Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH:31][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: NCCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCc3ccccc3Br)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (150 mg, 0.50 mmol, 1.00 equiv), 2-(2-bromophenyl)ethanamine (300.5 mg, 1.51 mmol, 3.00 equiv), potassium carbonate (347.3 mg, 2.52 mmol, 5.00 equiv), toluene/DMSO (5/1 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum and applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 110 mg (47%) of methyl 3-(2-bromophenethylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C.O>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ncnc2ccc(Cl)cc12
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2ccc(Cl)cc12)C(=O)OCC
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 79.6 %

Procedure:
A mixture of 4-amino-6-chloroquinazoline (8.7 g) and diethyl ethoxymethylenepropanedioate (11.53 g) in N,N-dimethylformamide (25 ml) was stirred for 2 hours and 40 minutes at 150° C. After the reaction mixture was cooled to ambient temperature, to the mixture was added water with stirring to give crystals, which were washed with water, dried under reduced pressure and dissolved in ethyl acetate under heating. Insoluble materials were filtered off. To the filtrate was added hexane and allowed to stand at ambient temperature to give crystals, which were separated by filtration and washed with a mixture of ethyl acetate and hexane to give a mixture (13.48 g) of crystalline diethyl [(6-chloro-4-quinazolinylamino)methylene]propanedioate and ethyl 10-chloro-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate.
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[N:10]=[CH:9][N:8]=[C:7]([N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1>O=[Pt]=O.CCO.CO>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=2)=[C:2]([F:1])[CH:23]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(N)cc2F)ncn1
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of tert-butyl 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl(methyl)carbamate in 1:1 EtOH/MeOH (2 mL) was treated with PtO2 (10 mg) and the reaction mixture was stirred under a blanket of H2 (from a latex balloon) for 2 h. The reaction mixture was filtered and concentrated to give the desired product (30 mg, 75%) as a light brown solid. MS(ESI+) m/z 365.13 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[C:4]([F:17])[CH:3]=1.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[C:4]([F:17])[CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
TiCl4 (2.10 mL, 19.0 mmol) was added dropwise to a suspension of zinc powder (2.51 g, 38.4 mmol) in anhydrous THF (60 mL) at RT. After refluxing for 1 h, a mixture of 76 (1.40 g, 4.74 mmol) and cyclohexanone (1.40 g, 14.3 mmol) dissolved in THF (20 mL) was added dropwise. Refluxing was continued for 30 min. The reaction mixture was cooled to RT and filtered through Celite. Water (250 mL) was added and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.23 g (72%) of 77 as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.58 (br s, 6H), 2.05 (m, 2H), 2.25 (m, 2H), 4.68 (br s, 1H), 6.73 (d, J=8.6 Hz, 2H), 6.94-7.00 (m, 3H), 7.19 (d, J=7.9 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:32]([C:36]1[CH:60]=[CH:59][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52](/[C:55](=[N:57]/O)/[NH2:56])=[CH:51][CH:50]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[C:32]([C:36]1[CH:60]=[CH:59][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55](=[NH:56])[NH:57][O:14][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=3)=[CH:53][CH:54]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(/C(N)=N/O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)ONC(=N)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reaction time: 2 h

Procedure:
Prepared using General Procedure 5: To a solution of 4-(heptyloxy)benzoic acid (400.0 mg, 1.54 mmol) in anhydrous DMF (6 mL) were added HOBt (312.3 mg, 2.31 mmol) and EDC (442.75 mg, 2.31 mmol). After stirring for 2 h, (S,Z)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N′-hydroxycarbamimidoyl)phenyl)-propanoate, INT-2 (673.3 mg, 1.69 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, partitioned between saturated aqueous NaHCO3 (15 mL) and EA (15 mL), and concentrated under reduced pressure to afford the intermediate (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N-((4-(heptyloxy)benzoyl)oxy)carbamimidoyl)phenyl)propanoate. The intermediate was dissolved in DMF (10 mL) and heated to 100° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EA (10 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was extracted with water (2×10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated. The brown oil was purified by chromatography (EA/hexanes) to afford 710 mg (77%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate as a white solid. LCMS-ESI (m/z) calculated for C36H43N3O5: 597.3; no m/z observed, tR=12.80 min (Method 2). 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=8.0 Hz, 1H), 8.08 (t, J=17.2 Hz, 2H), 7.97 (dd, J=18.2, 8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.50 (dd, J=18.6, 8.3 Hz, 4H), 7.18 (d, J=8.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.09 (dd, J=13.8, 7.3 Hz, 2H), 3.67 (s, 3H), 3.24 (ddd, J=23.8, 15.7, 7.3 Hz, 4H), 2.08 (s, 4H), 1.74 (dd, J=14.1, 6.9 Hz, 2H), 1.42 (dd, J=13.6, 6.3 Hz, 2H), 1.30 (d, J=14.5 Hz, 9H), 0.88 (t, J=6.8 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 174.05, 170.87, 133.81, 165.14, 161.43, 153.21, 140.51, 129.70, 128.85, 128.78, 126.06, 125.84, 123.93, 123.39, 114.36, 114.25, 66.86, 52.66, 50.88, 34.32, 33.47, 30.06, 29.74, 27.33, 27.24, 24.23, 20.89, 12.80.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=O)[S:7][C:6]=2[CH:11]=1.[C:12](=O)([O-])[O-].[K+].[K+].C(Br)C=C>CC(C)=O>[CH3:8][O:9][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][C:6]=1[S:7][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: O=c1oc2ccc(O)cc2s1
Agent: [K+]
Solvent: CC(C)=O
Solvent: C=CCBr
Product: COc1ccc(O)cc1SC
Reaction time: 24 h
Yield: 93.8 %

Procedure:
5-Hydroxy-1,3-benzoxathiol-2-one (2 g, 11.9 mmol) [prepared according to J. Org. Chem. 1990, 55, 27361] was dissolved in acetone (13 mL) and treated with potassium carbonate (3.29 g, 23.8 mmol) followed by allyl bromide (1.13 mL, 13.1 mmol). The mixture was then stirred under nitrogen atmosphere for 24 h. The reaction mixture was evaporated to dryness and the residue was partitioned between water and diethyl ether (50 mL each). The organic fraction was separated and the aqueous layer was re-extracted with diethyl ether (50 mL). The combined organic fractions were dried (MgSO4) and evaporated to a brown oil. Purification by flash chromatography [SiO2; pentane/EtOAc (95:5→90:10)] afforded the desired compound as a colourless oil (1.9 g, 77%); δH (CDCl3, 400 MHz) 4.50 (2H, d), 5.28 (1H, d), 5.38 (1H, d), 6.00 (1H, ddt), 6.83 (1H, dd), 6.91 (1H, d), 7.15 (1H, d).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH:19]=O)[C:11]=2[N:21]=1.[NH2:22][C@@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH2:19][NH:22][C@@H:23]3[CH2:27][N:26]([C:28]4[CH:29]=[CH:30][C:31]5[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=5[N:37]=4)[C:25](=[O:39])[CH2:24]3)[C:11]=2[N:21]=1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCCN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Reaction time: 0.17 h
Yield: 11.4 %

Procedure:
Acetic acid (0.06 g, 1 mmol) was added dropwise to a mixture of 3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (synthesized with reference to WO2008/9700; 0.2 g, 0.85 mmol), 6-[(4S)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 22; 0.25 g, 1.0 mmol) and N,N-dimethylformamide (4 ml). Sodium triacetoxyborohydride (0.23 g, 1.1 mmol) was gradually added under cooling on ice to the obtained mixture, which was then stirred for 10 minutes. The mixture was further stirred at room temperature for 2 hours, cooled on ice, a saturated sodium hydrogen carbonate aqueous solution was added thereto, and the resultant was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol) to yield 45 mg (11%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:27])[CH2:12][N:13]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:51][C@H:52]1[CH2:56][CH2:55][C@@H:54]([CH2:57]O)[O:53]1>CN(C)C=O>[CH2:3]([O:10][C:11]([C:12]1([N:13]=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:57][CH:54]2[O:53][CH:52]([CH2:56][CH2:55]2)[CH2:51]1)=[O:27])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CN=C(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: OC[C@@H]1CC[C@H](CO)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1(N=C(c2ccccc2)c2ccccc2)CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.41 grams, 17.1 mmole) in N,N-dimethylformamide (50 mL) at 0° C. is added dropwise a solution of N-diphenylmethylene glycine benzyl ester (7.8 mmole) in N,N-dimethylformamide (50 mL). After stirring for 30 minutes at room temperature, a solution of cis-2,5-bis(hydroxymethyl)-tetrahydrofuran ditosylate (4.1 grams, 9.3 mmole,)(prepared by literature methods such as those described in JOC, 47, 2429-2435 (1982)) in N,N-dimethylformamide (50 mL) is added dropwise. The reaction mixture is gradually heated to 100° C. in an oil bath and stirred at this temperature overnight. The solvent is evaporated under vacuum and the residue is taken up in water and extracted twice with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate and concentrated to a crude product.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[CH2:28][C:29](O)=[O:30]>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:21]3[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[CH:23][C:22]=3[CH3:27])[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: Cc1cc(C)c(CC(=O)O)c(C)c1
Product: Cc1cc(C)c(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)c(C)c1

Procedure:
The product of Example 1B and 2-(2,4,6-trimethylphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (d, J=7.3 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.96-8.00 (m, 1H), 7.88-7.92 (m, 1H), 6.84-6.85 (bs, 2H), 3.77-3.85 (m, 4H), 3.66 (s, 2H), 3.08-3.13 (m, 4H), 2.31 (s, 6H), 2.21 (s, 3H); MS (ESI+) M/Z 407 (M+H)+.
Reaction SMILES: C(O)=O.[I:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17].Br[CH2:19][C:20](=[O:36])[CH2:21][C@H:22]1[C@H:27]([O:28][CH3:29])[CH2:26][CH2:25][CH2:24][N:23]1[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31]>>[I:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:19][C:20](=[O:36])[CH2:21][C@H:22]3[C@H:27]([O:28][CH3:29])[CH2:26][CH2:25][CH2:24][N:23]3[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17]
Reactant: CSc1cc2c(=O)[nH]cnc2cc1I
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Solvent: O=CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(I)c(SC)cc2c1=O

Procedure:
In the manner of Example 4, 1.09 g (0.003 mol) of 7-iodo-6-methylthioquinazolin-4(3H)-one formic acid salt and 1.0 g (0.003 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound: yield 0.53 g (31%); mass spectrum m/e 571 (molecular ion), 539 (-32, --CH3OH), 221 (parent peak). 1H--NMR(CDCl3) 1.4-2.1 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.6 (singlet, 3H, SCH3), 2.8-3.4 (multiplet, 4H, NCH2, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 = CH), 7.7 (singlet, 1H, aromatic H), 7.8 (singlet, 1H, N=CH--N), 8.2 (singlet, 1H, aromatic H).
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][S:8]([C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13])(=[O:10])=[O:9])=[O:5])C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:15][C:11]([S:8]([CH2:7][C@@H:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:4]([OH:3])=[O:5])(=[O:10])=[O:9])([C:12]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:13])[CH3:16]
Reactant: C1COCCN1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)Cl
Product: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In an analogous manner to that described in Example 1, paragraphs (d) and (e), starting from 2-mercaptoisobutyric acid and ethyl 2-benzylacrylate there was obtained (RS)-2-[[2-[(ethoxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride, reaction of which with morpholine analogously to Example 2, paragraph (a), and subsequent enzymatic hydrolysis analogously to Example 6, paragraph (c), yielded (S)-α-[[[1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnamic acid, MS: 383 (M)+, as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].CO.[H][H]>[Pd].O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:12])=[O:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
2-Amino-5-nitro-benzenesulfonamide (5.00 kg, 23.0 mol), methanol (65 L), tetrahydrofuran (65 L), and 10% palladium on carbon (250 g) were charged to an autoclave. The mixture was cycled with nitrogen and hydrogen purges (3×), and the mixture was then stirred under hydrogen (50 psi) at 23° C. overnight. The catalyst was removed by filtration and the filtrate was then concentrated in vacuo to give a brown solid. The solid was further dried in vacuo at 45° C. to afford the desired product, 2,5-diamino-benzenesulfonamide (4.21 kg, 22.4 mol, 98%), as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.54 (2H, bs), 4.98 (2H, bs), 6.55-6.60 (2H, m), 6.87 (1H, d, J=2.2 Hz), 6.99 (2H, bs). LC-MS (ESI) calcd for C6H9N3O2S 187.04, found 188.3 [M+H+].
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[OH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[OH:21])[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.O>C(Cl)(Cl)Cl.S(=O)(=O)(O)O>[C:2]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C:12]3[C:17](=[C:16]([OH:21])[CH:15]=[CH:14][CH:13]=3)[C:18](=[O:20])[C:19]=2[C:6]=1[OH:5])([CH3:3])([CH3:1])[CH3:4]
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc2c(c1O)C(=O)c1c(O)cccc1C2
Yield: 27.7 %

Procedure:
About 7 gm of isobutylene were introduced into a refluxing solution of 11.3 gm of 1,8-dihydroxy-9-(10H)anthracenone in 100 ml of chloroform and 6 ml of sulfuric acid. The resulting mixture was poured into water, and the organic phase was separated and worked up as described in Example 2. 3.9 gm of 2-tert. butyl-1,8-dihydroxy-9-(10H)anthracenone, m.p. 126°-127° C., corresponding to 27% of theory, were obtained.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:17][C:16]=2[F:34])=[N:6][C:7]([S:12][CH3:13])=[N:8][C:9]=1[NH:10][NH2:11])(=[O:3])[NH2:2].[CH:35]([O-])([O-])OC>CC(N(C)C)=O>[C:1]([C:4]1[C:9]2[N:8]([CH:35]=[N:11][N:10]=2)[C:7]([S:12][CH3:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]2)=[CH:17][C:16]=1[F:34])(=[O:3])[NH2:2]
Reactant: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Reactant: COC([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CSc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)c(C(N)=O)c2nncn12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 28D (240 mg, 0.5 mmol) in dimethylacetamide (2 mL) was added methyl orthoformate (2 mL). The mixture was stirred at ambient temperature for 1 hour and at 60° C. for 4 hours. After cooling to ambient temperature, petroleum 9/1 ether/ethyl acetate (50 mL) was added and the precipitate was filtered. The solid was washed with petroleum ether and dried under vacuum to give the title compound. MS: 503 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:14][C:15]([C:17]1[C:18]([OH:34])=[C:19]([C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[C:20](=[O:24])[O:21][C:22]=1[CH3:23])=[O:16])[CH3:13]>C(OCC)(=O)C>[C:8]([O:34][C:18]1[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[C:22]([CH3:23])[O:21][C:20](=[O:24])[C:19]=1[C:25]1[C:26]([CH3:33])=[CH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1c(C)oc(=O)c(-c2c(C)cc(C)cc2C)c1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)oc(=O)c(-c2c(C)cc(C)cc2C)c1OC(C)=O
Temperature: 20 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
1.0 g (10 mmol) of triethylamine and then 0.8 g (10 mmol) of acetyl chloride are added dropwise at 0° C. to 3.2 g (10 mmol) of 5-ethoxycarbonyl-4-hydroxy-6-methyl-3-(2,4,6-trimethylphenyl)pyrone in ml of ethyl acetate. The mixture is stirred for 20 hours at 20° C. and filtered, the organic phase is washed with semi-concentrated sodium chloride solution and dried over sodium sulphate and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (35-70 μm) using toluene/acetone (40:1 parts by volume). 2.9 g of 4-acetoxy-5-ethoxycarbonyl-6-methyl-3-(2,4,6-trimethylphenyl)pyrone are obtained (yield: 81% of theory). M.p.=107° to 109° C.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:27]([Si:29]([CH2:33][CH3:34])([CH2:31][CH3:32])Cl)[CH3:28]>C1COCC1>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([Si:29]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:27][CH3:28])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: CC[Si](Cl)(CC)CC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A dry flask is charged with 1.256 g (5 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) and 15 ml dry THF. To the resulting clear solution, 2.02 g (20 mmol) triethylamine is added followed by 904 mg (6 mmol) triethylchlorosilane (TES-Cl). The reaction mixture is stirred at room temperature for 4 h and then quenched on addition of 5 ml saturated NaHCO3 solution, 10 ml water and 10 ml isopropyl acetate. The layers are separated and the aqueous layer extracted with 10 ml isopropyl acetate. The combined organic layers are dried over MgSO4, filtered and evaporated. The resulting residue is purified by column chromatography (dichloromethane+1% v/v triethylamine) to give (S)-5-Biphenyl-4-ylmethyl-1-triethylsilanyl-pyrrolidin-2-one (1-a, R1=TES) as a yellow oil. NMR (300 MHz, DMSO-d6, □/ppm): 7.63 (m, 4 H); 7.55 (m, 2 H); 7.32 (m, 3 H); 3.80 (m, 1 H); 2.85 (m, 1 H), 2.70 (m, 1 H), 2.10-1.70 (m, 4 H), 1.02-0.80 (m, 15 H). MS (ESI, m/e) 366 [M+H]+; 731 [2M+H]+. IR (solution in CH2Cl2, □/cm−1): 3426; 3047; 2957; 1698; 1672; 1487; 1378; 1242; 1114; 1008.