C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
In a mixed solvent of 250 ml of toluene and 50 ml of ethanol were dissolved 20 g of ethyl 2-chloroisonicotinate and 20 g of 2-methyl-4-fluorophenylboronic acid, and 5.8 g of palladium tetrakistriphenylphosphine and 250 ml of a 2M aqueous sodium carbonate solution, and the mixture was stirred at 50 to 70° C. for 2 hours. The solution was cooled down to room temperature and extracted by adding ethyl acetate and water. The organic layer was further washed with water, and dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1), to give 24.8 g of 4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)pyridine as shown in Table 132 below.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1)[CH:8]=[C:7]([F:20])[CH:6]=2.NC1C(=O)NC2C(N=1)=C(OC1C=C([N:40]3[CH2:45][CH2:44][N:43]([C@H:46]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)[CH3:47])[CH2:42][CH2:41]3)N=CN=1)C=CC=2>>[NH2:1][C:2]1[C:3](=[O:21])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([N:40]3[CH2:41][CH2:42][N:43]([C@H:46]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)[CH3:47])[CH2:44][CH2:45]3)[N:16]=[CH:15][N:14]=1)[CH:8]=[C:7]([F:20])[CH:6]=2
Reactant: Nc1nc2c(Oc3cc(Cl)ncn3)cc(F)cc2[nH]c1=O
Reactant: C[C@@H](c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4[nH]c(=O)c(N)nc34)ncn2)CC1
Product: C[C@@H](c1ccc(F)cc1)N1CCN(c2cc(Oc3cc(F)cc4[nH]c(=O)c(N)nc34)ncn2)CC1

Procedure:
3-Amino-5-(6-chloropyrimidin-4-yloxy)-7-fluoroquinoxalin-2(1H)-one, Example 57(h), (150 mg, 0.49 mmol) was reacted with (S)-1-(1-(4-fluorophenyl)ethyl)piperazine (101 mg, 0.49 mmol, prepared as described in Example 27) under the conditions of Example 26(b) to give the title compound. MS (ESI, pos. ion.) m/z: 480 (M+1). Mp: 288° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]([F:20])([F:19])[F:18])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:17]([F:18])([F:19])[F:20])[CH:11]=1
Reactant: COc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(O)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
30 g (106.28 mmol) of 1-benzyloxy-4-methoxy-2-trifluoromethyl-benzene were dissolved in 60 mL ethyl acetate and then combined with 3 g palladium/C 10%. The mixture was shaken at RT and 50 psi hydrogen pressure for 4 h. The reaction mixture was suction filtered through Celite and the filtrate was evaporated down. The residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][CH2:12][C:13](=O)[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=1.[C:22]([S-:24])#[N:23].[K+].O.[OH-].[Na+]>CC(O)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:12]=[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:23]=[C:22]2[SH:24])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(NCC(=O)c2cccnc2)c1
Reactant: N#C[S-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2cc(-c3cccnc3)nc2S)c1
Temperature: 100 °C
Yield: 94.3 %

Procedure:
A mixture of 4-methyl-3-(2-oxo-2-pyridin-3-yl-ethylamino)-benzoic acid methyl ester (84.5 mg; 0.297 mmol) and KSCN (58 mg; 0.59 mmol) in 1.5 mL of HOAc were heated to 100° C. for 2 h. The mixture was then poured into water and carefully brought to pH 8 with NaOH. The mixture was immediately extracted with EtOAc, and the extract washed with brine. The washes were extracted once more with EtOAc, and the combined extracts were dried with Na2SO4, filtered, and concentrated to provide 3-(2-mercapto-4-pyridin-3-yl-imidazol-1-yl)-4-methyl-benzoic acid methyl ester (90 mg; 0.28 mmol; 93%). ESI MS m/z 326 [C17H15N3O2S+H]+.
Reaction SMILES: C1(CO[C:9]2[CH:10]=[CH:11][CH:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:13]3[C:17]=2[N:16]=[C:15]2CCCC[C:14]=32)C=CC=CC=1.[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C(OCC)(=O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH:12]2[C:13]3[C:31]4[CH:32]=[CH:33][C:34]([OH:30])=[CH:14][C:15]=4[NH:16][C:17]=3[CH2:9][CH2:10][CH2:11]2)=[CH:28][CH:27]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(CC2C=CC(OCc3ccccc3)=C3N=C4CCCCC4=C32)cc1
Solvent: CCOC(C)=O
Product: Oc1ccc2c3c([nH]c2c1)CCCC3Cc1ccc(F)cc1

Procedure:
The hydrogenation of 2.8 g of 1,2,3,4-tetrahydro-6-phenylmethoxy -9-[(4-fluorophenyl)methyl]-9H-dibenzo[b,d]pyrrole from Example 77 was carried out by using the procedure described in Example 86 except that 1:1 tetrahydrofuran-absolute ethyl alcohol was used instead of 1:1 ethyl acetate-absolute ethyl alcohol mixture as a solvent. The crude 5,6,7,8-tetrahydro-9-[(3-fluorophenyl)methyl]-9H-dibenzo[b,d]pyrrol-3-ol was used without further purification.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(O)C>CO>[C:1]1([NH:7][N:8]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Solvent: CO
Solvent: CCO
Product: CC(C)(C)c1ccc(C=NNc2ccccc2)cc1
Yield: 93.1 %

Procedure:
In 20 ml of methanol was dissolved 2.18 g of phenylhydrazine. While metering, 3.24 g of 4-tert-butylbenzaldehyde was added dropwise to the solution. Reaction quickly took place. With heat release, the entire solution solidified. 5 ml of ethanol was added to the mass and the crystals were washed and collected by suction filtration. The crystals were washed with a small amount of methanol and dried in vacuum for 1.5 hours, obtaining 4.69 g (yield 93%) of pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][C:5]=1[C:30]([F:33])([F:32])[F:31])([O-:3])=[O:2].B(Br)(Br)Br.CCOC(C)=O.CCCCCC>C(Cl)Cl>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[S:18][C:19]4[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:15][CH:16]=2)=[O:9])=[CH:6][C:5]=1[C:30]([F:33])([F:32])[F:31])([O-:3])=[O:2]
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4ccc([N+](=O)[O-])c(C(F)(F)F)c4)cc3)sc2c1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc3ccc(O)cc3s2)cc1)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 72.6 %

Procedure:
Prepared as described in the Demethylation section using 4-nitro-3-trifluoromethyl-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (0.10 g, 0.21 mmol) in dry DCM (10 ml) and BBr3 (1.0 M solution in DCM, 1.1 ml, 1.1 mmol) to give the title compound (0.07 g, 71%) as a yellow solid after work-up and flash chromatography (3:1 EtOAc/Hexane).
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23])=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]1[C@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23]
Reactant: O=C(N[C@@H]1C(=O)N[C@H]1Oc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N[C@@H]1C(=O)N[C@H]1Oc1ccccc1

Procedure:
(3S, 4S)-3-benzyloxycarbonylamino-4-phenoxy-azetidin-2-one (140 mg, 0.45 mmole) is hydrogenated with 100 mg of 10% palladium on activated carbon in ethyl acetate (20 ml) at 50 psi hydrogen pressure at room temperature for 2 hours. After removal of catalyst by filtration, deprotected (3S, 4S)-3-amino-4-phenoxy-azetidin-2-one in ethyl acetate is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.[NH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1>>[CH:29]1([CH2:28][NH:27][C:4]([C:6]2[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:3])[CH2:31][CH2:30]1
Reactant: NCC1CC1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nn1
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NCC2CC2)nn1
Yield: 63 %

Procedure:
As described for example 116e, 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (107 mg, 0.3 mmol) was converted, using aminomethylcyclopropane instead of cyclopropylamine, to the title compound (72 mg, 63%) which was obtained as a white solid. MS: m/e=382.5 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][N:22]3[CH2:25][CH2:26][O:27][Si](C)(C)C(C)(C)C)=[CH:18][CH:17]=2)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(/C=C/C(O)=O)=CC=1)(C)(C)C.C[Si](C)(OCCN1C2C(=CC=C(N)C=2)C=C1)C(C)(C)C>>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][N:22]3[CH2:25][CH2:26][OH:27])=[CH:18][CH:17]=2)=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3ccn(CCO[Si](C)(C)C(C)(C)C)c3c2)cc1
Agent: CC(C)(C)[Si](C)(C)OCCn1ccc2ccc(N)cc21
Agent: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3ccn(CCO)c3c2)cc1

Procedure:
(2E)-3-[4-(tert-Butyl)phenyl]-N-{1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indol-6-yl}prop-2-enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) and 1-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]indole-6-ylamine, Example 72(a), (290 mg, 1.0 mmol) provided the title product. MS (ESI, pos. ion) m/z: 477 (M+1).
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:51][CH3:52])=[C:31]([C:36]([CH2:39][S:40]([N:43]2[CH2:48][CH2:47][C:46]([F:50])([F:49])[CH2:45][CH2:44]2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>>[F:49][C:46]1([F:50])[CH2:47][CH2:48][N:43]([S:40]([CH2:39][C:36]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([O:51][CH3:52])[C:29]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:38][CH:37]=2)(=[O:42])=[O:41])[CH2:44][CH2:45]1
Reactant: COC(=O)c1c(CS(=O)(=O)N2CCC(F)(F)CC2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)N2CCC(F)(F)CC2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(4,4-difluoropiperidine-1-ylsulphonylmethyl)-2-methoxybenzoate (Intermediate 179), as a white solid.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=3[CH:17]=2)[OH:15])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].P([O-])([O-])O.[Na+].[Na+].[CH2:36]=O>O1CCOCC1>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:28])([CH3:29])[C:18]=4[CH:17]=3)[O:15][CH2:36]2)=[CH:10][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(NCC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: C=O
Agent: [Na+]
Agent: [O-]P([O-])O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(N2COC(c3ccc4c(c3)C(C)(C)CCC4(C)C)C2)cc1
Yield: 61.3 %

Procedure:
1.58 g (4 millimoles) of N-(4-carbethoxyphenyl)-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-aminoethanol were stirred with 20 ml of 1 N sodium hydrogen phosphite solution and 2 ml (20 millimoles) of formalin solution in 20 ml of dioxane for 1 hour at 60° C. The mixture was then poured onto water and extracted with ether, and the organic phase was washed with 2 N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated down. Recrystallization from methanol gave 1.0 g of the title compound, RF =0.51 (thin layer chromatography, silica gel; 7:1 n-heptane/ethyl acetate).
Reaction SMILES: S=C1N([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])CCS1.[NH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(C(C)C)CC)(C)C.C(N(CC)CC)C>C1COCC1.C(Cl)(Cl)Cl.C(Cl)Cl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:8])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: CCOC(=O)CN
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNC(=O)OCc1ccc(OC(C)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
Thiazolide VII (266.8 mg, 0.781 mmol) was dissolved in anhydrous THF (3 mL), and the resulting solution was added to a previously prepared solution of ethyl glycinate (130 mg, 1.19×0.781 mmol) and diisopropylethylamine (120 mg, 162 μL, 1.19×0.781 mmol) in chloroform (3 mL). To the resulting solution was added triethylamine (72.6 mg, 100 μL, 0.72 mmol) at which point a slight cloudiness developed. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with CH2Cl2 and extracted with 1N HCl and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel using a gradient of CH2Cl2/ethyl acetate (94:6-9:1, v/v) to yield 152.9 mg (60%) of a white solid 19: mp=62-64° C. (uncorrected); Rf=0.27 (CH2Cl2/EtOAc, 96:4, v/v); 1HNMR (CDCl3) δ 6.99 (d, 3J=8 Hz, 1H), 6.96 (bs, 1H), 6.92 (bd, 3J=8 Hz, 1H), 5.22 (bs, 1H), 5.08 (bs, 2H), 4.20 (q, 3J=7.15 Hz, 2H), 3.96 (d, 3J=5.55 Hz, 2H), 3.82 (s, 3H), 2.29 (s, 3H) and 1.27 (t, 3J=7.15 Hz, 3H). Exact mass (ESI) calculated for C15H20NO7 [M+H]=326.1234. found 326.1245.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C1COCC1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:22][CH2:21]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 47.3 %

Procedure:
A 1-liter-3-neck flask was loaded with 4-nitrobenzoyl chloride (50.5 g, 267 mmol) and THF (500 ml) and cooled to 0° C. Pyridine (44 ml, 544 mmol), then 1-methyl-piperazine (35 ml, 316 mmol) were added while mechanically stirring at 0° C. After the addition was completed the ice bath was removed and the mixture stirred for 1 hour, while warming to room temperature. A voluminous precipitate forms. The slurry was diluted with dichloromethane and 1 M aq. KOH and the layers separated. The organic layer was washed one more time with 1 M aq. KOH, then with brine and dried over MgSO4, filtered and concentrated in vacuum. 31.5 g yellow solid (4-methylpiperazin-1-yl)(4-nitrophenyl)methanone were isolated. MS (ESI) m/z 250 (M+H). 1H NMR (CDCl3) δ ppm 8.27 (d, 2H, J=7.9), 7.56 (d, 2H, J=7.9), 3.81 (bs, 2H), 3.37 (bs, 2H), 2.50 (bs, 2H), 2.34 (bs, 2H), 2.32 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].C(N(CC)CC)C.C(OC1C=CC2C=C(C)SC=2C=1)(=O)C>>[C:12]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1)(=[O:14])[CH3:13]
Reactant: Cc1cc2ccc(O)cc2o1
Reactant: CC(=O)Cl
Agent: CC(=O)Oc1ccc2cc(C)sc2c1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2cc(C)oc2c1
Yield: 101.3 %

Procedure:
This material was prepared from 6-hydroxy-2-methylbenzofuran (654 mg, 4.41 mmole) by treatment with acetyl chloride (0.41 ml, 5.74 mmole) and triethylamine (0.74 ml, 5.30 mmole) in a manner as previously described for 8b to give the desired product as an oil (850 mg, ˜quant). 1H NMR (CDCl3) δ 7.41 (1H, d, J=8.3 Hz), 7.13 (1H, s), 6.88 (1H, dd, J=8.3, 1.9 Hz), 6.32 (1H, s), 2.42 (3H, s), 2.30 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]3[CH2:25][C:24]([O:26]CC(C)C)=[CH:23][C:22]3=[O:31])[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CC(C)=O.Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]3[CH2:25][C:24](=[O:26])[CH:23]=[C:22]3[OH:31])[CH:15]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)COC1=CC(=O)C(Cc2cccc(CCNS(=O)(=O)c3ccc(Cl)cc3)c2)C1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C1C=C(O)C(Cc2cccc(CCNS(=O)(=O)c3ccc(Cl)cc3)c2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
A mixture of 32 (0.018 g, 0.04 mmol) in acetone (0.5 mL) and 2 N hydrochloric acid (0.2 mL) was stirred at rt for 6 h. The reaction mixture was diluted with water and the acetone was evaporated under reduced pressure. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by reverse phase preparative HPLC to provide the desired compound as a white solid. Yield: 88%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([F:24])[CH:15]=3)=[CH:12][C:11]([C:25]([O:27]CC)=[O:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[C:16]([F:24])[CH:15]=3)=[CH:12][C:11]([C:25]([OH:27])=[O:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cc(F)cc(C(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 48A in analogy to the synthesis of the compound of Example 71A. 851 mg of the title compound with 51% purity are obtained.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[C:6]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[C:6]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
To a solution of 253 (71.4 mg, 0,21 mmol) in acetic acid (2.1 mL) at 100° C., was added iron powder (59 mg, 1.05 mmol). The reaction mixture was stired for 5 minutes, filtered through a Celite® pad and concentrated under reduced pressure. The residue was purified by column chromatography, eluent EtOAc/hexane (2:1), to afford title compound 254 (27.9 mg, 40% yield). MS (m/z): 321.1 (M+1).