Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].C([O-])([O-])=O.[K+].[K+].[N:24](S(C(F)(F)F)(=O)=O)=[N+:25]=[N-:26]>O.CO>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][N:24]=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=NS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNN=[N+]=[N-])C(=O)O
Reaction time: 8 h
Yield: 50 %

Procedure:
Boc-Lys(N3)OH was synthesized from Boc-LysOH by using procedures for Cu(II)-catalyzed diazo-transfer to amines. (Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996, 37, 6029-6032.) Boc-LysOH (4.38 g, 17.8 mmol), CuSO4.5H2O (44.7 mg, 178.2 □mol) and K2CO3 (3.69 g, 26.8 mmol) were dissolved in H2O (57 mL) and MeOH (114 mL). N3Tf (triflyl azide, 17.8 mmol in 150 mL CH2Cl2) was added, and the reaction mixture was stirred overnight. MeOH was removed under reduced pressure. The resulting aqueous solution (50 mL) was diluted with H2O (0.10 L), and the pH was adjusted to 6.0 with HCl. Sodium phosphate buffer (150 mL, 0.25 M, pH 6.2) was added, and the solution was washed with EtOAc (3×) to remove the triflic amine byproduct. The pH of the washed aqueous layer was adjusted to 2.0 with HCl, and the resulting solution was washed with EtOAc (4×) to extract the desired product. The organic layer was then dried over MgSO4(s) and filtered, and the solvent was removed under reduced pressure to yield Boc-Lys(N3)OH as a clear oil (50%). Spectral data. 1H NMR (500 MHz, CDCl3) δ:10.93 (broad s, 1H), 5.11 (d, J=8.3 Hz, 1H), 4.34 (m, 1H), 3.30 (d, J=7.0 Hz, 2H), 1.80 (m, 2H), 1.65 (m, 2H), 1.49 (m, 2H), 1.46 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3) δ:179.96, 156.30, 97.44, 55.79, 53.79, 34.66, 31.07, 30.96, 25.20 ppm; MS (ESI) m/z 295.1383 (MNa+[C11H20N4O4Na]=295.1382).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:30])([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[CH:10]=2)[N:5]=[C:4]([CH3:31])[C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.F[C:44](F)(F)[C:45](O)=[O:46].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:30])([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[CH:13]3[CH2:16][N:15]([C:45](=[O:46])[CH3:44])[CH2:14]3)[CH:10]=2)[N:5]=[C:4]([CH3:31])[C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][CH:34]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc2ccc(C(O)(c3cnnn3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CC(C(O)(c2ccc3nc(C)c(Cc4ccc(C(F)(F)F)cc4)c(Cl)c3c2)c2cnnn2C)C1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A mixture containing tert-butyl 3-((4-chloro-2-methyl-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidine-1-carboxylate (250 mg, 0.42 mmol, Example 31) and trifluoroacetic acid (0.32 mL, 0.32 mmol) in dichloromethane (2 mL) was stirred at 23° C. After 18 hours, dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (25 mL) were added. The biphasic mixture was stirred for 5 minutes. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. The filtrate was concentrated to provide a residue. This residue was used in the next step without further purification. A mixture of the residue (174 mg), triethylamine (0.25 mL), and acetic anhydride (0.14 mL) in dichloromethane (3.5 mL) was stirred at 46° C. After 2 hours, the flask was cooled to 23° C. Dichloromethane (40 mL) and saturated aqueous sodium bicarbonate solution (25 mL) were added. The biphasic mixture was stirred for 10 minutes at 23° C. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Celite® (3 g) was added to the filtrate and the mixture was concentrated in vacuo. The dry solid was loaded onto a silica gel column for flash-column chromatography. Elution with 100% dichloromethane initially, grading to 5% methanol-dichloromethane provided the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3, 3:1 mixture of amide rotamers, asterisk denotes minor rotamer) δ ppm 8.44 (d, J=2.0 Hz, 1H), 8.38* (d, J=2.1 Hz, 1H), 8.00-7.94 (m, 1H), 7.60-7.51 (m, 3H), 7.48-7.42 (m, 1H), 7.25-7.20 (m, 2H), 6.23 (s, 1H), 5.09* (s, 1H), 4.54-4.45 (m, 2H), 4.43-4.36* (m, 1H), 4.34-4.28* (m, 1H), 4.27-4.19 (m, 1H), 4.19-4.13 (m, 1H), 4.08-3.96 (m, 1H), 3.80-3.65 (m, 4H), 3.63-3.54* (m, 1H), 3.54-3.46 (m, 1H), 2.69-2.63 (m, 3H), 1.82* (s, 3H), 1.65-1.54 (m, overlap with water, 3H); MS (ESI): mass calcd. for C27H25ClF3N5O2, 543.2. m/z found, 544.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[CH3:16][C:15]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1
Reactant: CC(=O)NN
Reactant: Clc1ccc(-c2ccccc2Cl)nn1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccccc3Cl)nn12

Procedure:
As in Example 36, a mixture of 5.5 g. of 3-chloro-6-(o-chlorophenyl) pyridazine, 3.6 g. of acetylhydrazine in 75 ml. of n-butanol is refluxed for 72 hrs. to give 2.2 g. or product as off-white crystals, m.p. 146°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10]OC)=[CH:5][C:4]=1[CH3:13].[ClH:14].[NH:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[ClH:14].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[N:16][NH:15][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:5][C:4]=1[CH3:13]
Reactant: NNc1ccncc1
Reactant: COC=Cc1ccc(OC)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CC=NNc2ccncc2)cc1C
Yield: 39.2 %

Procedure:
To a solution of 1-methoxy-2-methyl-4-(2-methoxyvinyl)benzene (17 g) and 4-hydrazinopyridine hydrochloride (15.4 g) in ethanol (300 ml), p-toluenesulfonic acid (2.7 g) was added, with stirring. The reaction mixture was stirred under reflux for 2 hrs, filtered, and the filtrate was concentrated in vacuo. The residue was recrystallized from methanol to yield 10.9 g (39%) of product, mp 224-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:27][C:25]1[CH:24]=[C:23]([S:28]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[N:10]=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:29])=[O:30])[CH:22]=[C:21]([Cl:20])[CH:26]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3,5-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>CN(C)C=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>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=2)[N:6]=1)=[O:4]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1cccc(Br)n1
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: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 80 °C
Yield: 44.7 %

Procedure:
162 mg (0.14 mmol)Pd(PPh3)4 was added under argon at room temperature to a solution of 2.0 g (9.25 mmol) methyl-6-bromo-pyridine-2-carboxylate in 46 ml N,N-dimethylformamide and the mixture was heated to 80° C. Then 4.52 g (13.9 mmol) cesium carbonate and 2.1 g (10.18 mmol) of 4-(trifluoromethoxy)phenylboronic acid were added and the mixture was stirred at 80° C. over night. The reaction mixture was cooled to room temperature, filtered, and the filtrate evaporated. The residue was taken up with ethyl acetate, washed twice with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 1.23 g (39%) of 6-(4-Trifluoromethoxy-phenyl)-pyridine-2-carboxylic acid methyl ester
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:10]=[C:9]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[C:22](=O)[O:23][C:24](=[O:36])[C:25]=3[C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)=[CH:13]2)[CH:8]=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[OH-].[NH4+:39]>CN(C)C=O>[N:1]([CH2:4][C:5]1[N:10]=[C:9]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[C:22](=[O:23])[NH:39][C:24](=[O:36])[C:25]=3[C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)=[CH:13]2)[CH:8]=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: Cn1cc(C2=C(c3cn(Cc4cccc(CN=[N+]=[N-])n4)c4ccccc34)C(=O)OC2=O)c2ccccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(Cc4cccc(CN=[N+]=[N-])n4)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
The product from step b) was heated with ammonium hydroxide (5 mL) and dimethylformamide (5 mL) at 75° C. for 5 h in a sealed flask. The flask was cooled and the content partitioned between ethyl acetate and water. The organic phase was washed with ammonium hydroxide. Evaporation afforded 188 mg of the sub-title product, which was used without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:17])[C:10]=2[CH:9]=[CH:8]1.C(O)C.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>>[OH:25][NH:24][C:16]([C:15]1[C:10]2[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:19])([CH3:18])[CH3:1])[C:11]=2[N:12]=[CH:13][CH:14]=1)=[NH:17]
Reactant: C[Si](C)(C)CCOCn1ccc2c(C#N)ccnc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2c(C(=N)NO)ccnc21
Temperature: 25 °C
Yield: 97.9 %

Procedure:
1-[2-(Trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.05 g, 0.0002 mol) was dissolved in ethanol (2.0 mL, 0.034 mol), and then hydroxylamine hydrochloride (0.023 g, 0.00033 mol) and potassium carbonate (0.10 g, 0.00073 mol) were added. The reaction was heated to reflux for 5 h, and the reaction was then allowed to cool to rt and filtered to remove the solids. The filtrate was concentrated to give the product 0.06 g as yellow oily residue, LC/MS (M+H)+ 307.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1
Reactant: COc1ccc(Cl)cc1-c1cc(N)cc(Cl)n1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)cc(Cl)n1
Yield: 56 %

Procedure:
Following the method described in Example 1, 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-amine and 4-chloro-phenylboronic acid gave 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-(4-chloro-phenyl)-amine in 56% yield. 1H NMR (acetone-d6) δ 3.92(s, 3H, CH3), 6.86 (d, 1H, J=8.9 Hz, Ar), 6.90 (t, 1H, J=1.9 Hz, Ar), 7.18 (d, 1H, J=8.9 Hz, Ar), 7.20 (d, 1H, J=8.9 Hz, Ar), 7.36 (d, 2H, J=8.9 Hz, Ar), 7.41 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.46 (d, 2H, J=8.9 Hz, Ar), 7.72 (t, 1H, J=1.9 Hz, Ar), 7.95 (d, 1H, J=2.8 Hz, Ar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([F:10])[F:9].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([Br:11])([F:10])[F:9]
Reactant: FC(F)c1ccccc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(Br)c1ccccc1Br
Reaction time: 72 h

Procedure:
A solution of 1-bromo-2-difluoromethylbenzene (9.6 g, 46.8 mmol) and N-bromosuccinimide (24.8 g, 139 mmol) in carbon tetrachloride (100 mL) was irradiated with a sunlamp. After 3 days, the reaction mixture was diluted with hexane, the precipitate was filtered off, and the collected organic filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (100% hexanes) provided the title compound: 1H NMR (500 M=Hz, CD2Cl2) δ7.74 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.37 (td, J=7.7, 1.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:26][C:27]1([CH3:35])[CH2:32][CH:31]([CH3:33])[CH2:30][CH:29](O)[CH2:28]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:20])([CH3:21])[C:17]([O:19][C@H:29]3[CH2:30][C@H:31]([CH3:33])[CH2:32][C:27]([CH3:35])([CH3:26])[CH2:28]3)=[O:18])=[CH:22][CH:23]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: CC1CC(O)CC(C)(C)C1
Reactant: CC(C)(Oc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: C[C@H]1C[C@H](OC(=O)C(C)(C)Oc2ccc(CCNC(=O)c3ccc(Cl)cc3)cc2)CC(C)(C)C1
Reaction time: 24 h
Yield: 45 %

Procedure:
12.5 g (0.034 mol) of 2-(4-(2-parachlorobenzamidoethyl)phenoxy)-2-methylpropionic acid are dissolved in 100 ml of anhydrous dimethylformamide, and 4.8 g of 3,3,5-trimethylcyclohexanol (transform) (0.034 mol) and 0.5 g of dimethylaminopyridine are added. After solubilization, a solution of 7 g of dicyclohexylcarbodiimide (0.034 mol) in 20 ml of dimethylformamide is added slowly at a temperature of around 0° C. The reaction is allowed to continue for 24 hours at ordinary temperature and the precipitate of dicyclohexylurea is filtered off; after evaporation of the filtrate under reduced pressure, the residue is chromatographed on a silica column in a mixture of petroleum ether and ethyl acetate. After evaporation of the solvent, the title derivative is obtained in the form of white crystals melting at 100° C.; the yield is 45%. This product, chromatographed under the conditions of Example 1, shows a single spot of Rf 0.2. The IR spectrum run in KBr has the following characteristic bands: one broad band at 3250 cm-1, a group of fine bands at 3000-2840 cm-1 an strong bands at 1750 cm-1 and 1640 cm-1.
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)([O-:10])=[O:9].[OH-].[Na+]>C(O)(=O)C>[CH3:7][N:5]([CH3:6])[CH2:4][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[CH:19][C:11]=2[N+:8]([O-:10])=[O:9])[NH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: CN(C)CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
N,N,N′,N′-Tetramethyldiaminomethane (2.2 mL, 15.6 mol) in acetic acid (30 mL) was added dropwise over 60 min to a solution of 4-nitroindole (2.30 g, 14.2 mol) in acetic acid (30 mL). After 3.5 h, the reaction was cooled to 0° C., and 20% aqueous sodium hydroxide was added to adjust the pH to 11. The mixture was extracted with CHCl3 (3×300 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=220 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15]C)[CH:11]=2)[CH:6]=1.O>Br.C(O)(=O)C>[CH3:17][C:4]([CH3:18])([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)[C:3]([OH:19])=[O:2]
Reactant: COC(=O)C(C)(C)c1ccc2cc(OC)ccc2c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C(=O)O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of α-methyl-6-methoxy-2-naphthaleneacetic acid methyl ester (12.2 g, 50 mmol) in tetrahydrofuran (100 ml) at -70° C. is added a solution of lithium diisopropylamide in cyclohexane (50 ml, 1.5 equiv). After 20 min, methyl iodide (4.0 ml, 1.3 equiv) is added followed by hexamethylphosphoramide (20 ml). After allowing the reaction mixture to warm to room temperature and stir 16 hours, the reaction is quenched by addition of acetic acid (4.3 ml, 75 mmol). The solvent is then removed and the residue is partitioned between ethyl acetate and water. The organic layer is washed with water 3 times and finally with brine. After drying over magnesium sulfate, the organic extract is evaporated to afford a crude solid. Recrystallization of this solid from hexane affords 8.56 g (66%) of α,α-dimethyl-6-methoxy-2-naphthaleneacetic acid methyl ester as white crystals, m.p. 97°-98° C. A solution of this ester (7.4 g, 28.6 mmol) in 48% HBr (50 ml) and acetic acid (50 ml) is refluxed for 3 hours. After the reaction mixture is cooled to room temperature, 0.8 L of water is added and the reaction mixture is extracted with ethyl acetate 5 times. The combined organic extract is washed sequentially with saturated sodium bicarbonate solution and water. After drying over magnesium sulfate, the organic extract is evaporated to afford 6.1 g (93%) of α,α-dimethyl-6-hydroxy-2-naphthaleneacetic acid as white crystals, m.p. 208°-210° C. The title compound is prepared according to the method of Example 7 using α,α-dimethyl-6-hydroxy-2-naphthaleneacetic acid. A white solid is obtained having a melting point of 207°-209° C.
Reaction SMILES: [H-].[Na+].[OH:3][N:4]=[CH:5][C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:27])[CH:12]=2)[N:7]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>CN(C)C=O>[CH2:33]([O:32][C:30]([CH2:29][O:3][N:4]=[CH:5][C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:27])[CH:12]=2)[N:7]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: ON=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CON=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
0.10 g (2.5 mmol) of sodium hydride was added to a suspension of 0.50 g (1.4 mmol) of 2-hydroxyiminomethyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 25 ml of dimethylformamide. The obtained mixture was stirred. After 30 minutes, 25 ml (2.3 mmol) of ethyl bromoacetate was dropped into the mixture. The mixture thus obtained was stirred at room temperature for several hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reducer pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 0.52 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C[Al](C)C.CC[O:17][C:18]([C:20]1[N:21]([CH2:32][C:33]2[CH:37]=[C:36]([C:38]3[S:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[O:35][N:34]=2)[CH:22]=[C:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[N:24]=1)=O>C(Cl)Cl>[C:28]([O:27][C:25]([C:23]1[N:24]=[C:20]([C:18](=[O:17])[NH:10][CH:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)[N:21]([CH2:32][C:33]2[CH:37]=[C:36]([C:38]3[S:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[O:35][N:34]=2)[CH:22]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1nc(C(=O)OC(C)(C)C)cn1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CC(C)N1CCC(N)CC1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2nc(C(=O)OC(C)(C)C)cn2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.9 %

Procedure:
To a solution of 1-isopropyl-piperidin-4-ylamine (142 mg) in DCM (4 mL) was added trimethyl aluminium (0.5 mL, 2M solution in hexanes) dropwise under an Ar atmosphere. The mixture was stirred for 15 min at RT. A solution of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-imidazole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester [example 1, (i)] (438 mg) in DCM (4 mL) was added dropwise and stirring was continued for 17 h at RT and 3 h at 35° C. After cooling the reaction was quenched by dropwise addition of 1M aqueous KHSO4 solution, concentrated, taken up in 6N HCL and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC. The fractions containing the product were evaporated to provide 154 mg of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-imidazole-4-carboxylic acid tert-butyl ester (example 2) as its trifluoroacetate salt. MS (ESI+): m/e=534, chloro pattern.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[N:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[N:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4cccnc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn4cccnc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Br:1][CH:2]([CH3:20])[CH:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:17])[OH:16])=[N:10][C:9]=2[C:8]([O:18][CH3:19])=[CH:7][CH:6]=1)[OH:4]>O.C(O)(=O)C>[Br:1][CH:2]([CH3:20])[C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:16])[OH:17])=[N:10][C:9]=2[C:8]([O:18][CH3:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(C(O)C(C)Br)c2sc(NC(=O)O)nc12
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(C)Br)c2sc(NC(=O)O)nc12
Temperature: 70 °C

Procedure:
5.0 g of [7-(2-bromo-1-hydroxy-propyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyll ester 0.0133 Mol) were suspended in water (30 ml) and 2.0 g of CrO3 (0.02 Mol), dissolved in acetic acid (30 ml), were added. The reaction mixture was heated to 70° C. for 2 hrs. and then evaporated to dryness. The residue was taken up in sat. NaHCO3 (200 ml), extracted 4× with ethyl acetate (200 ml each) and the combined organic phases were dried over MgSO4. The title compound was obtained as orange crystals (74%); F.p.: 199-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[CH:17](OCC)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:15][CH:14]3[N:16]([CH:17]=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(OC2CC3CCC(C2)N3)nc1
Reactant: CCOC=O
Product: O=CN1C2CCC1CC(Oc1ccc(Cl)cn1)C2

Procedure:
To 10 ml of ethyl format was added 0.4 g of 3-(5-Chloro-pyridin-2-yloxy)-8-aza-bicyclo[3.2.1]octane, the mixture was heated at reflux for 48 hours and evaporated to dryness, crystallized from ethyl acetate petroleum ether. Yield 200 mg (53%), Mp. 112-114° C.