Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10].[NH2:25][OH:26].[OH-].[K+].CO>C1COCC1>[OH:26][NH:25][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: COC(=O)CCCCCS(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCCCCS(=O)c1ccc(-c2ccc(Cl)cc2)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of the 6-(4′-chloro-biphenyl-4sulfinyl)-hexanoic acid methyl ester (400 mg, 1.1 mmol) in distilled THF (10 mL) containing 50% aqueous hydroxylamine (0.65 mL, 9.9 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1.9 mL, 1M, 1.9 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (10 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×20 mL) and the combined extracts were washed with brine (40 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (315 mg, 79%) as a white powder, mp 108-110° C.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([NH2:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CO>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C@@H:2]1[CH2:8][CH2:9][CH2:10][N:30]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:7]
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(=O)C(Br)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCCCCN1CCC[C@H]1C(=O)OCC

Procedure:
In 150 ml of ethanol was dissolved 22.8 g of ethyl 2,5-dibromovalerate, and 15 g of potassium carbonate was suspended in the solution. To the suspension was added dropwise a methanolic solution of 18.5 g of laurylamine under ice-cooling. After the addition, the reaction mixture was allowed by react at a refluxing temperature of methanol for 5 hours to obtain N-dodecylproline ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[CH:19][C:18]([F:30])=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([F:16])=[C:9]([NH:11][S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=1.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:30][C:18]1[CH:17]=[C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([F:16])=[C:9]([NH:11][S:12](=[O:14])(=[O:15])[NH2:13])[CH:10]=2)[C:2]([NH:1][S:34]([CH:31]2[CH2:33][CH2:32]2)(=[O:36])=[O:35])=[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[CH:19]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1ccc(F)c(NS(N)(=O)=O)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: NS(=O)(=O)Nc1cc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)ccc1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 6.2 %

Procedure:
547 mg crude N-(5-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}-2-fluorophenyl)sulfuric diamide (Intermediate 14.A) (0.993 mmol, 1. eq.) was dissolved in 8.5 mL pyridine, cooled to 0° C. and treated with 140 mg cyclopropanesulfonyl chloride (0.993 mmol, 1 eq.). The reaction mixture was stirred at rt for 18 h. Another 70 mg of cyclopropanesulfonyl chloride (0.497 mmol, 0.5 eq.) were added and stirring was continued for 24 h. The reaction mixture diluted with toluene and concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the aqueouse layer reextracted twice with ethyl acetate. The combined organic layers were washed once with half saturated brine and once with brine, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (n-hexane/ethyl acetate gradient) providing 40 mg of the desired product (6% yield).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:19]Br.[CH2:22]([O:24][CH2:25][CH2:26][NH2:27])[CH3:23].C(N(CC)CC)C>C(O)C>[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[CH2:19][C:5]2[C:4](=[CH:9][CH:8]=[C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[CH:6]=2)[C:3]1=[O:21])[CH3:23]
Reactant: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1CBr
Reactant: CCOCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOCCN1Cc2cc(Oc3ccc(O)cc3)ccc2C1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-Bromomethyl-4-(4-methoxy-phenoxy)-benzoic acid methyl ester (0.2 grams, 0.57 mmol) and 3 mL of ethanol was added ethoxyethylamine (0.073 mL, 0.062 grams, 0.70 mmol) and triethylamine (0.098 mL, 0.071 grams, 0.7 mmol). After shaking for 4 hours at 50° C., the mixture was cooled to room temperature and concentrated under a stream of nitrogen. The residue was treated with methanesulfonic acid (3 mL) and methionine (0.13 grams). The mixture was shaken for 24 hours at room temperature and was then heated to 50° C. for 6 hours. After cooling to room temperature, the mixture was poured into aqueous 5 M sodium hydroxide with cooling in an ice bath, and the pH was adjusted to 8 with aqueous sodium bicarbonate. The aqueous phase was extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by radial chromatography (2 mm silica gel plate) eluting with 3% methanol-methylene chloride afforded 30 miligrams of 2-(2-Ethoxy-ethyl)-5-(4-hydroxy-phenoxy)-2,3-dihydro-isoindol-1-one as a colorless syrup. MS: 314.3 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][C:8](=O)[C:7]=2[CH:15]=1.Cl.[NH2:19][CH2:20]C(OC)=O.CC(O)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:20][NH:19][C:8](=[O:9])[C:7]=2[CH:15]=1
Reactant: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Reactant: COC(=O)CN
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)N(C)C(=O)CNC2=O
Temperature: 130 °C
Yield: 71 %

Procedure:
Heat under reflux for 6 hours a mixture of 320 mg (1.35 mmol) of 6,7-dimethoxy-1-methyl-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (XVI), 452 mg (3.24 mmol) of methyl glycinate hydrochloride in 4 ml of pyridine. Add 3 ml of AcOH and heat at 130° C. for 12 hours. Evaporate to dryness. Add 10 ml of a water-ice mixture. Allow to crystallize at 0° C. for 30 minutes. Filter and wash twice with 2 ml of H2O, twice with 1 ml of EtOH and twice with 5 ml of Et2O. Recrystallize in EtOH. One obtains 240 mg of the abovenamed product in the form of colorless crystals. Yield: 71%. M: 260–263° C. 1H-NMR (CDCl3, 300 MHz): d 3.42 (s, 3H, NCH3), 3.75–3.92 (m, 2H, CH2), 3.98 (s, 6H, 2×OCH3), 6.39 (s, 1H exchangeable, NH), 6.69 (s, 1H Ar), 7.37 (s, 1H Ar).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:15]([O:18][C@@H:19]([CH3:23])[C:20](Cl)=[O:21])(=[O:17])[CH3:16]>CN(C)C(=O)C.C(OCC)(=O)C>[C:15]([O:18][C@@H:19]([CH3:23])[C:20]([NH:14][NH:13][C:11]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH:3]=[C:2]([Br:1])[C:6]=2[CH:7]=1)=[O:12])=[O:21])(=[O:17])[CH3:16]
Reactant: NNC(=O)c1ccc2occ(Br)c2c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)O[C@@H](C)C(=O)NNC(=O)c1ccc2occ(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a solution of 3-bromo-1-benzofuran-5-carbohydrazide (2.64 g, 10.35 mmol) in N,N-dimethylacetamide (10 mL) was added dropwise (1S)-2-chloro-1-methyl-2-oxoethyl acetate (1.44 mL, 11.38 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (3.41 g, yield 89%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.O>CN(C)C=O>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[CH2:14][C:10]1[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(O)c(Cc2nc3ccccc3s2)c1
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
855.5 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 2.83 g of 4-nitrophenol in 30 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 5 minutes, after which a solution of 4.88 g of 2-bromomethylbenzothiazole in 25 ml of dimethylformamide was added thereto. The temperature of the resulting mixture was elevated to room temperature, and the mixture was then stirred at this temperature for 4 hours. At the end of this time the reaction mixture was cooled in an ice-water bath and 100 ml of water was added to said reaction mixture resulting in the precipitation of a crystalline solid which was filtered off, washed with water and then further washed with hexane. The resulting crude crystalline solid was purified by column chromatography through silica gel using a 10:1 by volume mixture of hexane and ethyl acetate, to give 4.99 g (yield 86%) of the title compound having a melting point of 189° to 191° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[NH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)=[O:46])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:50])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C1CNCCN1
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)N2CCNCC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine, respectively.
Reaction SMILES: ClC1C(O[C:9](=[O:16])[C@@H:10]2[CH2:14][CH2:13][C:12](=[O:15])[NH:11]2)=C(Cl)C(Cl)=C(Cl)C=1Cl.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH2:21]([NH:25][C:9](=[O:16])[C@@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11]1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C1CC[C@@H](C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)N1
Reactant: CCCCN
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@@H]1CCC(=O)N1

Procedure:
7.5 g (20 mmols) of L-pyroglutamic acid pentachlorophenyl ester and 1.75 g (2.4 mmols) of n-butyl amine were stirred in 100 ml of tetrahydrofurane for 5 hours. The solvent was distilled off. The residue was dissolved in methanol and treatment with strongly basic and then with strongly acidic ion exchangers followed. After filtration, methanol was distilled off. The oily residue was dissolved and precipitated with petroleum ether. After a prolonged period of time, the product, which has precipitated in oily form, became solid. It was filtered off, washed with petroleum ether and dried under vacuum.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:12]=[CH:11][C:10]=1[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=O)(C)(C)C.[ClH:35]>O1CCOCC1.C(OCC)C>[ClH:35].[NH2:8][C:9]1[C:10]([C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])=[CH:11][CH:12]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(NC2CCCN(C(=O)OC(C)(C)C)C2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
670 mg (1.37 mmol) of tert-butyl 3-({6-[(tert-butoxycarbonyl)amino]-5-(trifluoroacetyl)pyridin-2-yl}amino)piperidine-1-carboxylate (Example 12A) were dissolved in 25 ml of a hydrochloric acid solution in dioxane (4 M) and stirred at RT for 20 h. On completion of reaction, the reaction mixture was diluted with diethyl ether (100 ml), and the precipitate was filtered off completely and washed with diethyl ether (100 ml) and dried. 286 mg (64% of theory) of the product were obtained in solid form.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]4[CH:17]([C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:1][C:2]1[C:10]2[N:9]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:8]3[CH2:11][CH2:12][N:13]4[CH:17]([C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1)[CH2:16][CH2:15][CH2:14]4
Reactant: Cc1cc(C)c2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(c1)c1c(n2CC(O)c2ccncc2)CCN2CCCC12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
8,10-Dimethyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (700 mg, 2.92 mmol) in DMF (20 mL) was stirred at 0° C. for 5 min. NaH (580 mg, 14.60 mmol) was added slowly at 0° C. After 10 min. stirring, 4-(oxiran-2-yl)pyridine (710 mg, 5.87 mmol) was added and the reaction mixture was stirred at RT for 15 h. The reaction mixture was poured in ice-cold water (150 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was washed with water (6×300 mL), dried over anhydrous sodium sulfate and concentrated to obtain semi-solid residue that was washed with hexane (3×20 mL). The residue was suspended in ether (30 mL) stirred for 1 h. The suspension was filtered to give 200 mg of 2-(8,10-dimethyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.79 (d, 2H), 8.03 (d, 2H), 7.13 (s, 1H), 6.82 (s, 1H), 5.22 (dd, 1H),5.01 (t, 1H), 4.67 (dd, 1H), 4.48 (dd, 1H), 4.79 (m, 1H), 3.64 (t, 2H), 3.4 (m, 3H), 2.9 (m, 1H), 2.73 (s, 3H), 2.37 (s, 3H), 2.22 (m, 3H). Separation by chiral HPLC provided diastereomers II-125a-b.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=2[O:2]1.[H-].[Na+].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]I)[CH3:17]>CN(C)C=O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][CH:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[C:11](=[O:13])[CH3:12])[CH3:17]
Reactant: CC(=O)Cc1ccc2c(c1)OCO2
Reactant: CCOC(CI)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CC(C(C)=O)c1ccc2c(c1)OCO2)OCC
Yield: 94.7 %

Procedure:
To 11.7 g of 3,4-methylenedioxyphenylacetone in 100 ml of dimethylformamide, 2.76 g of 60% oily sodium hydride was added under cooling with ice with stirring, and after stirring at the same temperature for 30 minutes, 20.9 g of iodoacetaldehyde diethyl acetal in 20 ml of dimethylformamide was added. The reaction solution was stirred at room temperature for 2 hours and partitioned between water and ethyl ether. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=15/1→10/1] to give 18.3 g of the title compound.
Reaction SMILES: Cl.[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[C:3]([NH2:5])=[NH:4].Cl.Cl.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH:28](O)[OH:29].C(O)(=O)CCCC(O)=O.Cl.Cl.Cl.NCCCC(N)CCCNC(=O)C(NC(=O)CCCCCCNC(N)=N)O>O>[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH:28]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[OH:29]
Reactant: N=C(N)NCCCCCCC(N)=O
Reactant: NCCCNCCCCNC(=O)C(O)O
Agent: Cl
Agent: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCC(N)CCCN
Agent: O=C(O)CCCC(=O)O
Solvent: O
Product: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCCNCCCN
Temperature: 60 °C
Yield: 50.5 %

Procedure:
A mixture of 360 mg (1.62 mmoles) of 7-guanidinoheptanamide hydrochloride, 568 mg (1.94 mmoles) of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide dihydrochloride, 214 mg (1.62 mmoles) of glutaric acid and 0.36 ml of water was heated at 60° C. for 24 hours. After completion of the reaction, 5 ml of water was added to the reaction mixture and the resulting mixture was purified in a manner similar to that in Example 1, using CM-Sephadex® C-25 (Na-type) and Sephadex® LH-20 to obtain 317 mg (39% yield) of a white powder of N-[4-(3-aminopropyl)-aminobutyl]-2-(7-guanidinoheptanamido)-2-hydroxyethanamide trihydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:25])[CH2:23]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC(=O)c2ccccc2-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
4-Hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.721 g) in dimethylformamide (8 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 30 minutes and then 1-[1,1'-biphenyl]-2-yl-2-bromoethanone (1.1 g) in dimethylformamide (4 mL). The mixture was stirred at room temperature overnight and worked up as in Example 20. The residual oil (1.5 g) was purified by flash chromatography over silica gel (dichloromethane) to afford of 0.62 g of 4-[2-[[1,1'-biphenyl]-2-yl]-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([NH2:9])=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Cl)cc1Oc1ccccc1
Yield: 143.8 %

Procedure:
2-Fluoro-4-chloro-nitrobenzene (0.50 g), phenol (0.27 g) and potassium carbonate (0.40 g) in dry DMSO (10 ml) were stirred at RT for 2 h. The mixture was diluted with water, extracted with diethylether, dried and evaporated under reduced pressure to give a yellow oil (0.90 g). The oil was dissolved in glacial acetic acid (20 ml) and treated with reduced iron powder (0.90 g). The mixture was vigorously stirred at RT for 2 h, filtered through celite, washed with DCM and the filtrate evaporated under reduced pressure, yield 0.9 g.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][N:27]=2)CC2C=CC(OC)=CC=2OC)(=[O:10])=[O:9])[CH:7]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([OH:49])=[C:36]([CH:38]2[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]2)[CH:37]=1.FC(F)(F)C(O)=O>ClCCl>[NH:40]1[CH2:41][CH:38]([C:36]2[CH:37]=[C:32]([Cl:31])[CH:33]=[CH:34][C:35]=2[O:49][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:23]3[S:24][C:25]([Cl:28])=[CH:26][N:27]=3)(=[O:9])=[O:10])=[C:5]([F:29])[CH:4]=2)[CH2:39]1
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncc(Cl)s1)c1cc(Cl)c(Oc2ccc(Cl)cc2C2CNC2)cc1F

Procedure:
5-Chloro-N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4-difluorobenzenesulfonamide (Preparation 655) and tert-butyl 3-(5-chloro-2-hydroxyphenyl)azetidine-1-carboxylate (Preparation 237) were stirred in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) to prepare the title compound using Method F above but where the N,N-dimethylformamide was replaced with dimethyl sulphoxide. The crude product was concentrated in vacuo and purified by preparative HPLC to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([N+:11]([O-])=O)=[CH:9][N:8]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5]2=[N:6][CH:7]=1.[In].Cl>O1CCCC1.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([NH2:11])=[CH:9][N:8]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: Cl
Agent: [In]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12

Procedure:
2-bromo-7-nitro-5-trityl-pyrrolo[2,3-b]pyrazine (5 g, 10.30 mmol) dissolved in tetrahydrofuran (200.0 mL)/water (50.00 mL) and indium (11.83 g, 103.0 mmol) then HCl (20.60 mL of 6 M, 123.6 mmol) added. Indium dissolves then precipitates out over 5 minutes. Reaction mixture is filtered through celite, washing with EtOAc. Filtrate basified by careful addition of NaHCO3. Emulsion forms and mixture is filtered again before layers separated. Aqueous is extracted with EtOAc. Combined organics dried and concentrated in vacuo to a black foam. Residue is taken up in DCM and purified by chromatography eluting with 0-50% EtOAc—petroleum ether). Product obtained as a green/brown foam. Dried on high vacuum and taken directly on to acylation reaction. (3.43 g, 73%). 1H NMR (400.0 MHz, DMSO) δ 8.46 (s, 1H), 8.40 (s, 1H), 7.38-7.36 (m, H), 7.23-7.20 (m, 8H) and 3.32 (s, 7H) ppm; MS (ES+) 457.0
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1Cl)=[O:5])C.Cl.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][NH2:26]>C1(C)C(C)=CC=CC=1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[C:4](=[O:5])[C:6]2=[N:7][NH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:15]2=[N:26]1
Reactant: CCOC(=O)c1nnc2c(c1Cl)CCCC2
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=c1c2n[nH]c3c(c-2nn1-c1ccccc1F)CCCC3
Yield: 42.3 %

Procedure:
4-Chloro-5,6,7,8-tetrahydrocinnoline-3-carboxylic acid ethyl ester (0.5 g), 2-fluorophenylhydrazine hydrochloride (0.34 g) and H{umlaut over (u)}nig's base (0.73 ml) in xylene were heated under reflux for 3 h. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography using a gradient elution: CH2Cl2 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 99:1 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 98:2 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 97:3 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 96:4 (500 ml), CH2Cl2(MeOH/NH3 10:1) 95:5 (500 ml). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (250 mg, 42%). δH (360 MHz; DMSO) 1.83 (4H, m, CH2), 2.61 (2H, t, J=5.3 Hz, CH2), 2.75 (2H, t, J=5.3 Hz, CH2), 7.30-7.57 (4H, m, ArH), m/z (ESP+) 285 (MH+). C15H13FN4O requires C, 63.37; H, 4.61; N, 19.71; found C, 63.18; H, 4.70; N, 19.35%.