Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:26][CH3:27])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH3:35].COC1C2N=C(NC(=O)C3C=CC(CN4CCCC4)=CC=3)SC=2C(C2C=CC=CC=2)=CC=1>>[O:24]1[CH2:25][CH:19]([C:18]2[C:12]3[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:28]=[CH:29][C:3]([CH2:2][N:34]([CH2:33][CH2:32][O:31][CH3:30])[CH3:35])=[CH:4][CH:5]=4)=[N:14][C:13]=3[C:15]([O:26][CH3:27])=[CH:16][CH:17]=2)[CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CNCCOC
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Agent: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(CN4CCCC4)cc3)nc12
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCOC4)c3s2)cc1

Procedure:
4-Chloromethyl-N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-benzamide and N-(2-methoxyethyl)-methylamine were reacted as described for N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-pyrrolidin-1-ylmethyl-benzamide in WO01/97786. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown powder. MS: m/e=486(M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.CI.[C:17](=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:17][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2)[N:11]=[C:2]([CH3:1])[C:3]1=[O:14]
Reactant: Cc1cc2nc(C)c(=O)[nH]c2cc1C
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc2nc(C)c(=O)n(C)c2cc1C
Temperature: 25 °C

Procedure:
A mixture of 3,6,7-trimethyl-2(1H)-quinoxalinone (5.0 g., 0.027 mol.), methyl iodide (15 ml.), sodium carbonate (5.0 g., 0.047 mol.) and dimethylformamide (75 ml.) were stirred at room temperature for eighteen hours, then heated at 75°-80° C. for three hours. Removal of the dimethylformamide under reduced pressure and dilution with water gave a brown solid. Crystallization from acetone (Darco) gave light tan needles. (2.85 g., m.p. 164°-166°, 53%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:25]([CH2:34][CH:31]2[CH2:33][CH2:32]2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a suspension of NaH (37 mg, 50% suspension, 0.79 mmol) in 25 ml of DMF was slowly added a mixture of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (300 mg, 0.719 mmol) and cyclopropylmethyl bromide (108 mg, 0.782 mmol) in 20 ml of DMF at 0° C. for 15 min under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred for 15 min at 0° C. The reaction mixture was poured onto crushed ice and extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Flash column Chromatography to give ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate in 62% yield. (0.210 g). 1HNMR (CDCl3): 7.69 (s, 4H); 7.41 (s, 1H); 7.21 (s, 1H); 4.19 (q, 2H); 3.63 (t, 1H); 3.41 (d, 2H); 1.94 (m, 1H); 1.78 (m, 1H); 1.27 (t, 3H); 0.97 (bs, 1H); 0.72 (bs, 1H); 0.42 (m, 4H); 0.13 (m, 2H); 0.1 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:13][CH3:14])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccccc1O

Procedure:
The stirred solution of 2-(2-Hydroxyphenyl)acetic acid (10 g, 65.7 mmol) and p-Toluenesulfonic acid monohydrate (1.40 g, 7.3 mmol) in abs ethanol (100 ml) was refluxed for 4 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with ethyl acetate and washed with 1M HCl and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]=1[C:6]#[N:7])([O-])=O>[Fe]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(N2CCCCC2)cccc1[N+](=O)[O-]
Agent: [Fe]
Product: N#Cc1c(N)cccc1N1CCCCC1

Procedure:
2-Amino-6-(1-piperdinyl)benzonitrile is prepared from 2-nitro-6-(1-piperidinyl)benzonitrile as in example 1 by iron reduction.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:7][CH:8]=1)=[O:1]
Reactant: O=S(=O)(Nc1ccc(CO)cc1)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1ccc(NS(=O)(=O)c2ccccn2)cc1
Yield: 60.2 %

Procedure:
To a stirred solution of pyridine-2-sulfonic acid (4-hydroxymethyl-phenyl)-amide (200 mg, 0.76 mmol), and pyridine (612 μL) in anhydrous CH2Cl2 (3mL) was added Dess-Martin periodiane (450 mg, 1.06 mmol). The resultant solution was stirred at room temperature for 1 h. The mixture was diluted with 100 mL CH2Cl2, filtered through celite, and concentrated. The crude material was purified by recrystallisation from cold CH2Cl2 to give the title compound (120 mg, 60%) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 7.34 (d, 2H, J=8.4 Hz), 7.49-7.50 (m, 1H), 7.74 (br s, 1H), 7.75 (d, 2H, J=8.4 Hz), 7.89-7.70 (m, 1H), 8.03 (d, 1H, J=8.1 Hz), 8.70 (d, 1H, J=4.2 Hz), 9.87 (s, 1H).
Reaction SMILES: [Br:1]Br.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[N:5][CH:4]=1.CCOCC>C(O)(=O)C>[Br:1][C:11]1[C:12](=[O:15])[NH:13][CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][N:5]=2)[CH:10]=1
Reactant: BrBr
Reactant: O=c1ccc(-c2ccncn2)c[nH]1
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=c1[nH]cc(-c2ccncn2)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.7 g of bromine are added over a period of one minute to a solution of 4.5 g of 5-(4-pyrimidyl)-2(1H)-pyridone in 60 ml glacial acetic acid. The mixture is allowed to cool, stirred at RT for 1 hour and then poured into 100 ml of anhydrous ether and stirred for 30 minutes. The slurry is filtered and the filtered solid washed with ether and dried. The solid is suspended in 100 ml of H2O and the pH adjusted to about 6 with anhydrous K2CO3. The mixture is stirred for 15 minutes, filtered, the solid washed with H2O and briefly dried. The moist solid is added to 40 ml of 5% aqueous hydrochloric acid and the resultant mixture stirred for 30 minutes, diluted with an equal volume of isopropyl alcohol, stirred for an additional 10 minutes and filtered. The resulting solid is washed with isopropyl alcohol ether and dried, giving 3-bromo-5-(4-pyrimidyl)-2 (1H)-pyridone as a green powder, M.P. >250° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH2:6]([O:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22](N(CC)CC)C>N1C=CC=CC=1>[N:17]1([C:1]([CH3:2])=[O:3])[CH2:18][C@H:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:15][C@H:16]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C(O)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(C)=O
Temperature: 25 °C

Procedure:
Acetyl chloride (3.3 mL, 46 mmol) was added dropwise to a solution of trans-4-benzyloxy-L-proline hydrochloride (H-Hyp(OBzl)-OMe.HCl; 12.5 g, 46 mmol), triethylamine (6.4 mL, 46 mmol) in pyridine (150 mL) at 0° C. while stirring under argon. The reaction mixture was stirred for 30 min at 0° C. then slowly warmed to room temperature over 16 h. The reaction mixture was concentrated in vacuo, diluted with CH2Cl2, washed with 1 N aqueous HCl (3×), 10% aqueous Na2CO3, saturated aqueous NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (3:2) to give Ac-Hyp(OBzl)-OMe as an oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Product: c1cc(N2CCC(N3CCOCC3)CC2)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 19 and morpholine.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34]Br)=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][O:13][N:14]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)CCNc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-methoxycarbonylethyl)-amine (0.052 g, 0.181 mmol), potassium carbonate (0.062 g, 0.452 mmol) and 4-chlorophenacyl bromide (0.047 g, 0.199 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as hygroscopic solid of undefined melting point. 1H-NMR (400 MHz, d6-DMSO): 8.14 (d, 2H); 7.87 (m, 2H); 7.41 (m, 2H); 7.32 (d, 2H); 7.29 (t, 1H); 6.37 (s, 2H); 3.63 (m, 2H); 3.61 (s, 3H); 2.76 (t, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[C:10]([NH:13][C@H:14]1[C@H:22]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[O:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C@@H:15]1[NH:29][C:30]#[N:31])(=[O:12])[CH3:11]>CO>[C:10]([NH:13][C@H:14]1[C@H:22]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[O:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C@@H:15]1[NH:29][C:30]([NH2:31])=[N:2][OH:3])(=[O:12])[CH3:11]
Reactant: NO
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1NC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1NC(N)=NO
Temperature: 21 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
Hydroxylamine hydrochloride (1.1 g, 15.85 mmol)(dried under vacuum over P2O5) was dissolved in dried (over 3 A mol. sieves) methanol (20 ml) and sodium carbonate (0.835 g, 7.9 mmol) was added. This was stirred at 21° C. under N2 for 15 min., then solid was filtered off. To the filtrate was then added the product of Example 1, step (i) (500 mg, 1.585 mmol) and stirring under N2 at 21° C. continued for 16 hr. White solid was filtered off, air dried, then dried under high vacuum to give the title compound (Yield, 180 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][O:7]C(C)(C)[O:5][CH2:4][CH:3]1[NH:11][C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([S:19](=[O:33])(=[O:32])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[CH:15][CH:14]=1.C(O)C>O>[OH:1][CH:2]([CH2:8][OH:7])[CH:3]([NH:11][C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([S:19](=[O:32])(=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=2)=[CH:15][CH:14]=1)[CH2:4][OH:5]
Reactant: CC1(C)OCC(O)C(NC(=O)c2ccc(S(=O)(=O)Nc3ccc(F)c(C(F)(F)F)c3)cc2)CO1
Solvent: O
Solvent: CCO
Product: O=C(NC(CO)C(O)CO)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
2 g (3.95 mmol) of 4-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]-benzoic acid-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-amide as well as 2 ml of cation exchanger in H. form are added to a solution of 10 ml of ethanol and 5 ml of distilled water and warmed for 90 minutes on the water bath. It is filtered from the exchanger, rewashed with distilled water, evaporated to dryness in a vacuum, and again taken up in water and by freeze-drying of this solution, 1.55 g=84.2% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[O:18])[CH2:13][CH2:12]1>CCOC(C)=O>[Br-:1].[F:34][C:30]1[CH:29]=[C:28]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[O:19][C:17]([CH:14]2[CH2:13][CH2:12][N+:11]([CH3:10])([CH2:2][C:3](=[O:4])[C:5]3[CH:9]=[CH:8][S:7][CH:6]=3)[CH2:16][CH2:15]2)=[O:18])[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(CBr)c1ccsc1
Reactant: CN1CCC(C(=O)OC(c2cccc(F)c2)c2cccc(F)c2)CC1
Solvent: CCOC(C)=O
Product: C[N+]1(CC(=O)c2ccsc2)CCC(C(=O)OC(c2cccc(F)c2)c2cccc(F)c2)CC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
2-Bromo-1-(thiophen-3-yl)ethanone (23.7 mg, 0.12 mmol) was added to a solution of bis(3-fluorophenyl)methyl 1-methylpiperidine-4-carboxylate (40 mg, 0.12 mmol, prepared as in example 40) in EtOAc (3 ml). The reaction was stirred at room temperature overnight. The solvent was evaporated, and the crude was purified by preparative HPLC (eluent: CH3CN/H2O) to obtain 4-((bis(3-fluorophenyl)methoxy)carbonyl)-1-methyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)piperidinium bromide (36.1 mg).
Reaction SMILES: [OH:1]O.[NH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5](=[O:15])C1=O.Cl>[OH-].[Na+]>[NH2:3][C:14]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[C:5]([OH:15])=[O:1]
Reactant: OO
Reactant: O=C1Nc2cc3c(cc2C1=O)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2c(cc1C(=O)O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Add 30% aqueous hydrogen peroxide solution (3 mL) to a solution of 1,5,6,7-Tetrahydro-1-aza-s-indacene-2,3-dione (2.18 g, 11.66 mmol) in 2 N sodium hydroxide (23 mL) over a period of 5 minutes, stir the mixture at room temperature for 3 h. Add 1N hydrochloric acid to pH=5 and extract with ethyl acetate (3×20 mL). Wash with brine, dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to afford 6-Amino-indan-5-carboxylic acid (1.7 g, 86%). Dissolve in ethylacetate (2 mL) and ethanol (2 mL) and add (trimethylsilyl) diazomethane (9.6 mL, 19.2 mmol, 2M in hexane) at room temperature and stir the solution for 16 h. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (9:1), to afford the title compound (1.19 g, 66%). 1H NMR (CDCl3, 300 MHz) δ 2.05 (quintuplet, J=7.3 Hz, 2H), 2.80 (q, J=7.7 Hz, 4H), 6.59 (s, 1H), 7.69 (s, 1H). MS (ES+): 192 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:6][CH:5]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].Cl>CN(C)C=O.O>[CH3:26][C:25]1[O:24][C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:22][C:21]=1[CH2:20][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)C(CCc2ccc(O)cc2)S1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
Oily sodium hydride (60%, 0.10 g) was added to a solution of 5-[2-(4-hydroxyphenyl)ethyl]-2,4-thiazolidinedione (0.30 g) in N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 15 minutes. Then, 4-chloromethyl-5-methyl-2-phenyloxazole (0.29 g) was added, and the mixture was stirred at 90 to 100° C. for 2 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-chloroform (1:9, v/v) gave 5-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-2,4-thiazolidinedione (0.30 g, 59%). This product was recrystallized from dichloromethane-isopropyl ether. Colorless needles. mp: 146-147° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=O.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Si]([N:36]=[N+:37]=[N-:38])(C)(C)C.C([O-])(O)=O.[Na+]>CC#N.O.CCOC(C)=O>[CH:14]1([C:12]2[N:11]([C:3]3[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=3[F:1])[N:38]=[N:37][N:36]=2)[CH2:16][CH2:15]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)C1CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(-n2nnnc2C2CC2)c1
Reaction time: 0.03 h
Yield: 44.9 %

Procedure:
A stirred solution of N-(2-fluoro-5-nitrophenyl)cyclopropanecarboxamide (210 mg, 1.0 mmol) in MeCN (6 mL) under nitrogen was cooled to −10 to −20° C. (ice/MeOH bath) and a precipitate developed. Tf2O (0.34 mL, 2.0 mmol) was added dropwise over 3-5 min (a solution developed). The mixture was stirred in the cold bath for a further 2 min then TMS-N3 (0.53 mL, 4.0 mmol) was added dropwise over 2 min (bath temp ca. −10° C.). After complete addition, the mixture was stirred for 90 min (bath temperature ca. 15° C.). The mixture was worked-up by addition of EtOAc (30 mL) and saturated NaHCO3 (15 mL). After stifling for 2 min, the mixture was placed in a separating funnel and H2O (30 mL) added. The aqueous and organic layers were partitioned and the aqueous layer extracted with EtOAc (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent removed under vacuum to leave a crude residue. The residue was dry-loaded on to silica gel then purified by column chromatography on silica gel using EtOAc/heptane (2:8 to 4:6) as eluent to give the desired product (112 mg, 45% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[O:8]=[C:9]1[C@@H:16]2[C@@H:12]([CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2)[CH2:11][CH2:10]1>>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH:16]2[C:9]([OH:8])([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][CH2:11][CH:12]2[CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCC(=O)[C@H]2C1
Reactant: Brc1cccnc1
Product: CC(C)(C)OC(=O)N1CC2CCC(O)(c3cccnc3)C2C1
Yield: 26.6 %

Procedure:
3-Bromopyridine (4.36 g, 27.6 mmol) and the product from Example 44A (2.07 g, 9.19 mmol) were processed as described in Example 1E to afford the title compound (0.743 g, 27%). MS (DCI/NH3) m/z 305 (M+H)+.
Reaction SMILES: CCOCC.[OH:6][CH2:7][P:8](=[O:17])([O:13][CH:14]([CH3:16])[CH3:15])[O:9][CH:10]([CH3:12])[CH3:11].C(N(CC)CC)C.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>C(OCC)(=O)C>[F:38][C:26]([F:25])([F:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([O:6][CH2:7][P:8](=[O:17])([O:9][CH:10]([CH3:12])[CH3:11])[O:13][CH:14]([CH3:16])[CH3:15])(=[O:34])=[O:35]
Reactant: CC(C)OP(=O)(CO)OC(C)C
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)OP(=O)(COS(=O)(=O)c1ccccc1C(F)(F)F)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A solution of 30 ml of ether, 13.3 g of diisopropyl P-(hydroxymethyl)phosphonate, prepared in Example 17, and 10.5 ml of triethylamine was added dropwise over 60 minutes to a solution of 15.35 g of 2-(trifluoromethyl)benzenesulfonyl chloride and 50 ml of ether. After the mild exotherm, the reaction was allowed to stir at room temperature overnight and then was diluted with 200 ml of ethyl acetate, the ethyl acetate solution washed with two 100 ml portions of water, dried with magnesium sulfate, filtered, and concentrated to yield 16.3 g of the desired product as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[C:5]#[N:6].S(=O)(=O)(O)[OH:15]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[C:5]([NH2:6])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: NC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A total of 7.2 g of 3,4-dihydroxy-5-nitrobenzonitrile are introduced portionwise into 130 ml of conc. sulfuric acid while stirring within 10 minutes, whereupon the mixture is stirred at 50° for 4 hours. The reaction mixture is poured into 800 ml of ice-water. The separated precipitate is filtered under suction, washed with water and taken up in ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. After recrystallization from acetone/ethyl acetate there is obtained 3,4-dihydroxy-5-nitrobenzamide in the form of orange crystals of m.p. 235°-236°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1
Reactant: Nc1nc(NCCNc2nc(Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: C1COCCO1
Product: Nc1nc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
60 mg (0.16 mmol) of N6-{2-[(7-chloro[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 6A), 30.3 mg (0.16 mmol) of (2,4-dichlorphenyl)boronic acid and 18.4 mg (0.016 mmol) of tetrakis(triphenylphosphine)palladium(0) are introduced into a mixture of 3.4 ml of dioxane and 1.1 ml of saturated aqueous sodium carbonate solution under argon. The mixture is degassed with argon and then heated in a microwave at 150° C. for 30 min. Cooling is followed by filtration through an Extrelut® cartridge. Purification by preparative HPLC results in 10.9 mg (13% of theory) of the product as a solid.