Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>CN1C(=O)CCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc(Nc2nc3ccccc3o2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
A mixture of N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine (0.50 g) and 2-chloro-3-nitropyridine (0.352 g) in NMP (3.0 mL) was stirred at 140° C. for 1.5 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 ethyl acetate/methylene chloride) to afford N-(1,3-benzoxazol-2-yl)-N′-(3-nitropyridin-2-yl)benzene-1,4-diamine (0.335 g) as a red solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: Oc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Oc1ccc(F)cc1)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of 2.7 g of p-fluorophenol in 20 ml of methanol was added 1.89 g of sodium methoxide. To the solution was added 7.98 g of methyl α-bromo-α-[p-(p-methylsulfonylphenoxy)phenyl]acetate in 40 ml of methanol. The mixture was refluxed and stirred for 18 hours, chilled and filtered to give 4.3 g of white crystals, mp 135°-137° C. Recrystallization from acetone-hexane gave the product as white crystals, mp 136°-138° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:14]([C:13]4[CH:17]=[CH:18][C:10]([C:7]5([N:3]6[CH2:4][CH2:5][CH2:6][S:2]6(=[O:19])=[O:1])[CH2:9][CH2:8]5)=[CH:11][CH:12]=4)=[O:15])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(C2(N3CCCS3(=O)=O)CC2)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(C3(N4CCCS4(=O)=O)CC3)cc2)CC1
Yield: 32.8 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)cyclopropyl]benzoic acid (141 mg) described in Preparation Example 31 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (114 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (79 mg) was obtained.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[H-].[Na+].[CH3:19][CH:20]([CH3:26])[CH2:21][C:22](=O)[CH2:23]Br.N.CN(C)C=[O:31]>>[OH:31][C:14]1[N:6]([CH2:5][O:4][CH2:3][CH3:2])[C:7]2[N:8]=[C:9]3[N:10]([CH:23]=[C:22]([CH2:21][CH:20]([CH3:26])[CH3:19])[NH:16]3)[C:11](=[O:15])[C:12]=2[N:13]=1
Reactant: CC(C)CC(=O)CBr
Reactant: CN(C)C=O
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Agent: N
Agent: [H-]
Agent: [Na+]
Product: CCOCn1c(O)nc2c(=O)n3cc(CC(C)C)[nH]c3nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 676 mg a 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir), 18 mL N,N-dimethylformamide (DMF), and 200 mg sodium hydride (80%) was stirred at room temperature for 15 min, then 0.7 mL 4-methyl-1-bromopentan-2-one was added dropwise into the solution. Changing to dark-brown color, the solution was stirred at room temperature for 3 hr, added 15 mL ammonia, and was continuously stirred overnight. The solvent was removed to obtain a residue, which was purified by column chromatography (silica gel) with an elute of chloroform/methanol (6/1) to obtain an oil. Recrystallization of the oil produced compound 1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][C:21]([OH:23])=O)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:30]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:30]=[C:20]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=1)[C:21]2=[O:23]
Reactant: CN(C)C=O
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1ccc(-c2coc3cc(O)c(Cl)cc3c2=O)cc1OC

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (0.87 g, 6 mmol), 3,4-dimethoxy-phenylacetic acid (1.18 g, 6 mmol), BF3Et2O (4 ml), PCl5 (1.9 g, 9.1 mmol), DMF (5 ml and 10 ml). The precipitate formed was filtered and re-crystallized from methanol to give 6-Chloro-3-(3,4-dimethoxy-phenyl)-7-hydroxy-chromen-4-one an off white solid (1.4 g, 70.20%); Rf 0.72 ethyl acetate.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]3[S:10][C:11]([Cl:14])=[CH:12][CH:13]=3)[C:5]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:3][CH2:2]1.I[CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:1]1([C:4]2[N:8]([CH:22]([CH3:24])[CH3:23])[N:7]=[C:6]([C:9]3[S:10][C:11]([Cl:14])=[CH:12][CH:13]=3)[C:5]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:3][CH2:2]1.[CH:1]1([C:4]2[C:5]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:6]([C:9]3[S:10][C:11]([Cl:14])=[CH:12][CH:13]=3)[N:7]([CH:22]([CH3:24])[CH3:23])[N:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1ccc(-c2n[nH]c(C3CC3)c2-c2ccncc2)s1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2ccc(Cl)s2)c(-c2ccncc2)c1C1CC1
Product: CC(C)n1nc(C2CC2)c(-c2ccncc2)c1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %
Yield: 28 %

Procedure:
To a solution of 4-[5-cyclopropyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (1 eq, 0.32 mmol) in 2 mL N,N-dimethylformamide were added 2-iodopropane (1.5 eq, 0.48 mmol) and cesium carbonate (2 eq, 0.64 mmol). The reaction mixture was stirred overnight at room temperature, diluted with water and extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane:ethyl acetate 5:1 to 1:1) to afford 28.8 mg of 4-[5-cyclopropyl-1-isopropyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (26% yield) and 30.2 mg of 4-[3-cyclopropyl-1-isopropyl-5-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (28% yield).
Reaction SMILES: [OH-].[K+].[C:3]([N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([O:29]C)=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])[CH3:4]>CO>[C:3]([N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([OH:29])=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N(Cc1ccccc1C(=O)O)c1ccccc1Oc1ccccc1
Temperature: 60 °C
Yield: 92.4 %

Procedure:
To a mixture of 23 ml of methanol and 3.6 ml of 2 N aqueous potassium hydroxide solution was added 2.26 g of N-acetyl-N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline synthesized in the same manner as in Example 2, followed by stirring at 60° C. for an hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was made acidic with 2 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:1) to give 2.01 g of N-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:24][C:25](=[O:33])[C:26]([O:29]C(=O)C)([CH3:28])[CH3:27].Cl.C(OCC)(=O)C>O.CO>[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH:8]=[CH:7][C:6]=1[NH:24][C:25](=[O:33])[C:26]([OH:29])([CH3:27])[CH3:28]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(NC(=O)C(C)(C)OC(C)=O)c(Cl)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(NC(=O)C(C)(C)O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A solution of lithium hydroxide monohydrate (0.106 g) in water (1 ml) was added to a stirred solution of N-[2-chloro-4-(4-acetamidophenylsulphonyl)phenyl]-2-acetoxy-2-methylpropanamide (Method 16) (0.230 g) in methanol (2 ml) and the mixture was stirred at ambient temperature for 2 hours. Water (5 ml) was added and the solution was acidified to pH 2-3 with 1M hydrochloric acid. Ethyl acetate (20 ml) was added and the organic layer was washed with water (20 ml) and brine, then dried. Volatile material was removed by evaporation and the off-white solid was washed with ether to give the title compound (0.150 g) as a solid. NMR (CDCl3): 1.3 (s, 6H), 2.2 (s, 3H), 7.4 (s, 1 H), 7.7 (d, 2H), 7.8 (m, 3H), 7.9 (s, 1H), 8.7 (d, 1H), 9.6 (s, 1H); MS (ESP−): 409.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.I[CH3:23]>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:23])[N:21]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-n2ccc3cc(-c4nnn[nH]4)ccc32)cc1
Reactant: CI
Solvent: CN1CCCC1=O
Product: Cn1nnc(-c2ccc3c(ccn3-c3ccc(F)cc3)c2)n1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluorophenyl)-5-tetrazol-5-yl-1H-indole (8a) (19 g) in NMP (200 mL) potassium t-butoxide (8.5 g) was added cautiously at 10° C. followed by dropwise addition of iodomethane (22 g) during 20 minutes. The mixture was allowed to reach room temperature and stirred for another 2 hours. Crude title compound was worked up according to the general procedure above. Purification was performed by column chromatography on silica gel using dichloromethane as eluent. Yield 15 g, mp 131-133° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][CH:2]([CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[C:13]([OH:15])=[O:14])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Yield: 74.5 %

Procedure:
By using 10 g of D-tryptophane and 9 g of 4-chlorobenzoyl chloride, and a method similar to that described in reference Example 6, recrystallized from methanol-water, there was obtained 12.5 g of 2-(4-chlorobenzoylamino)-3-(indol-3-yl)propionic acid. Colorless needle-like crystals. Melting point: 100°-102° C. [α]D20 +51.5° (C=1, methanol)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[C:10]([S@@:14]([NH2:16])=[O:15])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:16]/[S:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:15])=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1ccc(Br)cn1
Temperature: 73 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
To a solution of 5-bromo-2-formyl-pyridine (3.0 g, 16.1 mmol) in dry THF (95 mL), (S)-tert-butylsulfinamide (2.05 g, 16.9 mmol) was added at RT under argon. Then titanium tetra-isopropoxyide (7 mL, 33.9 mmol) was added drop wise. The reaction mixture was stirred at 73° C. (external temperature) for 2.5 h, and was allowed to cool down. The reaction mixture was slowly poured into a vigorously stirring mixture of ca. 200 mL of brine and ice. The slurry was filtered and washed with DCM. The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, evaporated to give a brown solid. The product was triturated in cold ether and successive filtered solids were combined to give the title intermediate (3.66 g, 12.4 mmol, 77%). HPLC: EtRet=4.987 min; LC-MS: m/z 291.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH:12]([OH:16])[C:13]#[C:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[CH2:1]([O:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH:12]([OH:16])/[CH:13]=[CH:14]\[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC#CC(O)CC(C)COCc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: C/C=C\C(O)CC(C)COCc1ccccc1

Procedure:
A mixture of 1 g. (4.31 mmoles) of rac. 1-benzyloxy-2-methylhept-5-yn-4-ol, 0.1 g. of Lindlar catalyst, 0.04 ml. of quinoline and 30 ml. of hexane was stirred in an atmosphere of hydrogen, at room temperature, for 40 minutes during which time approximately one equivalent of hydrogen was taken up. The catalyst was filtered and washed with hexane then the combined filtrate and washes were concentrated in vacuo giving 1.05 g. of oily product. This material was chromatographed on 50 g. of silica gel. Elution with 2:1 parts by volume and 1:1 parts by volume hexane-ether afforded 0.844 g. of a pale yellow oil. Evaporative distillation gave rac. Z-1-benzyloxy-2-methyl-5-hepten-4-ol as a colorless oil, b.p. 113°-123° C. (bath temperature (0.25 mm Hg.).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:10](=[O:13])[C:11]=1I.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC.[Sn]>CN(C)C=O.[Pd]>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:10](=[O:13])[C:11]=1[CH:30]=[CH2:31]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(I)c2=O)c1
Agent: [Pd]
Agent: [Sn]
Solvent: CN(C)C=O
Product: C=Cc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)OC)ccc2C)c1=O
Temperature: 60 °C

Procedure:
A round bottom flask containing methyl 3-[4-[(2,4-difluorobenzyl)oxy]-5-iodo-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (2.50 g, 4.88 mmol) in N, N-dimethylformamide was evacuated and flushed with argon. Tributyl(vinyl)tin (2.3 g, 7.3 mmol) and dichlorobis(triphenylphosphine) palladium (II) (0.34 g, 0.49 mmol) were added in the nitrogen atmosphere of a glove box. Heated at 60° C. under argon overnight. Added additional tin (0.7 mL) and palladium (0.17 g) reagents and continued over weekend. No progress observed. Distilled DMF, washed crude product with ethyl acetate, and filtered through celite. The filtrate was concentrated and purified by flash column using 25% ethyl acetate in hexane as eluent. Used without further purification.
Reaction SMILES: ClC1C(Cl)=CC=C2C=1C(O)=CC(O)=N2.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[N:22]=[C:21]([OH:27])[CH:20]=[C:19]2[OH:28].[N+:29]([O-])([OH:31])=[O:30]>C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[NH:22][C:21](=[O:27])[C:20]([N+:29]([O-:31])=[O:30])=[C:19]2[OH:28]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)c2cc(Cl)c(Cl)cc2n1
Agent: Oc1cc(O)c2c(Cl)c(Cl)ccc2n1
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2c(O)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 19 %

Procedure:
To a mixture of 1.25 g (5.43 mmol) of 5,6-dichloro-2,4-dihydroxyquinoline and 6,7-dichloro-2,4-dihydroxyquinoline in 8 mL of glacial acetic acid was added 1.5 mL of HNO3 (69-71%) and the mixture was heated at 90° C. for 2 h. The mixture was cooled to room temperature, filtered and washed with water, and dried to leave 280 mg (19%) of the title compound as a yellow solid, mp 235°-236° C. (decomposed). 1H NMR (CDCl3 +DMSO-d6), 7.362 (s, 1), 8.039 (s, 1), 11.369 (s, 1). MS, 274 (50, M+), 214 (100), 187 (18), 160 (20). High resolution MS, Calcd for C9H435Cl2N2O4 273.9544, found 273.9548.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(OC([NH:33][C@H:34]([C:37](O)=[O:38])[CH2:35][OH:36])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:51].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:51].[ClH:51].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:35](=[O:36])[C@@H:34]([NH2:33])[CH2:37][OH:38])[CH2:20][CH2:19]3)=[O:17])=[CH:24][CH:25]=2)=[N:2]1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: N[C@@H](CO)C(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 60 °C
Yield: 111.1 %

Procedure:
The product obtained using Compound 18 (300 mg, 0.90 mmol), N-(tert-butoxycarbonyl)-L-serine (155 mg, 0.76 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 0.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg, 1.06 mmol) and N-methylmorpholine (0.17 mL, 1.52 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 mol/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 123 (290 mg, 78%).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.B(O[O-])=[O:18].[Na+]>Cl>[ClH:3].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:18])=[CH:8][CH:9]=1
Reactant: O=BO[O-]
Reactant: Clc1ccc(SC2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(c1ccc(Cl)cc1)C1CCNCC1

Procedure:
A solution of 5.78 g (0.020 mole) of 4-[(p-chlorophenyl)thio]piperidine hydrochloride hydrate and 4.61 g (0.030 mole) of sodium perborate in 200 ml of dilute hydrochloride acid was stirred at room temperature overnight. The reaction mixture was quenched in dilute sodium hydroxide and the resulting basic solution was extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and the solvent was removed in vacuo to give a white solid, the free base of the title compound. The free base was reacted with ethereal hydrogen chloride and the salt was recrystallized from methanol-diethyl ether to give the product as a white crystalline solid, m.p. 220°-221° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Br[C:27]1[CH:28]=[C:29]2[C:35]([CH:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][CH:47]=3)[N:44]=[CH:43][CH:42]=[CH:41]4)[CH3:37])=[N:34][O:33][C:30]2=[N:31][CH:32]=1.C([Sn](CCCC)(CCCC)[C:53]1[N:54]=[CH:55][S:56][CH:57]=1)CCC>CN(C=O)C>[S:56]1[CH:57]=[C:53]([C:27]2[CH:28]=[C:29]3[C:35]([CH:36]([C:38]4[CH:39]=[C:40]5[C:45](=[CH:46][CH:47]=4)[N:44]=[CH:43][CH:42]=[CH:41]5)[CH3:37])=[N:34][O:33][C:30]3=[N:31][CH:32]=2)[N:54]=[CH:55]1
Reactant: CC(c1ccc2ncccc2c1)c1noc2ncc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Product: CC(c1ccc2ncccc2c1)c1noc2ncc(-c3cscn3)cc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a pressure vessel was added 2-(dicyclohexylphosphino)biphenyl (12 mg, 0.42 mmol), 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline (0.10 g, 0.28 mmol), and 4-(tributylstannyl)thiazole (0.16 g, 0.42 mmol) in anhydrous DMF (3 mL). The vial was flushed with argon, sealed and stirred at 90° C. for two hours. The mixture was concentrated and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to afford the product as an off-white solid. MS m/z=359.0 [M+1]+ Calc'd for C20H14N40S: 358.4.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.O.C(OC(=O)[NH:22][C@H:23]1[CH2:27][C:26](=[O:28])[N:25]([C:29]2[CH:30]=[CH:31][C:32]3[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=3[N:38]=2)[CH2:24]1)(C)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:22][C@@H:23]1[CH2:24][N:25]([C:29]2[CH:30]=[CH:31][C:32]3[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=3[N:38]=2)[C:26](=[O:28])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Aqueous trifluoroacetic acid (trifluoroacetic acid/water=95:5, v/v, 3.5 ml) was added to [(3S)-5-oxo-1-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (148 mg, 0.425 mmol) and the mixture was stirred in an ice bath for 2 hours. The reaction solution was diluted with ethyl acetate, neutralized by adding a saturated sodium hydrogen carbonate aqueous solution and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol) to yield 84.5 mg (80%) of the title compound in the form of a colorless solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:16])=[C:11](O)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])(CC)C.[C:22](=[O:24])=[O:23].C(OCC)C.O>C1COCC1>[Si:1]([O:8][C:9]1[C:10]([F:16])=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:22]([OH:24])=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1F
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)O)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-tert-butyldimethylsilyloxy-2-fluorophenol (10.59 g, 46.8 mmol) in THF (150 ml) cooled to -70° C. was added dropwise over 5 min. sec-butyllithium (42 ml, 1.12M in cyclohexane). The reaction mixture was stirred ad -70° C. for 1 h and then poured into a slurry of dry-ice/diethyl ether. Water (200 ml) was added cautiously and the organic layer separated and discarded. The aqueous layer was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (MgSO4) and evaporated to afford title compound (7.90 g, 70%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:23]2[CH:22]=[CH:21][C:20]([CH3:25])([CH3:24])[C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:20]([CH3:25])([CH3:24])[CH:21]=[CH:22][C:23]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCC2=C1C=CC2(C)C
Product: CC1C2=C(CCN1C(=O)c1cc3ncc(Cl)cn3n1)C(C)(C)C=C2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-[2]pyrindine to provide the title compound.