Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.O.O.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[C:23]1([S:29]([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]2=3)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)C(S(=O)(=O)c1ccccc1)c1ccccc1CO2

Procedure:
Compound b, 10 g, 15 g of sodium benzenesulfinate dihydrate and 25 ml of trifluoroacetic anhydride were treated in a manner similar to Example 109 to give 14.3 g of the objective compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]2=[O:28])[CH2:12][CH2:13]1
Reactant: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Reaction time: 2 h

Procedure:
A solution of tert-butyl{1-[2-(7-methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 107) (319 mg, 0.78 mmol) in dichloromethane (8 mL) was treated at room temperature under vigorous stirring with a trifluoroacetic acid (0.75 mL, 10 mmol). After 2 hours, the reaction mixture was concentrated under reduced pressure to give 324 mg (quantitative) of product as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:24]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
3-Fluorophenylacetic acid (4.90 g, 32.07 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (3.5 ml, 40.08 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 50 ml dichloromethane. To this mixture, 4-bromoanisole (5.0 g, 26.72 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (5.3 g, 40.08 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (6.6 g, 80% yield. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 12.02(s,1H), 7.94(d, J=2.4 Hz, 1H), 7.57(dd, J=8.9,2.4.1 Hz, 1H), 7.36(m,1H), 7.04(m, 3H), 6.90(d, J=8.9 Hz, 1H),4.28(s, 2H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]1[N:9]=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[O:7][N:6]=1>C(OCC)C.O>[CH3:4][C:5]1[N:9]=[C:8]([CH2:10][C:11]([O:13][CH3:3])=[O:12])[O:7][N:6]=1
Reactant: Cc1noc(CC(=O)O)n1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: O
Product: COC(=O)Cc1nc(C)no1

Procedure:
A solution of an excess of diazomethane in diethyl ether was added to a stirred, cold (about 2° C.) solution of 14 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in 500 ml of diethyl ether. After the initially vigorous evolution of nitrogen was finished, the solution was concentrated on the steam bath to about 250 ml. The solution was washed three times with 100 ml of water and the wash waters were combined, adjusted to a pH of 9.0 and were extracted with diethyl ether to obtain the part of the product which dissolved in water during the washings. The combined ethereal extracts were filtered through a water repelling paper filter and then were evaporated in vacuo. After keeping the residue for 1 hour at 8 mm the residual oil weighed 14.8 g. The yellow oil was distilled at 0.4-0.5 mm and the collected fraction with a boiling point 70°-71° C. to obtain 12.3 g of methyl 3-methyl-1,2,4-oxadiazol-5-yl-acetate with a refractive index nD25 =1.4472.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH:32][C:33]1[N:38]=[C:37]([C:39]([OH:41])=O)[CH:36]=[CH:35][CH:34]=1.FC(F)(F)C(O)=O.[CH3:49][O:50][C:51]1[CH:71]=[CH:70][C:54]([O:55][C:56]2[CH:69]=[CH:68][C:59]([CH2:60][NH:61][C:62]([C:64]3([NH2:67])[CH2:66][CH2:65]3)=[O:63])=[CH:58][CH:57]=2)=[C:53]([C:72]([F:75])([F:74])[F:73])[CH:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:71]=[CH:70][C:54]([O:55][C:56]2[CH:69]=[CH:68][C:59]([CH2:60][NH:61][C:62]([C:64]3([NH:67][C:39]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([OH:32])[N:38]=4)=[O:41])[CH2:65][CH2:66]3)=[O:63])=[CH:58][CH:57]=2)=[C:53]([C:72]([F:73])([F:74])[F:75])[CH:52]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cccc(O)n4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
74 μL (0.43 mmol) of DIPEA and 57.7 mg (0.18 mmol) of TBTU were added to a solution of 20 mg (0.14 mmol) of 6-hydroxypicolinic acid in 100 μL DMF and the mixture was stirred for 5 min at RT. Then 71 mg (0.14 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 84a) was added and the mixture was stirred for 3 days at ambient temperature. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[C:9](=[O:12])([O-])[O-].[K+].[K+].O.Br[CH:17]1[CH2:22][CH2:21]C[CH2:19][CH2:18]1>CS(C)=O.CN(C=O)C>[CH:9]1([O:12][C:3]2[CH:1]=[CH:8][CH:7]=[CH:6][C:4]=2[OH:5])[CH2:21][CH2:22][CH2:17][CH2:18][CH2:19]1
Reactant: BrC1CCCCC1
Reactant: Oc1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccccc1OC1CCCCC1
Temperature: 80 °C
Yield: 23 %

Procedure:
Under a nitrogen gas stream, resorcinol (55 g, 0.5 mol), potassium carbonate (207 g, 1.5 mol), water (25 ml, 1.4 mol) and N,N-dimethylformaldehyde (500 ml) were charged to a four necked flask (2 L) sufficiently dried, substituted with nitrogen, and equipped with a dropping funnel, Dimroth condenser tube, thermometer and stirring blade, so as to prepare a dimethylformaldehyde solution. Next, bromocylcohexane (408 g, 2.5 mol) was dropped through the dropping funnel for 10 minutes at room temperature, then this solution was heated at 80° C. for 14 hours by a mantle heater while stirring, and then heated at 100° C. for 11 hours. After the reaction terminated, it was stood to cool, and after it reached room temperature, it was cooled in an ice bath. The reaction solution was dissolved in 1 L toluene, and washed three times with 500 ml water. Toluen was distilled away by evaporation, and the residue was purified by column chromatography using hexane and ethyl acetate as developing solvents, to obtain a red brown objective product (hereinafter, referred to as R-1A) (21.9 g, 23% yield, 100% GC purity). The chemical shift value (δ ppm, TMS standard) of 1H-NMR of this compound in a heavy dimethyl sulfoxide solvent was 1.1 to 2.0 (m, 10H), 4.2 (m, H), 6.3 (m, 3H), 7.0 (m, H), 9.3 (s, H).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH:6]2[CH:3]1[CH2:4][C:5]2=[O:9].CCN(CC)CC.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([O:1][CH:2]1[CH2:8][CH2:7][CH:6]2[CH:3]1[CH2:4][C:5]2=[O:9])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CC2C(O)CCC12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC1CCC2C(=O)CC12)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a stirred solution of compound 1G (1.9 g, 15.1 mmol) in CH2Cl2 (10 mL) at 0° C. under nitrogen were added Et3N (3.1 mL, 22.2 mmol) and benzoyl chloride (2.33 g, 16.6 mmol). The reaction was stirred at 0° C. for 60 min and RT for 30 min, then quenched with water. The product was extracted with CH2Cl2, the organics were washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated. Purification by silica gel chromatography (5% EtOAc in hexanes) provide the title compound (3 g).
Reaction SMILES: C[C:2]([C@@H:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:22])[CH2:17][CH2:18][C@H:19]([OH:21])[CH2:20][C:15]4=[CH:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[CH3:24][O-:25].[Na+].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C1(=O)CCCCC1>C1(C)C=CC=CC=1.CO>[CH3:24][O:25][C:2]([CH:4]1[CH2:5][CH2:6][C@H:7]2[C@H:12]3[C@H:11]([CH2:10][CH2:9][C@:8]12[CH3:23])[C@:16]1([CH3:22])[C:15](=[CH:20][C:19](=[O:21])[CH2:18][CH2:17]1)[CH2:14][CH2:13]3)=[O:3]
Reactant: C[O-]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)[O-]
Agent: [Al+3]
Agent: [Na+]
Solvent: O=C1CCCCC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A preferred process for preparing 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, an especially preferred compound of the present invention, comprises the following steps: (a) pregnenolone (V), an available starting material, is treated by the haloform King reaction with iodine and pyridine to form the 20-pyridinum iodide derivative of the pregnenolone (VI); (b) the pyridinium iodide derivative (VI) is hydrolyzed to the methyl ester of 17-carboxy pregnenolone (VII) with sodium methoxide and methanol, the ester form being preferred for carrying out the following Oppenhauer reaction; (c) the methyl ester of 17-carboxy pregnenolone (VII) is treated with aluminum isopropoxide and cyclohexanone in an appropriate solvent such as toluene to yield methyl-4-androstene-3-one-17-carboxylate (VIII) (d) the methyl-4-androstene-3-one-17-carboxylate (VIII) thus formed is hydrolyzed to the 17-acid (IX) under acid conditions in a methanol: water solvent of approximately 4:1 proportions; (e) the 17 acid (IX) is then treated with an oxalyl chloride: pyridine complex of approximately 1:1 proportions in toluene or other suitable solvent, e.g. xylene, to form the 17-acid chloride (X); (f) the 17-acid chloride (X) is then treated in situ with an excess of diethylamine to form the 17β-N,N-diethylcarbamoyl-4-androstene-3-one (XI); (g) the 4-androstene-3-one (XI) thus formed is oxidized by treatment with sodium periodate and potassium permanganate, using tert-butanol and water as a solvent system, to the corresponding 5-oxo-3,5-secoandrostan-3-oic acid (XII); (h) the secoandrostanoic acid (XII) is then converted to the corresponding 4-aza compound (XIII) by treating it with methylamine in ethylene glycol for a period of about 1 hour over which time the reaction mixture temperature is raised to from 140°-180° C. where it is maintained from 0.5 to 5 minutes; (i) the resulting 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5-androsten-3-one (XIII) is then hydrogenated by treating it with hydrogen at room temperature to 60° C. or higher, using platinum oxide as the catalyst, to form the 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one (XIV) final product, which is then separated and purified.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][C:19]2[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:23]=2[CH3:24])[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:2]>C(O)(=O)C.O>[CH2:1]([C:3]1([CH2:18][C:19]2[N:20]=[CH:21][NH:22][C:23]=2[CH3:24])[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:2]
Reactant: CCC1(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CCc2c(C)c3ccccc3n2C1=O
Solvent: O
Solvent: CC(=O)O
Product: CCC1(Cc2nc[nH]c2C)CCc2c(C)c3ccccc3n2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 7-ethyl-8,9-dihydro-10-methyl-7-[(5 -methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]-indol-6(7H)-one (0.45 g) in acetic acid (10 ml) and water (2.5 ml) was stirred at 60° C. for 2 hours. After evaporation of the solvent, the residue was diluted with ether (10 ml) and an aqueous solution of sodium hydrogencarbonate (10 ml). The resultant mixture was stirred for 30 minutes at ambient temperature. The insoluble material was collected, washed with water and ether, and dried to give crystalline 7-ethyl-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]-pyrido[1,2-a]indol-6(7H)-one (0.20 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([O:51]CC5C=CC(Cl)=C(Cl)C=5)[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CCOC(C)=O.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:26][CH:27]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(O)c1)CO3
Reaction time: 4 h
Yield: 88.5 %

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (250 mg) was dissolved in 6 mL of EtOAc:MeOH (1:5) and Pd—C(30 mg, 10% by wt.) was added and stirred under a hydrogen atmosphere (balloon) for 4 hours. Triethylamine (0.3 mL) was added to the reaction mixture and stirred for 5 minutes. The catalyst was filtered and washed with MeOH. The filtrate was evaporated, and the residue was taken up in EtOAc (10 mL) and washed with water and brine, and then dried (Na2SO4), filtered, and evaporated to get (3S,8S)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-3-(3-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino-[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (180 mg). LCMS (m/z): 695.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:14][CH2:15][C:16](Br)=[O:17]>ClCCl>[Br:14][CH2:15][C:16]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:9])[CH3:8])=[CH:2][CH:3]=1)=[O:17]
Reactant: O=C(Br)CBr
Reactant: CC(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)CBr)cc1
Temperature: -1 °C
Yield: 99.5 %

Procedure:
To a solution of cumene (42 g, 350 mmol) and aluminum chloride (56.0 g, 420 mmol) in dichloromethane (500 mL) was added bromoacetylbromide (33.5 mL, 385 mmol) at −40° C. for 40 minutes, and the mixture was stirred until it was warmed to −1° C. for 2 hours. The reaction solution was poured into ice-cold water to separate the organic layer. The organic layer was washed with a saturated sodium hydrogen carbonate solution and a saturated brine, and then was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 84 g (yield 99%) of the title compound. Oily matter.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br.C(OCC)(=O)C>CC(C)=O.CN(C)C=O>[CH3:27][O:28][C:29]([CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)=[O:32]
Reactant: O=[N+]([O-])c1cccc(-c2nc(O)cc3cccnc23)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)COc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
A suspension of 6-hydroxy-8-(3-nitrophenyl)-1,7-naphthyridine (107 mg, 0.40 mmol; produced according to the preceeding example, optionally without further purification), potassium carbonate (55 mg, 0.40 mmol) and bromoacetic acid methyl ester (37 μl, 0.4 mmol) is stirred for two hours in acetone-dimethylformamide (2 ml, 1:1) at ambient temperature. Ethyl acetate is added and the organic phase is washed with 2N NaOH. the solvent is removed in vacuo and the crude product is purified by preparative thin-layer chromatography to give the title compound. Mass M+H 340; mp 160-162° C.
Reaction SMILES: C1(=O)N([N:6]([C:11](=[O:22])[CH2:12][S:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][C:8]([O-:10])=O)C(=O)CC1.[NH2:25][C@@H:26]([C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[CH2:27][OH:28].CO>C(O)C.O>[C:14]([S:13][CH2:12][C:11]([NH:6][CH2:7][C:8]([NH:25][C@@H:26]([C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[CH2:27][OH:28])=[O:10])=[O:22])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@H](CO)C(=O)NCC(=O)O
Reactant: O=C([O-])CN(C(=O)CSC(=O)c1ccccc1)N1C(=O)CCC1=O
Solvent: CCO
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)[C@@H](CO)NC(=O)CNC(=O)CSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To a solution of 6.4 g succinimidyl-N-(S-benzoylmercaptoacetyl)glycinate in 40 ml of ethanol at ? 0° C. is added in one portion a solution of 1.008 g of the above D-serylglycine in 10 ml of water at 70° C. The reaction mixture is refluxed for i hour and then stirred at room temperature overnight. After evaporation of the solvents the residue is agitated with 25 ml of acetone. The precipitate is removed by filtration. Diethylether is added to the filtrate until precipitation is complete. The precipitate is collected by filtration and washed with diethylether. After drying 1.56 g of a yellowish powder is obtained. To 600 mg of this is added 15 ml of chilled methanol. After agitation during 5 min. the white precipitate is filtered off, washed with cold methanol and dried to obtain 400 mg of S-benzoylmercaptoacetylglycyl-D-serylglycine as a white powder, m.p. 149° C. N.M.R. (DMSO-d6):δ3.61 (2H, d, CH2 --OH), 3.77 (2H, d, α--CH2 --N), 3.84 (2H, d,β--CH2 --N), 3.88 (2H, s, S--CH2), 4.38 (1H, dr, CH), 8.03 (1H, d,β--NH), 8.17 (1H, t,α--NH), 8.44 (1H, t,γ--NH).
Reaction SMILES: COC([C:5]1[C:9](=[O:10])[O:8][CH2:7][C:6]=1O)=O.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][NH:20][CH3:21])=[CH:15][CH:14]=1.S([O-])(O)(=O)=O.[K+].O>C(#N)CCC.ClCCl>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][N:20]([CH3:21])[C:6]2[CH2:7][O:8][C:9](=[O:10])[CH:5]=2)=[CH:15][CH:14]=1
Reactant: CNCc1ccc(Cl)nc1
Reactant: COC(=O)C1=C(O)COC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCCC#N
Solvent: ClCCl
Product: CN(Cc1ccc(Cl)nc1)C1=CC(=O)OC1
Temperature: 115 °C
Reaction time: 5 h
Yield: 105 %

Procedure:
To a suspension of 18 g of 4-(methoxycarbonyl)-5-oxo-2,5-dihydrofuran-3-ol and 15 g of N-[(6-chloropyridin-3-yl)methyl]methylamine in 210 ml of butyronitrile are added, at room temperature, 16 g of potassium hydrogensulphate. The mixture is stirred at a temperature of 115° C. for 5 hours. Subsequently, the mixture is cooled to room temperature and admixed with 150 ml of water and 70 ml of dichloromethane. The organic phase is removed and the aqueous phase is extracted twice with 70 ml each time of methylene chloride. The combined organic phases are concentrated to dryness. 24 g of 4-[[(6-chloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one are obtained in a purity of 88% (this corresponds to 92% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[F:30][C:31]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:32]=1[CH2:33][O:34][C:35]1[C:36]2[N:37]([C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=2)[CH:38]=[CH:39][CH:40]=1.Cl.[NH2:54][CH2:55][CH:56]1[CH2:65][CH2:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[N:57]1[C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67]>CN(C=O)C.O>[F:30][C:31]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:32]=1[CH2:33][O:34][C:35]1[C:36]2[N:37]([C:41]([C:45]([NH:54][CH2:55][CH:56]3[CH2:65][CH2:64][C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[N:57]3[C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[O:46])=[C:42]([CH3:44])[N:43]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CCC1CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCC1CCc2ccccc2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
145 mg (0.45 mmol) of TBTU and 0.2 ml (1.89 mmol) of 4-methylmorpholine were added to 120 mg (0.38 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 3A in 2.4 ml of DMF, and the mixture was stirred at RT for 10 min. 124 mg (0.42 mmol) of rac-tert-butyl 2-(aminomethyl)-3,4-dihydroquinoline-1(2H)-carboxylate hydrochloride were added and the reaction mixture was stirred at RT overnight. Water was added, and the reaction mixture was stirred at RT for 30 min. The precipitated solid was filtered off, washed with water and dried under high vacuum. This gave 190 mg (90% of theory; purity 100%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:38])[N:33]([O])[C:32]([CH3:36])([CH3:35])[CH2:31][CH:30]([NH2:37])[CH2:29]1.C(=O)([O-])[O-:40].[Cs+].[Cs+]>CS(C)=O.O>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:37][CH:30]5[CH2:29][C:28]([CH3:38])([CH3:27])[N:33]([OH:40])[C:32]([CH3:36])([CH3:35])[CH2:31]5)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(N)CC(C)(C)N1[O]
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CC(Nc2ccc(S(=O)(=O)Oc3ccc4nc(NC(=O)C5CC5)sc4c3)cc2)CC(C)(C)N1O
Reaction time: 48 h
Yield: 14.6 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-(cyclopropanecarbonylamino)-benzothiazol-6-yl ester (example 7) (0.352 mmol, 138 mg), 4-amino-TEMPO (0.387 mmol, 66 mg) and cesium carbonate (0.352 mmol, 114 mg) in 3.5 ml of dimethylsulfoxide is stirred for 24 hours. 4-Amino-TEMPO is added twice (2 times 66 mg) after 24 and 48 hours. After 48 hours, the reaction is placed at room temperature for 48 hours. The solution is then diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride solution and dried over sodium sulfate, and then evaporated to dryness, to give 258 mg of crude product. This product is purified by flash chromatography on a cartridge of 5 g of silica. The eluents used are, respectively, dichloromethane and then dichloromethane with 1% of 7M 0.01% ammoniacal methanol. 28 mg of 4-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-ylamino)benzenesulfonic acid 2-(cyclopropanecarbonylamino)benzothiazol-6-yl ester are obtained in a yield of 14%.