Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:24][NH:25][CH3:26].C1COCC1>>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:25]([CH3:26])[CH3:24])=[CH:18][CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CO)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CN(C)C)cc1

Procedure:
The title compound was prepared according to the procedures of Example 45, using the alcohol of Example 49 as starting material and using 2.0 M dimethylamine in THF (0.15 mL, 0.30 mmol, Aldrich) in the displacement (8.0 mg, 49%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:27][NH:28][CH2:29][CH2:30][OH:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:28]([CH2:29][CH2:30][OH:31])[CH3:27])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CNCCO
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN(C)CCO)cc2C)ncn1
Reaction time: 15 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with 2-(methylamino)ethanol (Aldrich, 112.7 mg; 0.42 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 15 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([O-:5])=[O:4].I[CH3:16]>CN(C)C=O>[CH3:16][N:10]1[C:11]2[C:7](=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: CI
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c([N+](=O)[O-])cccc21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred suspension of sodium hydride (0.14 g; 3.41 mM) in dimethylformamide (10 ml) at 0° C. under nitrogen was added 4-nitroindole (0.5 g; 3.1 mM) in dimethylformamide. After stirring for 0.5 h, iodomethane (0.21 ml; 3.41 mM) in dimethylformamide (1 ml) was added, and stirring was continued for 1 h. The reaction mixture was then quenched with water, and poured onto excess water with stirring. Filtration afforded the title compound (0.5 g; 92%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](Br)[N:8]2[CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[C:4]([OH:19])[N:3]=1.[NH2:20]N>O.[Ni]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([NH2:20])[N:8]2[CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[C:4]([OH:19])[N:3]=1
Reactant: NN
Reactant: Nc1nc(O)c2nc(Br)n(COC(CO)CO)c2n1
Agent: [Ni]
Solvent: O
Product: Nc1nc(O)c2nc(N)n(COC(CO)CO)c2n1

Procedure:
A mixture of 2-[(2-amino-8-bromo-6-hydroxy-9H-purin-9-yl)methoxy]-1,3-propanediol (13.7 g; 41 mmole) and 97% hydrazine (6.07 ml) in water (300 ml) is heated to reflux for 48 hours. At the end of this time, the solution is cooled and filtered to give 9.15 g of crude solid. The crude product is suspended in water (120 ml) and Raney nickel (9 g) is added. The mixture is heated at reflux for 6 hours, filtered hot and cooled. The crystals are collected and dried to give 7.15 g of the product, mp>280° dec.
Reaction SMILES: Cl.[C:2](=[NH:7])([NH2:6])[CH2:3][CH2:4][CH3:5].C[O-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35])[C:27](OC)=[O:28])=[CH:21][CH:20]=1)#[N:12]>CO>[CH2:32]([C:31]1[N:7]=[C:2]([CH2:3][CH2:4][CH3:5])[NH:6][C:27](=[O:28])[C:26]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(CCC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 81.6 %

Procedure:
A solution of butanimidamide hydrochloride (3.5 g), 28% sodium methoxide (8.7 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (5.0 g) in methanol (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (4.5 g, 82%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[C:3]([O:5][N:6]=[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[CH2:13][C:14](O)=[O:15])=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C(Cl)Cl>[Cl:1][CH:2]([Cl:17])[C:3]([O:5][N:6]=[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[CH2:13][C:14]([Cl:19])=[O:15])=[O:4]
Reactant: O=C(O)CC1C=CC=CC1=NOC(=O)C(Cl)Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CC1C=CC=CC1=NOC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of 2-dichloroacetoxyiminophenylacetic acid (syn-isomer) (0.276 g) in methylene chloride (10 ml) was added phosphorus pentachloride (0.208 g) and the mixture was stirred for one hour at room temperature, during which time solution took place. After removal of solvent under reduced pressure, benzene was evaporated from the residue, and the resulting oil freed from solvent under vacuum, giving 2-dichloroacetoxyiminophenylacetyl chloride (syn-isomer) (0.29 g., 100%), νmax. (liquid film) 1770 cm.-1 (COCl and CO2R).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C>[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[O:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2[nH]c(=O)oc(=O)c2c1)(c1ccccc1)c1ccccc1
Yield: 57.7 %

Procedure:
6-Hydroxy-1H-benzo[d][1,3]oxazine-2,4-dione (9.7 g, 54 mmol), tert-butyldiphenylchlorosilane (15.2 mL, 59 mmol) and imidazole (4 g, 59 mmol) were stirred in DMF (100 mL) for 24 h at rt. The reaction mixture was extracted with ethyl acetate (400 mL) and water 300 mL). The product in the organic layer was purified by chromatography on silica gel in hexane/ethyl acetate 2:1 and then crystallized from hot ethyl acetate/hexane, affording white crystals (13 g, 58%), mp. 185° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2([F:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:11](I)=[CH:10][N:9]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>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.CC#N>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2([F:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:11]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CNc2cc(Cl)ncc2I)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cnc(Cl)cc2NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Yield: 48.1 %

Procedure:
MeCN (0.72 mL) and 0.5M aqueous sodium carbonate (0.24 mL, 1.5 eq.) were added to a mixture of tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (37 mg, 0.079 mmol), 4-methoxyphenylboronic acid (11.97 mg, 0.079 mmol), and tetrakis(triphenylphosphine)palladium(0) (4.55 mg, 3.94 μmol) in a 0.5 mL microwave reaction vial. The sealed vial was heated at 100° C. for 20 mins by microwave irradiation. The volatiles were removed in vacuo. The residue was dissolved in dichloromethane and loaded onto a 12+S Biotage silica column. Chromatography, eluting with a gradient of EtOAc in hexanes, gave tert-butyl 4-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (17 mg, 0.038 mmol, 48%) as a colourless solid.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[CH2:1]([N:7]([CH2:8][CH:9]1[O:10][CH2:11][CH2:12][O:13]1)[C:28](=[O:29])[CH2:27][Cl:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCN(CC1OCCO1)C(=O)CCl

Procedure:
N-n-Hexyl-N-(1,3-dioxolan-2-ylmethyl)amine (12.0 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5.0 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-n-hexyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][NH:28]1>C1COCC1>[OH:1][C:2]1[C:3]([C:12]([N:28]2[CH2:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:27]2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: c1ccc2c(c1)CNC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc2cccnc2c1O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (189 mg, 1.0 mmol) and di(1H-imidazol-1-yl)methanone (162.2 mg, 1.0 mmol) in THF (10 mL) was heated to reflux for 4 h, under nitrogen. The reaction mixture was allowed to cool to RT and isoindoline (95.3 mg, 0.80 mmol) was added. The resulting mixture was stirred at RT for 3 h and then left to stand at RT overnight. The reaction mixture was then quenched with H2O and an aqueous saturated solution of sodium hydrogen carbonate, and twice extracted with DCM. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by SPE-SI cartridge (2 g, DCM to DCM:MeOH 99:1) affording the title compound (123 mg, 0.42 mmol) as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[I:23]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[I:23]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC#N
Product: Nc1c(I)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
To a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (0.182 g) in acetonitrile (3 ml) at room temperature was added N-iodosuccinimide (0.113 g). After 20 minutes the mixture was evaporated to dryness and the residue taken up in dichloromethane (20 ml). After washing with water (20 ml, ×2), brine (20 ml) and drying (MgSO4) the solution was evaporated. The residue was triturated with hexane and the supernatant evaporated to give the title compound as an off-white solid, m.p. 126° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[NH2:17][C:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:3][CH2:2][NH:1][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: NCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCNC(=O)c1ccccc1
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A mixture of 1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.40 g, 1.76 mmol) and anhydrous pyridine (60 mL) was heated until a clear solution was obtained. The solution was then cooled with an ice bath. Benzoyl chloride (0.25 g, 1.76 mmol) was added. The reaction mixture was maintained at ambient temperature overnight and then concentrated under vacuum. The residue was slurried with water (200 mL) and a solid was isolated by filtration. This material was recrystallized from isopropyl alcohol to provide 0.15 g of N1-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]benzamide as a white powder, m.p. 295° C. 1H NMR (500 MHz, DMSO-d6) δ 8.50 (t, J=6.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.04 (s, 1H), 7.75(d, J=8.0 Hz, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0, 1H), 7.41 (t, J=8.0 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 6.28 (broad s, 2H), 4.80(t, J=7.0 Hz, 2H), 3.80(q, J=6.0 Hz, 2H); MS (EI) m/e 331.1429 (331.1433 calcd for C19H17N5O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][O:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9]2)=[CH:4][C:3]=1[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=1.[H-].[Na+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C.O>[CH2:50]([O:14][C@@H:13]1[C@@H:12]([O:15][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:11]([O:16][CH2:38][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C@@H:10]([CH2:17][O:18][C:19]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=2)[CH:4]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 178 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol (9.8 g, 15 mmole) in dry DMF (50 mL), sodium hydride (3.2 g 50% in oil, 67.8 mmole) was added at 0° C. and stirred at room temperature for 2 hours. Benzyl bromide (5.9 mL, 49.7 mmole), tetrabutylammoniuliodide (500 mg) added and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with water (500 mL) and extracted with DCM (2×500 mL). The crude product obtained after removal of solvent to furnish 12.3 g of (2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]2[NH:25][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)=[CH:22][CH:21]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(Cl)cc2)[nH]c1-c1ccncc1
Yield: 34.3 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (3.9 g) and 4-chlorobenzylamine (3.0 g) were dissolved in toluene (80 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give tert-butyl 2-(4-chlorophenyl)-5-(4-pyridyl)imidazole-4-carboxylate (1.9 g), melting point 206-207° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[OH-:28].[K+].Cl>O1CCOCC1.OO>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]([NH2:22])=[O:28])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: [OH-]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C#N)cc3[nH]c4ncc(C)cc4c23)c1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2cc(C(N)=O)cc3[nH]c4ncc(C)cc4c23)c1
Reaction time: 18 h
Yield: 47 %

Procedure:
Compound 126 (30 mg, 0.08 mmol) stirred in dioxane (2 mL) at r.t. A solution of potassium hydroxide (25 mg, 0.44 mmol) in 30% H2O2 solution (1 mL) was added, and the reaction stirred for 18 h. The solution was neutralized with 1N HCl and concentrated in vacuo. Purification by silica gel chromatography (5 to 8% MeOH/CH2Cl2 gave 14.8 mg (47%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 8.10 (d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=7.6 Hz), 7.88 (t, 1H, J=7.68 (s, 1H), 7.62 (s, 1H), 3.34 (q, 2H, J=7.2 Hz), 2.31 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C21H19N3O3S, 394; found 394.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([CH2:22][P:23]([O:29]C(C)C)([O:25]C(C)C)=[O:24])=[CH:12][CH:13]([NH:19]C=O)[C:14]([O:16]CC)=[O:15])=[O:5])[CH3:2].C[Si](C)(C)Br.C(O)C>C(Cl)Cl>[NH2:19][CH:13]([CH:12]=[C:11]([CH2:22][P:23]([OH:29])([OH:25])=[O:24])[CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)COCCCC(=CC(NC=O)C(=O)OCC)CP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)COCCCC(=CC(N)C(=O)O)CP(=O)(O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2.4 g (5 mmol) of ethyl 7-ethoxycarbonylmethoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate are dissolved in 24 ml of CH2Cl2. Then 2.6 ml (20 mmol) of trimethylbromosilane are added dropwise at room temperature to this solution. The reaction mixture is allowed to stand for 24 hours at room temperature and, after the dropwise addition of 24 ml of ethanol, allowed to stand again for 24 hours. The reaction mixture is concentrated by evaporation and the residue is dissolved in 24 ml of ethanol. A mixture of 24 ml of propylene oxide and 24 ml of ethanol is then added dropwise to this solution. The suspension so obtained is stirred for 1 hour at 0° C. and then filtered with suction. The filter product is dried, giving 2-amino-7-ethoxycarbonylmethoxy-4-phosphonomethyl-hept-3-enoic acid with a melting point of 215°-218° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>ClCCl>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:2][C:3]2[CH:7]=[C:6]([CH3:8])[O:5][N:4]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc(CBr)no1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: Cc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of 3-bromomethyl-5-methylisoxazole (0.102 g, 0.58 mmol) in dichloromethane (6 ml) was added 1-BOC-piperazine (0.240 g, 1.30 mmol). The reaction mixture was stirred at room temperature for 18 h under argon, then concentrated in vacuo. The resulting residue was absorbed on silica and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of ethyl acetate (30 to 70%) in petroleum ether (60-80° C.) afforded the title compound as a white solid (0.124 g, 76%). 1H-NMR (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.32 (t, J=5.1 Hz, 4H, piperazine N(CH2)2), 2.38 (s, 3H, isoxazole 5-CH3), 3.35 (br t, 4H, piperazine N(CH2)2), 3.50 (s, 2H, NCH2 isoxazole), 6.17 (s, 1H, isoxazole 4-H); LC (Method B)-MS (ESI, m/z): Rt=2.60 min—282 [(M+H)+, 5%], 226 [(M-tBu)+, 100%].
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(=O)C)=[C:19]([CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[OH-].[K+]>O1CCCC1.CO>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CC(=O)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
To a solution of acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2, 3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester (6.5 g, 14.3 mmol) in tetrahydrofuran (240 mL) and methanol (80 mL) at room temperature was added dropwise aqueous potassium hydroxide (17.2 mL of a 1N solution, 17.2 mmol). After 4 h at room temperature the reaction mixture was placed in the freezer for 18 h. The reaction was removed from the freezer and allowed to stir at room temperature. More aqueous potassium hydroxide (41.5 nL of a 1N solution, 41.5 mmol), tetrahydrofuran (50 mL), and methanol (10 mL) were added. The mixture was diluted with water (500 mL), acidified with 1N aqueous solution of hydrochloric acid, and extracted with diethyl ether. The diethyl ether layer was washed twice with water (500 mL), and dried (MgSO4). Concentration under reduced pressure gave a residue which was adsorbed onto silica gel. Chromatography with petroleum ether:ethyl acetate (97:3, then 95:5) gave the title compound as a white foamy solid (5.5 g, 93%): NMR (CDC13) δ 8.41 (s, 1 H), 8.16 (d, 1 H), 7.64-7.54 (m, 2 H), 7.46-7.40 (m, 1 H), 6.89 (s, 2 H), 2.41 (s, 3 H), 2.23 (s, 6 H), 1.60 (s, 3 H). MS(-ESI), [M-H], 1 bromine isotope pattern, 409/411.