Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)[CH:18]=[CH:19][N:20](C)C)=[N:11]1.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]2[N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=[CH:19][CH:18]=2)=[N:11]1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccccc2OC(F)F)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccccc2OC(F)F)nc1-c1ccnn1-c1ccccc1
Yield: 4 %

Procedure:
To a solution of 1-[2-(difluoromethoxy)phenyl]-3-[3-(dimethylamino)prop-2-enoyl]pyridazin-4(1H)-one (crude 622 mg, 1.85 mmol) in 20 mL of methanol was added phenylhydrazine (800 mg, 7.40 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-[2-(difluoromethoxy)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (30 mg, 4% for two steps) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:25].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[F:1][C:2]1[CH:12]=[CH:11][C:10](/[CH:13]=[N:15]/[C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][O:19][C:20]3=[O:25])=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: CN(C)C(=O)c1cc(C=O)ccc1F
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CN(C)C(=O)c1cc(/C=N/c2cccc3c2COC3=O)ccc1F
Yield: 37.7 %

Procedure:
A solution of 2-fluoro-5-formyl-N,N-dimethylbenzamide (2.38 g, 12.2 mmol), 4-aminoisobenzofuran-1(3H)-one (1.82 g, 12.2 mmol), anhydrous magnesium sulfate (14.67 g, 122 mmol) in acetonitrile (100 ml) was heated to reflux for 2 days. The solution was filtered and removed in vacuum. The crude product was re-crystal with isopropanol to give the title compound (1.5 g, yield: 37%) 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.91-2.92 (d, J=0.4 Hz, 3H), 3.07 (s, 3H), 5.55 (s, 2H), 7.52-7.56 (t, J=8.8 Hz, 1H), 7.67-7.70 (m, 2H), 7.76-7.78 (m, 1H), 8.02-8.04 (m, 1H), 8.10-8.14 (m, 1H), 8.83 (s, 1H); LC-MS (ESI) m/z: 327 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=1)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:17][CH2:16][C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(=O)[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(=O)[nH]c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[CH:9]12[CH2:15][CH:12]([CH:13]=[CH:14]1)[CH2:11][CH:10]2[C:16](OC)=[O:17]>C[O-].[Na+].C1(C)C=CC=CC=1>[CH:9]12[CH2:15][CH:12]([CH:13]=[CH:14]1)[CH2:11][CH:10]2[C:16]([O:6][CH2:5][CH2:4][CH2:3][C:2]([OH:8])([CH3:7])[CH3:1])=[O:17]
Reactant: COC(=O)C1CC2C=CC1C2
Reactant: CC(C)(O)CCCO
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(O)CCCOC(=O)C1CC2C=CC1C2
Yield: 92.9 %

Procedure:
A mixture of 118 g of 4-methyl-1,4-pentanediol, 173 g of methyl 5-norbornene-2-carboxylate, 1.4 g of sodium methoxide and 400 ml of toluene was heated under reflux for 5 hours while distilling off the methanol which formed during the reaction. The reaction solution was cooled, washed with saturated sodium bicarbonate water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was purified by vacuum distillation, collecting 221 g of 4-hydroxy-4-methylpentyl 5-norbornene-2-carboxylate (yield: 93%). The physical data of this product were in good coincidence with those of Synthesis Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:4]=2[N:3]=1.[C:22]([C:30](OCCC)=[O:31])#[C:23][C:24]([O:26][CH2:27][CH2:28][CH3:29])=[O:25]>C(O)CC>[C:24]([C:23]1[N:3]2[C:4]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=3[C:6]([C:9]3[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=3[F:16])=[N:7][CH2:8][C:2]2=[N:1][C:30](=[O:31])[CH:22]=1)([O:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CCCOC(=O)C#CC(=O)OCCC
Reactant: NC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1
Solvent: CCCO
Product: CCCOC(=O)c1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 27, 2-amino-7-chloro-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine was heated in propanol with dipropyl acetylenedicarboxylate to give 1-carbopropoxy-9-chloro-7-(2,6-difluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C>C1COCC1.CCOCC>[CH3:6][C:7]1[S:8][C:9]([B:16]([OH:17])[OH:15])=[CH:10][CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
n-BuLi (2.38 M, 16 ml) was slowly added to a solution of 2-methyl thiophene (3.0 g, 31 mmol) in THF (20 ml) at −78° C. The solution was kept at −78° C. for 10 min. then warmed to 0° C. for an additional 0.5 hr. The solution was then transferred by steel canula under nitrogen into a vessel containing triisopropylborate (6.3 g, 33 mmol) in ether (15 ml) at −78° C. The resulting milky white solution was stirred at −78° C. for 20 min. then at room temperature for 2 hours. The reaction was quenched by the addition of 10% aqueous HCl (5.0 ml) and the solution was extracted into ether. The combined ether extracts were extracted with 10M NaOH (2×30 ml), the aqueous extracts were acidified with dilute HCl to pH 2 and extracted into ether (3×25 ml). The combined ether extracts were washed once with water (10 ml), once with brine (10 ml) and dried and evaporated to give 3.91 g 2-methylthiophene-5-boronic acid as a light brown solid. This was used in the next step with no further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29](=[O:32])[CH2:30]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29](=[O:32])[CH2:30][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CBr)c1ccc(F)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)cc2OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
1-(tert-Butoxycarbonyl)piperazine (808 mg, 4.34 mmol) was added to a mixture of 2′-(benzyloxy)-2-bromo4′-fluoroacetophenone (assumed 4.13 mmol) and potassium carbonate (856 mg, 6.20 mmol) in DMF, and stirred for 18 h at room temperature. The solvent was removed in vacuo, the residue taken up in ethyl acetate (150 mL) and washed with water (100 mL) and brine (100 mL). The organice layer was dried (MgSO4) and the solvents removed in vacuo. The crude product was purified by flash chromatography, eluting with 9:1 hexane:EtOAc followed by 1:1 hexane:EtOAc to give pure 2′-(benzyloxy)-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-4′-fluoroacetophenone (1.42 g, 80% over 2 steps) as a yellow oil; Rf 0.00 (9:1 hexane:EtOAc), 0.50 (1:1 hexane:EtOAc); δH (CDCl3) 7.89 (1H, dd, J=9.3 and 6.9 Hz), 7.48-7.44 (5H, m), 6.81-6.77 (2H, m), 5.17 (2H, s), 3.79 (2H, s), 3.51-3.47 (4H, m), 2.44-2.41 (4H, m), 1.50 (9H, s); LCMS retention time 2.10 min, M+H+ 429.4.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([NH:8][S:9]([C:12]1[CH:24]=[CH:23][C:15]2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])S[C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-:27]>C1COCC1.O>[CH3:6][CH:5]([CH3:7])[C@@H:4]([NH:8][S:9]([C:12]1[CH:24]=[CH:23][C:15]2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[O:27][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[C:3]([OH:2])=[O:25]
Reactant: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)OC)C(C)C)cc2s1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc2o1

Procedure:
(2R)-3-methyl-2-[(2-propylthiobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (0.19 g, 0.48 mmol) was dissolved in THF/H2O (2 mL/2 mL), and LiOH (0.10 g, 5 equi.) was added. After reflux for 6 hours, the reaction solution was distilled under reduced pressure and treated with 1N HCl. The product was extracted with ethylacetate (10 mL). The separated organic phase was washed with NaCl solution, dried over MgSO4, distilled under reduced pressure and dried under vacuum to prepare the titled compound, (2R)-3-methyl-2-[(2-propylthiobenzoxazol-6-sulfonyl)amino]butanoic acid (0.14 g, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2.B(F)(F)F.[C:21](O)(=[O:23])[CH3:22]>>[CH2:15]([O:14][C:12]([CH:7]1[CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[C:11]([C:21](=[O:23])[CH3:22])=[CH:10][C:9]=2[O:8]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C1CCc2cc(O)ccc2O1
Reactant: CC(=O)O
Agent: FB(F)F
Product: CCOC(=O)C1CCc2cc(O)c(C(C)=O)cc2O1
Temperature: 80 °C
Yield: 60 %

Procedure:
Into a solution of 2.23 g of racemic-ethyl 6-hydroxychroman-2-carboxylate in 30 ml of acetic acid was introduced a stream of boron trifluoride gas at 20°-25° C. A cold water bath was used during the introduction of the gas (30-45 minutes) to control the temperature of the exothermic reaction. The cold bath was removed and the reaction mixture was heated at 80° C. for 5 hours; then the reaction mixture was cooled and carefully poured into a mixture of saturated sodium bicarbonate and ice, and the product was extracted with 1:1 tetrahydrofuran-ether. The crude material obtained after evaporation of the solvent was chromatographed on a silica gel column to yield 1.6 g (60%) of racemic-7-acetyl-6-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester as a viscous oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]1([CH2:27][CH2:28][C:29]2[CH:37]=[CH:36][C:32]([CH2:33][CH2:34][NH2:35])=[CH:31][CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH2:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][CH2:34][NH:35][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])=[CH:36][CH:37]=1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCCc1ccc(CCC2CCCCC2)cc1
Product: Nc1nc(NCCc2ccc(CCC3CCCCC3)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Reaction of 2-chloroadenosine with p-(2-cyclohexylethyl)-phenethylamine as described in Example 14 gives 2-[2-(p-2-cyclohexylethyl-phenyl)-ethylamino]-adenosine, [alpha]D25 =-25.6° in DMSO, m.p. 154°-160°.
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[F:11][C:12]([F:18])([CH:15]([F:17])[F:16])[CH2:13][OH:14].[Br:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[C:22]([F:27])[CH:21]=1>O>[Br:19][C:20]1[CH:25]=[C:24]([O:14][CH2:13][C:12]([F:18])([F:11])[CH:15]([F:17])[F:16])[CH:23]=[C:22]([F:27])[CH:21]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: OCC(F)(F)C(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(Br)cc(OCC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
To a 50 mL flask flushed with nitrogen, equipped with a stir bar was added potassium tertbutoxide (1.1 g, 10 mmol, 95%). DMSO was added (10 mL) followed by addition of a solution of 2,2,3,3-tetrafluoropropan-1-ol (0.95 mL, 11 mmol) via syringe. After 5 min, 1-bromo-3,5-difluorobenzene (1.1 mL, 9.5 mmol) was added and the reaction mixture stirred at room temperature for 18 h. Water was added (100 mL), and the aqueous phase extracted with ether (2×100 mL). The organic portion was then washed successively with water (2×100 mL) and saturated NaCl solution (2×100 mL), dried over Na2SO4, decanted and concentrated under reduced pressure yielding a crude yellow liquid which was purified by distillation under reduced pressure at 140° C. yielding the 1-Bromo-3-fluoro-5-(2,2,3,3-tetrafluoropropoxy)benzene as a colorless oil (1.6 g, 54% yield).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH:8]=[C:7]([CH3:22])[C:3]=1[C:4]([OH:6])=O.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[C:3]([C:4]([N:31]2[CH2:32][CH2:33][CH:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:29][CH2:30]2)=[O:6])=[C:7]([CH3:22])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:19])([F:20])[F:21])[CH:12]=2)[N:10]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1cc(-c2cccc(OC(F)(F)F)c2)nc(C)c1C(=O)O
Product: Cc1cc(-c2cccc(OC(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedures described for example 1, for intermediate 5B and for intermediate 1, the title compound has been prepared by the following reaction sequence: i) 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester [Zhou, Y.; Bridger, G. J.; Skerlj, R. T.; Bogucki, D.; Yang, W.; Bourque, E.; Langille, J.; Li, T.-S.; Metz, M. U.S. Pat. Appl. Publ. (2005), US 2005277668 A1] was reacted with 3-trifluoromethoxy-phenyl boronic to give 2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-nicotinic acid ethyl ester; ii) 2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-nicotinic acid ethyl ester has been saponified to give 2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-nicotinic acid; iii) 2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-nicotinic acid was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as light yellow oil. MS: 448.2 (MH+).
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.O>C1COCC1>[C:21]1([CH3:26])[C:20]([NH:19][CH:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:16])[C:9](=[O:17])[C:8]3[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]2=3)=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1c2cccc(Cl)c2C(Br)c2cccc(Cl)c21
Reactant: Cc1ccccc1N
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1NC1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of compound (6) (2.0 mmol) in dry THF (20 ml) was added dropwise a solution of o-toluidine (10 ml) in dry THF (10 ml) under N2. The reaction mixture was stirred at room temperature for 24 hours. Water (250 ml) was added and then extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting precipitate was collected by filtration, washed with water and further purified by crystallization (CH3CN).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Br:23])=[CH:18][CH:19]=2)[N:14]=1.C(#N)C>O>[Br:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Br)nc2n1
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)Nc2ccc3ccc(Br)nc3n2)cc1
Temperature: 4 °C
Yield: 46.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (10.2 g), N,N'-carbonyldiimidazole (10.8 g) and 2-amino-7-bromo-1,8-naphthyridine (11.2 g). The product produced by precipitation in water (9.8 g; m.p. 220° C.) is dissolved in boiling acetonitrile (1000 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-bromo-1,8-naphthyridin-2-yl)-4-methoxybenzamide (8.3 g) is produced, m.p. 221° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15](O)=O)=[C:7]2[C:11]=1[O:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8]2.[NH2:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][N:20]=1>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:8][C:7]=2[C:6]([C:15]2[NH:25][C:24]3[C:19]([N:18]=2)=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:5][CH:4]=1
Reactant: Nc1cccnc1N
Reactant: COc1ccc(C(=O)O)c2cc(C(C)C)oc12
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3ncccc3[nH]2)c2cc(C(C)C)oc12

Procedure:
4.6 g of 7-methoxy-2-(1-methylethyl)benzofuran-4-carboxylic acid and 2.2 g of 2,3-diaminopyridine are boiled under reflux for 4 h in 80 ml of phosphorus oxychloride. The mixture is largely evaporated in vacuo, the residue is partitioned between 100 ml of ice water and 500 ml of ethyl acetate and the aqueous phase is rendered alkaline with 50 percent sodium hydroxide solution. The organic phase is separated off, the aqueous phase is extracted a further two times by shaking with ethyl acetate, and the organic phases are combined, dried over ignited calcium carbonate and concentrated in vacuo. The residue is chromatographed on silica gel using a 1:1 mixture of toluene and ethyl acetate. After the evaporation of appropriate fractions, 1.7 g (28.3% of theory) of title compound having the m.p. 242° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[N:9][CH:10]=2)[CH:7]=1.C1C(=O)N([I:27])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[N:9][C:10]=2[I:27])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: FC(F)(F)C(F)(F)CCc1ncc2ccc(Cl)cn12
Solvent: ClCCl
Product: FC(F)(F)C(F)(F)CCc1nc(I)c2ccc(Cl)cn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from Step G (3.64 g, 12.19 mmol) in anhydrous DCM (50 mL) was added NIS (5.48 g, 24.4 mmol). The reaction mixture was stirred at room temperature for 18 hours and concentrated. The residue was suspended in ethyl acetate and washed with saturated sodium thiosulfate (2×). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give a bright white solid. m/z=424.7 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[OH-].[Na+].[C:12](O)(=[O:14])[CH3:13]>C(OC(=O)C)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 1 h

Procedure:
A solution of 25.0 g (144 mmol) of 2-amino-5-bromopyridine in 50 mL of acetic acid and 250 mL of acetic anhydride was heated at reflux for about 2 hours. The reaction mixture was then cooled and poured into 750 mL of water with stirring. After about 1 hour, the solution was adjusted to pH=10 with 50% sodium hydroxide solution and the precipitate was filtered, washed with water and dried to give 26.5 g of the title product as a white flaky solid, mp 175-176° C. 1H nmr (deuteriochloroform): δ=8.29 (d, 1 H); 8.12 (d, 1 H); 7.96 (br, 1 H); 7.78 (d of d, 1 H); 2.19 (s, 3 H). MS (El): m/z=214, 216 (M+, Br isotopes).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[O:2].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+].[CH:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])[CH3:25].O>>[CH:24]([N:27]1[CH2:32][CH2:31][N:30]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[O:8])[CH2:29][CH2:28]1)([CH3:26])[CH3:25]
Reactant: CC(C)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1

Procedure:
A solution of 4-formyl-benzoyl chloride (2.80, 16.65 mol) (prepared as in Example 1 above) in toluene (43.3 g, 469.39 mmol) was added slowly to a solution of NaHCO3 (0.8 g, 9.52 mmol) and 4-isopropylpiperazine (2.50 g, 18.35 mmol) in water (5 g, 277 mmol) at 0° C. The reaction mixture was vigorously stirred until the reaction was deemed complete. The layers were split and the toluene phase was concentrated to yield the title compound as a yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.O.[Pd]>[CH3:25][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)c1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccnc1N(C)C1CCNCC1
Reaction time: 16 h

Procedure:
A mixture of 1-benzyl-4-[N-methyl-N-(3-methoxycarbonyl-2-pyridyl)amino]piperidine (EXAMPLE 136, 250 mg) and palladium hydroxide-on-carbon (20%, 45% moisture, 100 mg) in methanol (14 ml) is shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere at 40 psi for 2 hrs and at 28 psi for 16 hrs. The catalyst is then removed by filtration through diatomaceous earth and the filtrate is concentrated under reduced pressure and flushed through a short pad of silica gel (70-230 mesh, 5 g), eluting with a gradient of methanol/methylene chloride (5/95-20/80). Pooling of fractions with an Rf =0.06 by TLC (methanol/chloroform, 20/80) and removal of solvent under reduced pressure gives 4-[N-methyl-N-(3-methoxycarbonyl-2-pyridyl)amino]piperidine. To a flame-dried flask under nitrogen is added 5-(methanesulfonylamino)indolyl-2-carboxylic acid (135 mg), 1,1-carbonyldiimidazole (754 mg) and dry tetrahydrofuran (2.5 ml) and the mixture is stirred at 20°-25° for 1 hr. Then a mixture of the debenzylated intermediate 4-[N-methyl-N-(3-methoxycarbonyl-2-pyridyl)amino]piperidine (110 mg), in dry tetrahydrofuran (3 ml) is added and the resultant mixture is stirred at 20°-25° for 20 hrs and concentrated under reduced pressure to remove solvent. The residue is diluted with methylene chloride (20 ml), washed with water (5 ml), saturated aqueous sodium bicarbonate (5 ml) and saline (5 ml), dried over sodium sulfate, concentrated under reduced pressure and chromatographed (silica gel, 230-400 mesh, 25 g; eluting with a gradient of methanol/methylene chloride (1/99-3/97)). Pooling of fractions with an Rf =0.28 by TLC (methanol/chloroform, 5/95) and removal of solvent under reduced pressure gives the title compound, mp 223°-224°.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][C@H:14]1[CH2:18][NH:17]/[C:16](=[N:19]\[C:20]([C:22]2[C:27]([NH2:28])=[N:26][C:25]([NH2:29])=[C:24]([Cl:30])[N:23]=2)=[O:21])/[NH:15]1)C1C=CC=CC=1.I[Si](C)(C)C>C(Cl)Cl>[NH2:10][CH2:11][CH2:12][CH2:13][C@H:14]1[CH2:18][NH:17]/[C:16](=[N:19]\[C:20]([C:22]2[C:27]([NH2:28])=[N:26][C:25]([NH2:29])=[C:24]([Cl:30])[N:23]=2)=[O:21])/[NH:15]1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCNC(=O)OCc3ccccc3)N2)nc1Cl
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: NCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
To a solution of (3-{(S)-2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-imidazolidin-4-yl}-propyl)-carbamic acid benzyl ester (Ex. 30) (0.44 g, 0.98 mmol) in DCM (20 ml) is added iodotrimethylsilane (0.27 ml, 1.96 mmol) in a dropwise manner. The orange suspension is stirred at room temperature for 65 minutes. Purification by catch and release resin (SCX-2) eluting with MeOH followed by 7M NH3 in MeOH yields the title compound as a yellow foam; [M+H]+ 313.1