Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH2:6][NH2:7])[CH2:4][NH2:5].C[O-].[Na+].Cl.[NH2:12][C:13](N)=N>CO>[ClH:1].[CH3:2][CH:3]1[CH2:6][NH:7][C:13]([NH2:12])=[N:5][CH2:4]1
Reactant: N=C(N)N
Reactant: CC(CN)CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1CN=C(N)NC1
Temperature: 140 °C

Procedure:
To a solution containing 6.7 g (41.6 mmol) of 2-methyl-1,3-propanediamine hydrochloride (Tetrahedron (1994) 50(29), 8617–8632) in 50 ml of methanol was added 83 ml of a solution of sodium methylate in methanol (1 mmol/ml) and the resulting mixture was treated with 3.97 g (41.6 mmol) of guanidine hydrochloride. The reaction mixture was heated at 140° C. for 3 h. The solution was filtered, the solvent evaporated and the residue obtained was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH:9]1[CH2:15]C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][OH:26])=[NH:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH:9]1[C:15]1[O:26][N:25]=[C:23]([C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([Cl:19])[CH:21]=2)[N:24]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1CC(=O)O
Reactant: N=C(NO)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1c1nc(-c2cccc(Cl)c2)no1
Temperature: 135 °C
Yield: 53.9 %

Procedure:
2-Carboxymethyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (1.87 g, 7.25 mmol), 3-chloro-N-hydroxy-benzamidine (1.36 g, 7.98 mmol), HOBt (1.08 g, 7.98 mmol) and EDCl (1.53 g, 7.98 mmol) in DMF (20 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (3 times), saturated sodium bicarbonate (2 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in DMF (20 mL) and then heated at 135° C. for 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification was performed by flash chromatography on silica gel using hexanes:dichloromethane (1:1) to afford the titled compound (1.48 g, 52%, white foam solid). 1H NMR (CDCl3) δ (ppm): 8.08 (m, 1H), 7.97 (m, 1H), 7.46 (m, 2H), 6.35 (m, 1H), 5.04 (m, 1H), 4.31 (m, 1H), 3.68 (m,1H), 3.50 ( m, 2H), 3.27 (m, 2H), 1.35 (bs, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19](=O)[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].S(O)(O)(=O)=O.[NH2:33][OH:34]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19](=[N:33][OH:34])[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(COc2ccc(C(C)=O)cc2OC)cn1
Reactant: NO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(COc2ccc(C(C)=NO)cc2OC)cn1
Temperature: 25 °C
Reaction time: 64 h
Yield: 96.3 %

Procedure:
To a stirred suspension of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one (5.48 g, 19.07 mmol) and potassium carbonate (10.54 g, 76.29 mmol) in methanol (100 mL) and water (10 mL) was added hydroxylamine sulfate (4.70 g, 28.61 mmol). The resulting mixture was heated to reflux. After 64 h, the mixture was allowed to cool to room temperature and was diluted with water (250 mL). The resulting suspension was filtered, and the filtercake was washed with water (50 mL) and dried to provide 5.55 g (96%) of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one oxime as a white solid.
Reaction SMILES: [CH2:1]1[O:20][C:4]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)([CH3:5])[O:3][CH2:2]1.C(O)C.CCOCC.[OH-].[K+]>O>[CH2:1]1[O:20][C:4]([CH2:6][CH2:7][CH2:8][NH2:9])([CH3:5])[O:3][CH2:2]1
Reactant: CC1(CCCN2C(=O)c3ccccc3C2=O)OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC1(CCCN)OCCO1

Procedure:
Seventy-one grams of 5-phthalimido-2-pentanone ethylene ketal (0.26 moles) were suspended into 250 ml of 95% ethanol. Then 13.0 g of NH2 ·NH2 ·H2O (0.26 moles) was added and the reaction mixture was brought to reflux. The stirred mixture was refluxed for 2 hours. Ether (400 ml) was added to the cooled suspension, which was then treated with 40 g of potassium hydroxide in 150 ml of water. The two layers were separated and the aqueous The ether was combined and dried over sodium sulfate. The solvent was then removed under pressure and the remaining liquid that contained crude product was weighed.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:14]([NH:21][CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.O>[CH2:14]([N:21]([CH2:10][C:9]1[C:4]([CH:3]([O:12][CH3:13])[O:2][CH3:1])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(OC)c1ncccc1C=O
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(Cl)Cl
Product: COC(OC)c1ncccc1CN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.3 %

Procedure:
To a mixture of 2.0 g (11 mmol) of 2-dimethoxymethyl-pyridin-3-carbaldehyde and 1.6 mL (12 mmol) of N-benzyl methyl amine in 30 mL of dichloroethane is added 4.7 g (22 mmol) of sodium triacetoxyborohydride. The reaction is stirred for 18 hours at room temperature. To this mixture is added 20 mL of water. After 1 hour of stirring the pH of the reaction mixture is adjusted to 8.0 with 1N NaOH. The organic layer is separated from the water layer, dried and evaporated to yield 1.9 grams of benzyl-(2-dimethoxymethyl-pyridin-3-ylmethyl)-methyl-amine. 1H NMR (CDCl3) δ 8.5 (d, 1H), 7.9 (d, 1H), 7.3 (m, 6H), 5.6 (s, 1H), 3.7 (s, 2H), 3.5 (s, 2H), 3.3 (s, 6H), 2.1 (s, 3H). Mass spectrum: m/e=287.8 (p+1). TLC (1/1 ethyl acetate/hexanes) Rf=0.2. Step 6:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39](CCC(O)=O)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2].Cl.[NH2:48][C:49]([CH3:61])([CH3:60])[C:50]([O:52]CC1C=CC=CC=1)=[O:51].Cl.NCC([O:67][CH2:68][C:69]1C=CC=C[CH:70]=1)=O>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:70][CH2:69][C:68](=[O:67])[NH:48][C:49]([C:50]([OH:52])=[O:51])([CH3:60])[CH3:61])=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(CCC(=O)O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(N)C(=O)OCc1ccccc1
Agent: Cl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(CCC(=O)NC(C)(C)C(=O)O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Example 84 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(2-carboxyethyl)phenyl]ethyl}benzofuran and benzyl 2-amino-2-methylpropionate hydrochloride instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-carboxyphenyl)ethyl]benzofuran and benzyl 2-aminoacetate hydrochloride, respectively.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]([Cl:21])([Cl:20])[C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[O:14].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Cl:21][C:12]([Cl:11])([Cl:20])[C:13]([C:15]1[NH:16][CH:17]=[C:18]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=1)=[O:14]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2 h
Yield: 60 %

Procedure:
In a dry flask, phenylacetyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM) to dissolve the reactants. To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 1 in 60% yield. 1H NMR (CDCl3) δ 4.0 (s, 2H), 7.1-7.35 (m, 7H), 9.7 (br s, NH). HPLC using method B provided Rt of 4.9 minutes. LC/MS (M+1) 330.2, (M−1) 328.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([C:20]([NH2:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:15]([C:20]([NH2:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:7])[CH3:2]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ncccc1N
Product: CCOc1ccccc1C(=O)Nc1cccnc1C(N)=O

Procedure:
The title compound was prepared from 2-ethoxybenzoyl chloride and 3-aminopyridine-2-carboxamide (J. Chem. Soc., 1956, 1045) following the procedure of Preparation 7 and was obtained as an off-white solid (100 %), m.p. 172°-177° C. Found: C,62.91; H,5.30; N,14.51. C15H15N3O3 requires C,63.15; H,5.30; N,14.73%.
Reaction SMILES: C(O)CCC.CC1C2C(=CC=CC=2)CCN1.[Cl:17]C1C(C)=C(C)N=C(NC2C=CC(F)=CC=2)N=1.[CH3:34][C:35]1[C:36]([N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]2[CH3:60])=[N:37][C:38]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:39][C:40]=1[CH3:41]>C(O)CO.C(N(CC)CC)C>[ClH:17].[CH3:34][C:35]1[C:36]([N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]2[CH3:60])=[N:37][C:38]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:39][C:40]=1[CH3:41]
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(Cl)c1C
Agent: CC1NCCc2ccccc21
Agent: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Solvent: CCCCO
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Cl

Procedure:
110 ml of n-butanol, 240 ml of triethylamine and 236 g(1.60 mmole) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 600 ml of ethylene glycol. 400 g(1.59 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 140° C. for 48 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 485 g of purified 5,6-dimethyl -2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:13])([F:14])[C:9]([F:10])([F:11])[F:12])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(F)(F)C(F)(F)F)cc1
Product: Cc1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Prepared from 1-methyl-4-(perfluoroethyl)benzene (1.95 g, 9.28 mmol) with sulfuric and nitric acid as described in EP 0418175 (1.45 g, 61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[N:12][CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][S:16][C:13]1[CH:14]=[CH:15][C:10]([C:9](=[O:17])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:18]([O-:20])=[O:19])[CH:4]=2)=[CH:11][N:12]=1)[CH3:27]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(S)nc1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CSc1ccc(C(=O)Nc2ccc(F)c([N+](=O)[O-])c2)cn1
Reaction time: 0.17 h
Yield: 107.8 %

Procedure:
To mixture of the of N-(4-fluoro-3-nitrophenyl)-6-mercaptonicotinamide (200 mg, 0.68 mmol) and ethyl bromoacetate (113 μL, 1.02 mmol) in DMF (5 mL) was added DIPEA (243 μL, 1.4 mmol). The reaction mixture was stirred for 10 minutes before being poured into water and being extracted with ethyl acetate (3×50 mL). The combined extracts were washed with water and brine and were dried over magnesium sulfate. Filtration followed by concentration in vacuo gave 278 mg (100%) of [5-(4-fluoro-3-nitrophenylcarbamoyl)pyridin-2-ylsulfanyl]acetic acid ethyl ester as a solid: 1H NMR (300 MHz, acetone-d6) δ 10.0 (bs, 1H), 9.02 (m, 1H), 8.21 (m, 1H), 8.18 (m, 2H, 7.46 (m, 2H), 4.16 (m, 2H), 4.08 (s, 2H), 1.22 (m, 3H); MS (EI) m/z 377.88 (M−H)−.
Reaction SMILES: P([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[C@H:8]([O:19][CH2:20][CH2:21][C:22]#[N:23])[C@@H:7]1[OH:24])(N)O>C(#N)C>[C:22]([CH2:21][CH2:20][O:19][C@@H:8]1[C@H:7]([OH:24])[C@@H:6]([CH2:5][OH:4])[O:10][C@H:9]1[N:11]1[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]1=[O:13])#[N:23]
Reactant: N#CCCO[C@@H]1[C@H](O)[C@@H](COP(N)O)O[C@H]1n1ccc(=O)[nH]c1=O
Solvent: CC#N
Product: N#CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
RNA synthesis program (condensation time: 10 min.) was carried out using four kinds of anhydrous acetonitrile solution of 2′-O-cyanoethyluridine phosphoramidite unit (compounds 7, 14, 18 and 26, 0.1M) by means of a DNA/RNA automatic synthesizer (Applied Bio System) provided with a long aminoalkyl chain CPG (1 μl) in which 2′-O-cyanoethyluridine was introduced via a succinyl linker by a conventional way (16 μl mol/g), which was filled into a socket for solid-phase synthesis. After the synthesis had been completed, excision of the resulting oligonucleotide from the solid phase and removal of a protecting group of the nucleic acid base moiety were carried out by treatment with ammonia water-ammonium acetate (10% wt/wt: 1 ml) for 90 min. After diluted appropriately with ammonium acetate buffer, the oligonucleotides were purified with a reverse phase column cartridge and an anion exchange HPLC. The oligonucleotides obtained by a desalting operation with the reverse phase column cartridge were lyophilized to give a titled compound with a yield of 58%. Analysis profile obtained in the anion exchange HPLC is shown in FIG. 1B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:36])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:36])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: CSCc1cccc2c(C(CCCO)c3ccc(Cl)cc3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCCO)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg (0.11 mmol) of the compound from Example 15 were introduced into 7 ml of dichloromethane at 0° C., 27.4 mg (0.11 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, the residue after concentration was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 33 mg (79% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:17]=2[CH2:18][OH:19])[CH:3]=1.O>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]3[N:10]=[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]4[C:17]=3[CH2:18][O:19][C:5]2=[CH:6][CH:7]=1
Reactant: OCc1c(-c2cc(Br)ccc2O)nc2ccccn12
Solvent: Cc1cc(C)cc(C)c1
Solvent: O
Product: Brc1ccc2c(c1)-c1nc3ccccn3c1CO2
Temperature: 170 °C
Reaction time: 6 h
Yield: 553.5 %

Procedure:
4-bromo-2-(3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)phenol (0.2 g, 0.06 mmol) was dissolved in mesitylene (1 mL). The mixture was stirred at 170° C. for 6 hours, and then cooled to 25° C. H2O (20 mL) was added and extracted with EtOAc (3*50 mL), washed by brine (50 mL). After concentrated, the resulting residue was purified using Prep-TLC (petroleum ether:EtOAc=1:1) to provide 2-bromo-6H-chromeno[4′,3′:4,5]imidazo[1,2-a]pyridine (100 mg, yield: 53.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.98˜7.99 (m, 1H), 7.74˜7.76 (m, 1H), 7.66˜7.68 (m, 1H), 7.21˜7.28 (m, 2H), 6.82˜6.90 (m, 2H), 5.70 (s, 2H). MS (M+H)+: 301/303.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4](O)=[O:5].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=[N:37][CH2:38][CH2:39][CH2:40][N:41]([CH3:43])C.Cl.Cl.N1CC(C#N)C1.CN1CCOCC1>CN(C=O)C>[CH3:21][C:2]([CH3:1])([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([N:41]1[CH2:40][CH:39]([C:38]#[N:37])[CH2:43]1)=[O:5]
Reactant: CC(C)(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CC1CNC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2ccnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
(R)-3,3-Dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (80 mg, 0.278 mmol), HOBt hydrate (51.2 mg, 0.334 mmol), and EDC hydrochloride (80 mg, 0.418 mmol) were combined in DMF (2 mL). Azetidine-3-carbonitrile hydrochloride (49.5 mg, 0.418 mmol) and 4-methylmorpholine (0.124 mL, 1.114 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and purified by flash column chromatography (8% MeOH/DCM) to afford the title compound (38 mg, 39%). 1H NMR (500 MHz, CD3OD) δ 1.17 (s, 9H), 3.58-3.72 (m, 1H), 4.13-4.65 (m, 4H), 5.35-5.45 (m, 3H), 7.28-7.38 (m, 1H), 7.95 (d, J=15.5 Hz, 1H), 8.33-8.40 (m, 1H). [M+H] calc'd for C19H21N5O2, 352; found, 352.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH:10]([C:15]2[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5][C:4]=1[C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=1)=O.Cl.[NH2:39][OH:40].[CH3:41][OH:42]>C(OCC)(=O)C>[CH3:41][O:42][C:24](=[O:25])[CH2:23][CH2:22][NH:21][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([CH:10]([O:9][C:7]2[CH:6]=[CH:5][C:4]([C:29]3[CH:30]=[CH:31][C:32]([CH:35]([CH3:36])[CH3:37])=[CH:33][CH:34]=3)=[C:3]([CH:1]=[N:39][OH:40])[CH:8]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:28][CH:27]=1
Reactant: CC(C)CC(Oc1ccc(-c2ccc(C(C)C)cc2)c(C=O)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Reactant: NO
Reactant: CO
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)C)cc3)c(C=NO)c2)cc1
Reaction time: 4 h

Procedure:
To the solution of 3-{4-[1-(2-formyl-4′-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic acid (75 mg, 0.15 mmol) in methanol (10 ml) is added hydroxylamine hydrochloride (104 mg, 1.5 mmol). After 4 h, the mixture is diluted with ethyl acetate, washed with 1N HCl, water, brine, dried over MgSO4, and concentrated. The residue is purified by column chromatography to afford 38 mg of 3-(4-{1-[2-(hydroxyimino-methyl)-4′-isopropyl-biphenyl-4-yloxy]-3-methyl-butyl}-benzoylamino)-propionic acid methyl ester, which is hydrolyzed by 5N NaOH to afford the titled compound (36 mg). MS (ES): 517.2 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:47])=[C:41]([CH:46]=1)[C:42]([O:44]C)=[O:43]>>[C:42]([C:41]1[CH:46]=[C:37]([CH:38]=[CH:39][C:40]=1[CH3:47])[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)([OH:44])=[O:43]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COC(=O)c1cc(CCl)ccc1C
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)O)c2)cc1

Procedure:
Analogously to Method D, 1.68 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.700 g of methyl 5-chloromethyl-2-methylbenzoate are reacted. The title compound is obtained as a white foam. Rf=0.07 (1:2 EtOAc-heptane); Rt=5.65.
Reaction SMILES: Br.[C:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7](Br)[CH2:6]1)(=[O:4])[CH3:3].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[C:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:13]=[C:14]([NH2:16])[S:15][C:7]=2[CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCC(=O)C(Br)C1
Reactant: NC(N)=S
Agent: Br
Solvent: CCO
Product: CC(=O)N1CCc2nc(N)sc2C1
Reaction time: 1 h
Yield: 10.1 %

Procedure:
N-Acetyl-3-bromo-4-piperidone hydrobromide (3.0 g, 9.9 mmol) was added slowly to a solution of thiourea (756 mg, 9.9 mmol) in dry ethanol (13.5 ml) at 60°. After completion of the addition, the reaction mixture was allowed to stir at 40° for 1 hour; the ethanol was then distilled off at atmospheric pressure, and the residue was heated to 160°-170° for 20 minutes. The reaction mixture was then cooled and dissolved in water, neutralized with saturated aqueous sodium bicarbonate, and extracted three times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give an oil. Purification was effected by flash column chromatography (9:1 chloroform:methanol) to provide the title product as a solid (200 mg, 1.0 mmol, 10% yield).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[C:23]([C:24]#N)=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-:27].[Na+].Cl.[OH2:30]>C1COCC1>[C:4]([CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[C:23]([C:24]([OH:30])=[O:27])=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)([OH:3])=[O:26]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nccnc3C#N)cc(C)c21
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Oc2nccnc2C(=O)O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of [6-(3-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (100 mg, 0.283 mmol) in THF (3 mL) was added NaOH (1N in H2O, 2.0 mL). The resulting solution was stirred at room temperature overnight. The mixture was diluted with H2O and acidified to pH 3 with 1N HCl at 0° C. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The crude mixture was purified by prep HPLC to give the title compound (150 mg, 82%) as a white solid. 1H NMR (CD3OD) δ 8.33 (d, 1H), 8.23 (d, 1H), 7.20 (d, 1H), 7.08 (d, 1H), 5.64 (dd, 1H), 3.15 (dd, 1H), 2.34 (s, 3H), 2.26 (dd, 1H). MS found: (M+H)+: 345.