Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1.[O:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCCl.O.C(N(CC)CC)C>[CH3:28][N:2]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:6][CH2:5]1)[CH:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reactant: O=C1CCOCC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(C[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1)C1CCOCC1
Reaction time: 14 h

Procedure:
To a solution of benzyl trans-4-aminomethylcyclohexylcarbamate hydrochloride (11.56 g), tetrahydro-4H-pyran-4-one (3.85 g), triethylamine (8 ml) and 1,8-diazabicyco[5,4,0]-7-undecene (5.85 g) in 1,2-dichloroethane (100 ml) was added at room temperature sodium triacetoxyborohydride (8.96 g), and the resulting mixture was stirred for 14 hours. To the reaction mixture were added 37% formalin (3.43 g) and sodium triacetoxyborohydride, and the resulting mixture was stirred further for 7 hours. The reaction mixture was mixed with water and was extracted with dichloromethane. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethanol/ethyl acetate 1:4→1:2) to obtain benzyl trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylcarbamate (8.45 g) as colorless crystals.
Reaction SMILES: [Cl-].[Cl-].[Ca+2:3].[C:4](=[O:6])=[O:5].[OH2:7]>>[C:4]([O-:7])([O-:6])=[O:5].[Ca+2:3].[C:4](=[O:7])([OH:6])[O-:5]
Reactant: O
Reactant: O=C=O
Agent: [Ca+2]
Agent: [Cl-]
Product: O=C([O-])O
Product: O=C([O-])[O-]

Procedure:
Five moles of CaCl2 in 125 ml of deionized water was dissolved at room temperature. Three moles of Na2HPO4 were dissolved in 125 ml of deionized water and the two solutions were slowly mixed using a magnetic stirrer. Lanthanide chloride (1-5 wt % of the weighed amounts of the 3 molar parts of Na2HPO4 and 5 molar parts of CaCl2) was added into the solution. In FIG. 10, the shaded area indicates the preferred regime of pH control for close to ±0.1 volt. At higher pH there is a risk of the formation of Ca(OH)2 which with prolonged CO2 exposure will form CaCO3 via bicarbonate. The lanthanide-containing solution was hydrothermally treated in a steel pressure vessel for times ranging from a few hours to a few days at a temperature between room temperature and 200° C. At low temperatures the growth of particles was slow and more rounded than at high temperatures (see FIGS. 11a to 11c). The needles (several micrometers) grown for longer than 12 hours at 200° C. are coarser than those grown at 80° C. for the same time. Average needles sizes were found to be less than 1 micrometer below 80° C. for a 12 hour experiment. Long and fat needles shown in FIGS. 11a-11c are less preferable than the finer more spherical needles. The nHAp-containing mineral composition shown in FIG. 11b is ideal for filling tubules and resurfacing enamel.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH2:25][CH2:24]3)=[O:22])[O:18][C:17]2=[O:38])=[CH:12][CH:11]=1)=O)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([C:21]([N:23]3[CH2:24][CH2:25][CH:26]([O:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:27][CH2:28]3)=[O:22])[O:18][C:17]2=[O:38])=[CH:12][CH:11]=1.[F:39][C:40]([F:45])([F:44])[C:41]([O-:43])=[O:42]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)C2CN(c3ccc(CNC(=O)OC(C)(C)C)cc3)C(=O)O2)CC1
Product: NCc1ccc(N2CC(C(=O)N3CCC(OCC(=O)O)CC3)OC2=O)cc1
Product: O=C([O-])C(F)(F)F

Procedure:
0.53 g of tert-butyl 2-{1-[3-(4-tert-butoxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperidyloxy}acetate is stirred in 10 ml of trifluoroacetic acid at room temperature. After customary workup, the crude product is triturated with ether and dried. 2-{1-[3-(4-aminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperidyloxy}acetic acid, trifluoroacetate, is obtained, FAB (M+1): 378.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C=O)C.C(Cl)(=O)C([Cl:21])=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:21])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and this solution was-cooled to 0° C. DMF (0.5 mL, catalytic) was added followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction was stirred for 3 h and then rotoevaporated at reduced pressure to give an oil which was placed on a high vacuum pump for 1 h to afford 3,5-difluorophenylacetyl chloride as a thin yellow oil. Other acid chlorides can be prepared in a similar manner.
Reaction SMILES: BrCC1C=CC=C(C(F)(F)F)C=1CBr.N[C@H]([C:20](O)=[O:21])C(C)C.FC(F)(F)[C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][N:28]([CH:34]([CH:38]([CH3:40])[CH3:39])[C:35]([OH:37])=[O:36])[CH2:29]2.S(O[CH:48](C#N)[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([O:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:50]=1)(=O)(=O)C>>[CH3:20][O:21][C:32]1[CH:31]=[C:30]2[C:26](=[CH:25][CH:33]=1)[CH2:27][N:28]([CH:34]([CH:38]([CH3:39])[CH3:40])[C:35]([O:37][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([O:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH:50]=1)=[O:36])[CH2:29]2
Reactant: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)C(C(=O)O)N1Cc2cccc(C(F)(F)F)c2C1
Agent: FC(F)(F)c1cccc(CBr)c1CBr
Product: COc1ccc2c(c1)CN(C(C(=O)OCc1cccc(Oc3ccccc3)c1)C(C)C)C2

Procedure:
The α-cyano-m-phenoxybenzyl esters of the above are prepared using the procedure of Example 10 by reacting, e.g. 1,2-bis(bromomethyl)-3-trifluoromethylbenzene with valine to prepare 2-(4-trifluoromethyl-2-isoindolinyl)-3-methylbutanoic acid and esterifying using α-cyano-m-phenoxybenzyl mesylate.
Reaction SMILES: C(OC([NH:8][C:9]([NH:25]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[ClH:33].[CH3:24][O:23][C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:25])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cccnc1-c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methoxypyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-methoxypyridin-2-yl)phenylguanidine dihydrochloride (135 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:8](=[O:10])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH2:27][CH2:26]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H](NC(=O)c2cccc(Br)n2)CC1
Temperature: 50 °C

Procedure:
A solution of 6-bromopicolinic acid acid (3 g, 14.85 mmol), and 1,1′-carbonyldiimidazole (2.41 g, 14.85 mmol) in dimethylformamide (30 mL) was heated at 50° C. for 2 hours. After this time, trans-4-methylcyclohexylamine hydrochloride (2.2 g, 14.85 mmol), and N,N-diisopropylethylamine (3.88 mL, 22.3 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with ethyl acetate (300 mL). The organic solution was washed with water (4×300 mL). The aqueous extracts were washed with ethyl acetate (2×250 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated. Chromatography of the crude product through a Biotage silica cartridge (15×4 cm i.d.) using ethyl acetate-hexane (1:3, containing 1% diethylamine) afforded 3.84 g (87%) of 409:
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][OH:19])([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:20])[CH:3]=1.[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29]S(C2C=CC(C)=CC=2)(=O)=O)=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1.CCN(CC)CC>C(#N)C>[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29][C:3]2[C:4](=[O:20])[O:5][C:6]([CH2:11][CH2:12][C:13]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:18][OH:19])([CH:8]([CH3:9])[CH3:10])[CH2:7][C:2]=2[OH:1])=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2ccsc2CO)CC(O)=CC(=O)O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(SC2=C(O)CC(CCc3ccsc3CO)(C(C)C)OC2=O)c(C(C)(C)C)cc1N

Procedure:
The title compound was prepared as described in General Method 16b using 4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-24; 1 mmol), toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methyl-phenyl)ester (Example BB-11; 1.05 mmol), NEt3 (2.2 mmol) in acetonitrile (5 mL). The product was triturated from Et2O, mp 107-115° C. MS (APCI): 488 (M−H).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:10]>CN(C=O)C>[C:2]1([C:1]2[S:8][C:3]3[CH2:4][NH:10][CH2:6][CH2:7][C:2]=3[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccccc1
Reactant: N
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3c(s2)CNCC3)cc1
Reaction time: 6 h

Procedure:
4.5 g of the product of step a) are charged to a round-bottomed flask with 34 ml of DMF and 2.6 g of thiobenzamide. Heating is carried out at a temperature of 60° C. for 6 hours. An aqueous ammonia solution is added until a basic pH is obtained and evaporation is carried out under vacuum.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:23]([O-:25])=[O:24])=[C:11]([NH:15][S:16]([C:19]([F:20])([F:21])[F:22])(=[O:18])=[O:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1cccc(Oc2ccc(Cl)nn2)c1)C(F)(F)F
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)nn2)cc1NS(=O)(=O)C(F)(F)F
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
15 g of 1 was added in portions to 200 ml of chilled (4°-5° C.), stirred 90% nitric acid, and the mixture was stirred at 4° C. for 30 minutes. The resulting mixture was poured into ice water and the resulting solid was filtered. The filter cake was washed with water and purified by silica gel column chromatography, using as eluent a 66:30:4 (v:v:v) mixture of hexane, ethyl acetate and tetrahydrofuran, to give 2, as an amber glassy solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH:17]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[C:16]3[C:27]([CH3:33])=[CH:28][C:29]([CH3:32])=[C:30]([CH3:31])[C:15]=3[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:34]C(OC(Cl)C)=O>O1CCCC1>[ClH:34].[CH:24]([C:21]1[CH:22]=[CH:23][C:18]([CH:17]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:14][C:15]3[C:30]([CH3:31])=[C:29]([CH3:32])[CH:28]=[C:27]([CH3:33])[C:16]2=3)=[CH:19][CH:20]=1)([CH3:26])[CH3:25]
Reactant: Cc1cc(C)c2c(c1C)OC1(CCN(Cc3ccccc3)CC1)C2c1ccc(C(C)C)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(c1C)OC1(CCNCC1)C2c1ccc(C(C)C)cc1
Product: Cl
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution of 1′-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine] (10.26 g, 23.34 mmol) in tetrahydrofuran (100 ml) was added a-chloroethyl chloroformate (3.76 g, 26.60 mmol) and the resulting mixture was refluxed with heating for 1 hour. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. Methanol (80 ml) was added into the resulting residue and the mixture was refluxed for 1 hour. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was crystallized from ethanol to obtain 7.32 g (81% yield) of the title compound. Melting point: >260° C. (decomposed).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[NH:12][CH3:13])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:50]1[CH2:55][CH2:54][CH2:53][C@@H:52]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[CH2:51]1>CN(C)C=O.C(Cl)Cl>[C:59]([O:58][C:57](=[O:63])[NH:56][C@@H:52]1[CH2:53][CH2:54][CH2:55][N:50]([C:6](=[O:8])[C:5]2[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([NH:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:51]1)([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CNc1c(OC)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNc1c(OC)cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 3-methoxy-4-(methylamino)-5-nitrobenzoic acid (11.09 g, 49.0 mmol) and HATU (18.64 g, 49.0 mmol) in N,N-dimethylformamide (DMF) (300 mL) was added DIPEA (17.13 mL, 98 mmol) and the mixture stirred for 30 mins. Upon addition of the DIPEA the mixture went cloudy after ˜1 min with stirring. (R)-tert-Butyl piperidin-3-ylcarbamate (9.82 g, 49.0 mmol) was then added and stirred for 1.5 hr, after which time LCMS showed the reaction was complete. To 5 mL of the reaction mixture was added sat.aq. LiCl solution (5 mL) and Et2O (10 mL) and the layers separated. The aqueous layer was re-extracted with Et2O (2×10 mL), the combined organics were backwashed with water (10 mL), dried with Na2SO4, filtered and concentrated in vacuo to give the crude product as an orange gum. The gum was dissolved in the minimum amount of DCM and purified by Si SNAP 25 g column using a 50-100% ethyl acetate/cyclohexane. The appropriate fractions were combined and evaporated in vacuo before being azeotroped with cyclohexane and dried under vacuum to give the required product, 281 mg as an orange solid. The remaining reaction mixture was concentrated in vacuo to remove some of the DMF. Saturated aq.LiCl solution (300 mL) and Et2O (700 mL) were added and the mixture separated. The aqueous layer was re-extracted with Et2O (2×700 mL), the combined organic layers were backwashed with water (1 L), dried with Na2SO4, filtered and concentrated in vacuo to give the crude product as an orange gum. This was purified on a 340 g SNAP silica cartridge eluting with 30%-60% ethyl acetate in cyclohexane. Appropriate fractions were combined and concentrated in vacuo to yield the title compound as an orange solid (19.4 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])N=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.[C:21]([O-])([O-])=O.[K+].[K+].CO[CH2:29][CH2:30]OC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:29]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:21]=2)[N:10]=[CH:9][CH:8]=1)=[CH2:30]
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: COCCOC
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Product: C=Cc1ccnc2ccc(OC)cc12
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 6-(methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate (5.0 g, 16.23 mmol) in DME (80 mL) and H2O (40 mL) was added trivinyl boronate (1.96 g, 8.1 mmol), K2CO3 (2.23 g, 16.23 mmol) and Pd(PPh3)4 (0.19 g, 0.16 mmol). After 3 h at 90° C. under N2, the reaction solution was concentrated under vacuum and purified on silica (hexane/EtOAc, 4:1) to give the title compound as a yellow oil (2.44 g, 81%): LC/MS (m/z) (ES) 186 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[C:8]([Br:11])[C:7]([Br:12])=[C:6]([Br:13])[C:5]=1[Br:14].C1([O-])C=CC=CC=1.[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>COCCO>[Br:3][C:4]1[C:9]([O:10][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[CH2:23][Cl:22])=[C:8]([Br:11])[C:7]([Br:12])=[C:6]([Br:13])[C:5]=1[Br:14]
Reactant: O=C(Cl)c1ccccc1CCl
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Agent: [Na+]
Agent: [O-]c1ccccc1
Agent: [OH-]
Solvent: COCCO
Product: O=C(Oc1c(Br)c(Br)c(Br)c(Br)c1Br)c1ccccc1CCl
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
In a 500-ml three-necked flask, 4 g (= 0.1 mole) of sodium hydroxide was dissolved at 60° C in 270 ml of methyl glycol, and 48.9 g of pentabromophenol was stirred in for the preparation of a phenolate solution, as in Example 8c. At 30° to 34° C, 18.9 g (- 0.1 mole) of o-chloromethylbenzoyl chloride was added drop by drop, with stirring, over a period of about 40 minutes, whereupon a white, crystalline preciptate settled out, which after 1 hour was suction filtered. After the product had been stirred up in water, suction filtered, washed and dried, 58 g (= 90.5%) of o-chloromethylbenzoic acid pentabromophenyl ester was obtained, which melted at 201°-205° C.
Reaction SMILES: O[C@H:2]([CH:22]([CH3:24])[CH3:23])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].O[C@@H](C(C)C)[C@@H](NC(OCCCCCC1C=CC=CC=1)=O)C(O)=O.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@@H:2]2[CH:22]([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CC(C)[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-4-methyl-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid and (2R*,3S*)-3-hydroxy-4-methyl-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid (0.076 g, 0.24 mmol) in dry CH2Cl2 (10.0 mL), at 0° C., Et3N (0.2 mL, 1.44 mmol) and subsequently TBTU (0.091 g, 0.28 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 100:0 to 80:20) to afford the pure title compound (0.041 g, 56%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 337 [M−NH4]+; (ESI) m/z: 318 [M−H]−. 1H NMR (DMSO-d6) δ 0.87 (d, J=6.75 Hz, 3H), 0.95 (d, J=6.55 Hz, 3H), 1.27-1.43 (m, 2H), 1.49-1.69 (m, 4H), 1.87-2.08 (m, 1H), 2.57 (t, J=7.67 Hz, 2H), 3.99 (t, J=6.59 Hz, 2H), 4.22 (dd, J=4.39, 9.13 Hz, 1H), 4.73 (dd, J=4.40, 8.18 Hz, 1H), 7.10-7.35 (m, 5H), 8.06 (d, J=8.16 Hz, 1H).
Reaction SMILES: [N:1]1(C(C2C=C(NC3(O)C(C(=N)NC(C)CO)=CSN3)C=CC=2)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1([C:41]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]3[S:54][N:53]=[C:52]([OH:55])[C:51]=3[C:56]#[N:57])=[CH:45][CH:44]=2)=[O:42])C2C(=CC=CC=2)CC1.[NH2:58][CH:59]([CH3:62])[CH2:60][OH:61]>CCO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:41]([C:43]2[CH:44]=[CH:45][C:46]([NH:49][C:50]3[S:54][N:53]=[C:52]([OH:55])[C:51]=3[C:56]([NH:58][CH:59]([CH3:62])[CH2:60][OH:61])=[NH:57])=[CH:47][CH:48]=2)=[O:42])[CH2:2]1
Reactant: N#Cc1c(O)nsc1Nc1ccc(C(=O)N2CCc3ccccc32)cc1
Reactant: CC(N)CO
Reactant: CC(CO)NC(=N)C1=CSNC1(O)Nc1cccc(C(=O)n2ccc3ccccc32)c1
Solvent: CCO
Product: CC(CO)NC(=N)c1c(O)nsc1Nc1ccc(C(=O)C2CNc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
5-[3-(3-(1H-indole-1-carbonyl)phenylamino]-3-hydroxy-N-(1-hydroxypropan-2-yl)isothiazole-4-carboximidamide 6: 5-[3-(3-(1H-indole-1-carbonyl)phenylamino]-3-hydroxyisothaizole-4-carbonitrile 5: (0.362 gm, 1 mmol) was taken into anhydrous EtOH (10 ml) and to this 2-amino-propan-1-ol (0.375 gm, 5 mmol) was added. The reaction mixture was stirred at 80° C. for 16 h., then concentrated to dryness and purified by column chromatography to provide 5-[4-(2,3-dihydro-indole-1-carbonyl)-phenylamino]-3-hydroxy-N-(2-hydroxy-1-methyl-ethyl)-isothiazole-4-carboxamidine 6.
Reaction SMILES: [OH:1][C@H:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][N:7]3[C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Mn]([O-])(=O)(=O)=[O:25].[K+]>C(Cl)(Cl)Cl>[CH:17]([C:13]1[N:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:12])[C@H:2]([OH:1])[C@@H:3]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:4][C:5]=3[C:6]2=[N:15][C:14]=1[CH3:16])=[O:25]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2c3c(ccn2c1C=O)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Temperature: 25 °C
Reaction time: 960 h
Yield: 6.7 %

Procedure:
(8R,9R)-8-hydroxy-2,3-dimethyl-7-oxo-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine (1 g) is dissolved in 20 ml of dried chloroform, and 5 g of potassium permanganate was added. After stirring the reaction mixture at room temperature for 40 days, the solids are filtered off. The filtrate is chromatographed twice on silica gel (eluents: dichloromethane/methanol 13/1) to give 0.07 g of the title compound as a semisolid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)([O-:5])=[O:4].O.[ClH:15].CC[O:18][CH2:19][CH3:20]>CS(C)=O.CCOCC>[ClH:15].[Cl:15][C:8]1[CH:7]=[CH:6][N:3]=[CH:20][C:19]=1[O:18][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(COc2cnccc2Cl)cc1

Procedure:
The starting material was prepared by reaction of 4-nitro-3-hydroxy pyridine-N-oxide with acetyl chloride under reflux for 1 hour. The crude product was purified by rapid chromatography on silica gel using CH2Cl2 /MeOH 7:3 v/v as eluant to give 4-chloro-3-hydroxypyridine-N-oxide. Reduction of this compound with Raney nickel and hydrogen at ambient temperature for 2 hours in MeOH gave 4-chloro-3-hydroxypyridine. This compound was reacted with NaH in DMSO at 50°, the reaction mixture cooled and treated with 4-nitrobenzyl bromide for 1 hour. The reaction mixture was worked up with water and ether and the product treated with HCl/ether to give 4-chloro-3-(4-nitrobenzyloxy)pyridine hydrochloride. Reaction of the free base with excess methyl iodide at ambient temperature for 24 hours gave 4-chloro-1-methyl-3-(4-nitrobenzyloxy)pyridinium iodide. n.m.r. in d6DMSO: 4.35(s, 3H); 5.6(s, 2H); 7.7(d, 2H); 8.3(d, 2H); 8.4(d, 1 H); 8.7(d, 1H); 9.15(s, 1H).