Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH:9]1([C:13]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1.CO>S(=O)(=O)(O)O>[CH:9]1([C:13]2[CH:22]=[C:21]([CH3:23])[C:20]([I:1])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(C)cc1C1CCC1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(I)c(C)cc1C1CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Iodosuccinimide (5.25 g, 23.3 mmol) was added portionwise to a solution of methyl 2-cyclobutyl-4-methylbenzoate (219.2, 4.77 g, 23.3 mmol) in concentrated sulfuric acid (100 ml) at 0° C. The mixture turned very thick after it was stirred at 0° C. for 30 min and at RT for 2 hours. The mixture was cooled to 0° C. again and MeOH (100 ml) was added. The mixture was heated at 60° C. for 2 hours. The methanol was removed under reduced pressure and the residue was poured into ice water (200 ml). The mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, then aq. 1N NaHCO3, dried (Na2SO4), and concentrated. The residue was purified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 5.0 g, clear oil, 65%. 1H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.24 (s, 1H), 4.17-4.04 (m, 1H), 3.86 (s, 3H), 2.48-2.44 (s, 3H), 2.40-2.28 (m, 2H), 2.13-1.92 (m, 3H), 1.85-1.75 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:43](=[O:44])[C:42]3[CH:46]=[CH:47][C:39]([Cl:38])=[CH:40][CH:41]=3)=[CH:17][C:16]=2[CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSc2ccccc2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
[3-(4-Amino-2-phenylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.4 g, 0.9 mmol) and triethylamine (1 mL) were combined in CH2Cl2 (10 mL). 4-Chlorobenzoyl chloride (0.29 mL, 2.3 mmol) was added, and the reaction was stirred at room temperature for 20 minutes. The mixture was concentrated to give the title compound, which was used directly in the hydrolysis step.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([N+:13]([O-])=O)[CH:6]=1.C>CO.[Fe](Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([CH:6]=1)[NH2:13]
Reactant: CCc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CCc1ccc(Cl)cc1N
Yield: 97.1 %

Procedure:
A solution of hydrazine hydrate (6.95 mL, 134.7 mmol) in MeOH (50 mL) was added dropwise to a solution of 4-chloro-1-ethyl-2-nitrobenzene (6.25 g, 33.7 mmol) in MeOH (120 mL), in the presence of iron(III) chloride (547 mg, 3.4 mmol) and activated charcoal (547 mg), and the reaction mixture was stirred under reflux for 13 h. The solids were filtered over celite, the filtrate concentrated and purified by flash chromatography (hexane:AcOEt 9:1) to obtain the title compound as a light-pink oil (5.09 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22][S:23][CH3:24])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[OH:31]O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22][S:23]([CH3:24])=[O:31])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: OO
Reactant: CSCc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Solvent: O=CO
Product: CS(=O)Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 50.7 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide (prepared as in Example 36, 514.3 mg, 1.099 mmol) in formic acid (11 mL) was treated with a 30% aqueous hydrogen peroxide solution (113 μL, 1.106 mmol). The reaction was stirred at 25° C. for 4 d. The reaction was then partitioned between ethyl acetate (250 mL) and water (250 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (250 mL) and a saturated aqueous sodium chloride solution (150 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 5% methanol/methylene chloride) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinylmethyl-pyrazin-2-yl)-propionamide (269.9 mg, 51%) as a light yellow foam: mp 102–106° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O4S2 (M+H)+ 484.1126, found 484.1134.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)nn1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(6-methoxy-pyridazin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M36) (282 mg, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (214 mg).
Reaction SMILES: [Br-].[CH3:2]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH3:27][C:28]1[N:33]=[C:32]([C:34]([C:36]2[N:37]=[CH:38][N:39]([C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:40]=2)=O)[CH:31]=[CH:30][CH:29]=1.CCOCC>C1COCC1>[CH3:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:34]([C:36]2[N:37]=[CH:38][N:39]([C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:40]=2)=[CH2:2])[N:33]=1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc(C)n1
Temperature: -50 °C
Yield: 50 %

Procedure:
Methyl triphenylphosphine bromide (commercially available from Aldrich) (2.2 g, 6.16, mmol) in THF(60 mL) at −70° C. was treated with nBuLi (2.44 mL, 2.5M in hexane). The reaction mixture warmed to −50° C. in 1 h. A solution of (6-methyl-pyridin-2-yl)-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate D3) (1.38 g, 3.2 mmol) in THF (25 mL) was added to the mixture via syringe at −50° C. The mixture was allowed to warm to rt for 1.5 h. The mixture was poured into ether (mL) and washed with water (2×10 mL). The organic solution was dried over MgSO4, filtered and evaporated to leave a residue. This was purified by chromatography on SiO2 with diethyl ether to give 2-methyl-6-[1-(1-trityl-1H-imidazol-4-yl)-vinyl]-pyridine (Intermediate D4) 0.68 g (50%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 57 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 57% of theory, C36H45N7O5 (655.8); Rf value: 0.46 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=656; (M+H+Na)++=339.7; (M+2H)++=328.7.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19].C1CCN2C(=NCCC2)CC1>CC(C)=O>[I:1][C:2]1[C:3]([S:12]([NH:15][C:21]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22])(=[O:14])=[O:13])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCCCN=C=O
Reactant: COC(=O)c1cccc(S(N)(=O)=O)c1I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cccc(C(=O)OC)c1I
Temperature: 25 °C

Procedure:
27.3 g of 2-iodo-3-methoxycarbonylbenzenesulfonamide and 9.0 ml of n-butyl isocyanate in 300 ml of absolute acetone are treated with 12 ml of DBU at room temperature and heated at the boil for 3 hours. The reaction solution is cooled to room temperature, concentrated to approximately 1/3 of its volume and poured into 1 l of water. The aqueous phase is acidified with concentrated hydrochloric acid to a pH of 1-2, and the precipitate obtained is filtered off with suction. 31.3 g of methyl 2-iodo-[[[(n-butylamino)carbonyl]amino]sulfonyl]benzoate of melting point 163°-7° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4](=[N:6][OH:7])[NH2:5].[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O)([O-:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]1[N:5]=[C:19]([C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[O:7][N:6]=1
Reactant: NC(=NO)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2nc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
2,6-Dichlorobenzamidoxime (1.0 g) was dissolved in pyridine and m-nitrobenzoyl chloride (0.91 gm, 1.0 molar equivalent) was added. The solution was stirred at room temperature for 1 h under nitrogen, then heated at 90° C. for 4 h. The solution was cooled to room temperature, and poured into ice water. The pH of the solution was adjusted to approximately pH 10 with 2M aqueous sodium carbonate solution. The mixture was extracted with ether and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness. The residue was dissolved in ethyl acetate. Addition of hexanes to the solution gave 3-(2,6-dichlorophenyl)-5-(3-nitrophenyl)-1,2,4-oxadiazole as a white solid (0.69 g). NMR (300 MHz, DMSO-d6): 8.52 (s, 1H), 8.38 (d, 1H), 8.18 (d, 1H), 7.78 (t, 1H), 7.57 ppm (m, 3H). LC-MS tr=38.2 min (Method W) MH++NA=359
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CCO.O>[C:17]1([C:14]2[O:13][C:12]([CH:9]3[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:23])=[O:3])[CH2:11][CH2:10]3)=[N:16][N:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CN1CCC(c2nnc(-c3ccccc3)o2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCC(c2nnc(-c3ccccc3)o2)CC1
Reaction time: 4 h

Procedure:
To a stirred solution of [4-(5-phenyl-[1,3,4]oxadiazol-2-yl)-piperidin-1-yl]-acetic acid ethyl ester in EtOH was added NaOH (36.6 mg, 0.916 mmol, 2 eq) in water (0.421 mL). The mixture was stirred for 4 h and the cloudy suspension was treated dropwise with 2.3 mL of 1N HCl until pH ˜7. The solvent was evaporated in vacuo to yield the title compound in quantitative yield used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=7.58 Hz, 2H) 7.56-7.64 (m, 3H) 2.92-3.08 (m, 5H) 2.29-2.42 (m, 2H) 2.01-2.12 (m, 2H) 1.80-1.96 (m, 2H). MS (m/z, MH+): 288.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.N1CCCCC1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:5]\[C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[C:3]=3[F:10])/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cccc(Cl)c1F
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C\c1cccc(Cl)c1F
Reaction time: 8 h
Yield: 96.1 %

Procedure:
3-Chloro-2-fluorobenzaldehyde (6.24 g, 39.4 mmol) was added to a solution of piperidine (3.88 mL, 39.4 mmol) and 6-chlorooxindole (6.0 g, 35.8 mmol) dissolved in methanol (100 mL). After stirring overnight, the resulting solid was filtered and washed with methanol and hexanes to give 10.6 g of (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one (3) as a green solid.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[C:33]([C:37]1[CH:38]=[C:39]([CH3:55])[C:40](=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=1)([CH3:36])([CH3:35])[CH3:34].Cl>C(OCC)C>[C:33]([C:37]1[CH:38]=[C:39]([CH3:55])[CH:40]([C:42]([C:10]2[C:9]3[CH2:8][C:7]4[C:15](=[CH:16][CH:17]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=4)[C:14]=3[CH:13]=[CH:12][C:11]=2[C:18]([CH3:21])([CH3:20])[CH3:19])([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:41]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccccc1)(c1ccccc1)c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 2.53 g of 2,7-di-tert-butyl-fluorene (9.10 mmol) was dissolved in 70 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 6.4 ml of a n-butyl lithium/hexane solution (1.56M: 9.98 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, a solution prepared by dissolving 3.01 g of 3-tert-butyl-1-methyl-6,6-diphenyl fulvene (10.0 mmol) in 40 ml of dehydrated diethyl ether was added and stirred with refluxing for 7 days. The reaction mixture was added to 100 ml of a hydrochloric acid aqueous solution (1N) and thereafter diethyl ether was added to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a reddish-brown liquid. The liquid was purified by a column chromatography using 180 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. The remainder was re-crystallized using methanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.65 g (2.85 mmol) as a pale yellow solid (yield: 31%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[CH3:18][NH:19]C=O.O>C1(C)C(C)=CC=CC=1>[CH3:18][N:19]=[C:7]([OH:8])[C:6]1[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=1)[C:10]([OH:9])=[O:11]
Reactant: CNC=O
Reactant: O=C1OC(=O)c2c1cc([N+](=O)[O-])cc2[N+](=O)[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Yield: 77.8 %

Procedure:
238.11 g (1 mol) of 3,5-dinitrophthalic anhydride are dissolved under reflux in 1 liter of xylene. 62.02 g (1.05 mols) of N-methylformamide are added dropwise under reflux in the course of 30 minutes. After 18 hours under reflux, the water formed and the formic acid, together with some xylene (total 140 ml), are distilled off, the boiling point rising to 137° C. The solution is filtered hot. After slow cooling and concentration of the mother liquor, 209.42 g (83% of theory) of 3,5-dinitrophthalic acid N-methylimide are obtained; melting point: 174°-6° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]([C:9]([OH:11])=[O:10])([CH2:5][CH2:6][CH2:7][NH2:8])[NH2:4].[Cl:12][CH2:13][CH:14]=[N:15][OH:16]>O>[ClH:12].[ClH:1].[NH2:4][C:3]([CH3:2])([CH2:5][CH2:6][CH2:7][NH:8][C:14](=[N:15][OH:16])[CH3:13])[C:9]([OH:11])=[O:10]
Reactant: ON=CCCl
Reactant: CC(N)(CCCN)C(=O)O
Agent: Cl
Solvent: O
Product: CC(=NO)NCCCC(C)(N)C(=O)O

Procedure:
α-Methyl-D,L-ornithine hydrochloride is protected as a copper complex via reaction with cupric carbonate in water at reflux. This protected amino acid is then reacted with chloroacetaldoxime as in Example 1. The product is eluted from Dowex with 1N ammonium hydroxide. Concentration in vacuo, followed by acidification with hydrochloric acid affords the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][CH2:11]O.S(Br)([Br:15])=O>C1(C)C=CC=CC=1>[Br:15][CH2:11][CH2:10][CH2:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: O=S(Br)Br
Reactant: OCCCc1c(F)cccc1F
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1CCCBr

Procedure:
6.86 g (39.8 mmol) of 3-(2,6-difluorophenyl)propan-1-ol (Example 1.2.4) is dissolved in 50 ml toluene and 19.1 g (92.0 mmol) of thionyl bromide is added. The mixture is refluxed for 3 hours, the solvent is eliminated and excess thionyl bromide is eliminated. Then the residue is purified by flash chromatography (cyclohexane). Yield: 6.98 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[O:22]([C@@H:29]1[CH2:33][NH:32][C@H:31]([CH2:34][O:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:32]3[CH2:33][C@@H:29]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:30][C@H:31]3[CH2:34][O:35][C:36]3[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 101.1 %

Procedure:
In DMF (10 ml), a mixture of 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (351 mg, 1.07 mmol), methyl 4-((2S,4S)-4-phenoxy-2-pyrrolidinylmethoxy)benzoate (303 mg, 1.07 mmol), EDC•HCl (308 mg, 1.61 mmol), HOBt (218 mg, 1.61 mmol) and triethylamine (0.74 ml, 5.35 mmol) was stirred at room temperature for 21 hours. The reaction mixture was poured in ice water (30 ml), followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 40 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (640 mg, 100%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:7][C:6](=O)[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>O=P(Cl)(Cl)Cl>[Cl:15][CH:6]1[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:13])([CH3:1])[NH:7]1
Reactant: CC1(C)NC(=O)c2ccccc2O1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)NC(Cl)c2ccccc2O1
Reaction time: 2 h

Procedure:
A solution of 2,2-dimethyl-4-keto-1,3-benzoxazine (1.77 g, 10.0 mmol) and PCl5 (2.09 g, 10.0 mmol) in POCl3 (3.0 mL) was stirred at RT for 1 h then at 50-60° C. for 2 h. The reaction was concentrated and the product distilled (90-95° C./2-3 mm Hg) to afford 4-chloro-2,2-dimethyl-3H-1,3-benzoxazine. (0.496 g, 25%) as a clear oil: 1H NMR (CDCl3, 300 MHz, ppm) 7.58 (d, 1H), 7.48 (m, 1H), 6.97 (m, 1H), 6.94 (d, 1H), 1.63 (s, 6H).
Reaction SMILES: [CH2:1]([N:4]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3]>C(O)(=O)C.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[CH2:1][CH:2]3[C:6]([C:7]([O:9][CH3:10])=[O:8])([CH2:3]3)[C:5]2=[O:11])=[CH:13][CH:14]=1
Reactant: C=CCN(C(=O)CC(=O)OC)c1ccc(F)cc1
Agent: [Cu+2]
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C12CC1CN(c1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.1 %

Procedure:
A solution of methyl 3-(allyl(4-fluorophenyl)amino)-3-oxopropanoate (10 g, 39.7 mmol) in acetic acid (50 mL) was added into a suspension of manganese (III) acetate dihydrate (21 g, 79.7 mmol) and copper (II) acetate monohydrate (7.9 g, 39.7 mmol) in acetic acid (200 mL). The reaction was allowed to stir for 3 days at room temperature. The reaction was quenched with 10% aqueous sodium bisulfite solution (100 mL). The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (50% EtOAc in hexane) to afford the product (1.2 g, 12% yield) as a brown power. LRMS (APCI pos) m/e 250.1 (M+1). 1H NMR: (CDCl3, 400 MHz) δ 7.49-7.54 (m, 2H), 7.02-7.07 (m, 2H), 4.02-4.07 (m, 1H), 3.83 (s, 3H), 3.70 (d, 1H), 2.45-2.53 (m, 1H), 2.02-2.09 (m, 1H), 1.29-1.33 (m, 1H).