Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[N:27]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)n1
Temperature: 120 °C
Yield: 12.8 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (65 mg, 0.151 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.7 mL). 2-(Methyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (53.1 mg, 0.226 mmol), tetrakis(triphenylphosphine)palladium(0) (17.40 mg, 0.015 mmol) and potassium carbonate (62.4 mg, 0.452 mmol) were then added and the mixture heated in a microwave at 120° C. for 15 min (×2). Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, and then further purified by MDAP (acidic conditions), to give the title compound (8.9 mg). LCMS (A) m/z: 460 [M+1]+, Rt 1.45 min (acidic).
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][N:5]=1.[IH:12].[PH2](O)=O.[OH-].[Na+]>O>[I:12][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:3]([OH:2])=[O:11])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: I
Agent: O=[PH2]O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(I)ccn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of 4-chloropicolinic acid methyl ester (2.4 g, 14.1 mmol), 57% hydriodic acid (13.3 mL) and 50% aqueous hypophosphorous acid (0.66 mL) was stirred at 85° C. for 2 h and then was stirred at 107° C. overnight. The mixture was cooled to 95° C. At this temperature were added in 30 minutes 10 M sodium hydroxide aqueous solution (4.2 mL), followed by the addition of water (15.2 mL). The mixture was cooled to rt, stirred for 1 h during which time product precipitates. The precipitate was filtered, washed with cold water and dried under high vacuum overnight to give a yellow solid 11a, 4-Iodopicolinic acid (3.5 g, 66%): 1H NMR (300 MHz, DMSO d6) δ 8.39 (d, J=5.1, 1), 8.35 (d, J=1.8, 1), 8.07 (dd, J=1.7, 5.2, 1); MS (ESPOS): 250.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH2:18])=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8](Cl)=[CH:7][C:6]=1[CH3:16].C[C:20]1[CH:28]=[C:27](Cl)[C:26]([S:30](C)(=O)=O)=[CH:25][C:21]=1C(Cl)=O.N[C:35](N)=N.C1(S)C=CC=CC=1>O.C(N(CC)CC)C>[NH2:1][C:2]([NH2:18])=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([S:30][C:26]2[CH:25]=[CH:21][CH:20]=[CH:28][C:27]=2[CH3:35])=[CH:7][C:6]=1[CH3:16]
Reactant: N=C(N)N
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)Cl
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Agent: Sc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1Sc1cc(C)c(C(=O)N=C(N)N)cc1S(C)(=O)=O

Procedure:
A suspension of 1 g of N-diaminomethylene-2-methyl-4-chloro-5-methylsulfonylbenzamide [obtainableby reaction of 2-methyl-4-chloro-5-methylsulfonylbenzoyl chloride with guanidine in the presence of triethylamine], 7 ml of thiophenol and 6 g ofK2CO3 is heated at 180° for 90 min. It is dissolved in water and extracted with ethyl acetate, and the extract is evaporated. N-Diaminomethylene-2-methyl-4-(2-methylphenylthio)-5-methylsulfonylbenzamide is obtained, from which, after treatment with 1.5 g of sodium perborate in 30 ml of glacial acetic acid over a period of 2 hours at 60° C. in a water bath, N-diaminomethylene-2-methyl-4-(2-methylphenylsulfonyl)-5methylsulfonylbenzamide is obtained after customary working up.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH2:42]([NH:49][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[CH:20][CH:19]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 40 mL scintillation vial containing 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid (150 mg, 0.55 mmol, 1.0 eq.), EDCI (157.2 mg, 0.82 mmol, 1.5 eq.), HOBt (111.5 mg, 0.82 mmol, 1.5 eq.) and DMAP (12 mg, 0.1 mmol, 0.2 eq.) in DCM (10.0 mL) was added benzylamine (24 μL, 2.2 mmol, 4.0 eq.) drop wise. The mixture was stirred at room temperature overnight. The mixture was treated with H2O (10 mL) and the layers were separated. The aqueous was extracted with DCM (2×5 mL), combined organic phase was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give N-benzyl-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide as a white solid. LCMS (m/z) 360 (M+H); 1H NMR (DMSO-d6) δ: 9.01 (t, J=6.0 Hz, 1H), 7.91-8.00 (m, 2H), 7.76 (d, J=7.9 Hz, 1H), 7.29-7.36 (m, 5H), 7.21-7.27 (m, 1H), 7.08-7.13 (m, 2H), 7.02-7.07 (m, 2H), 4.95 (s, 2H), 4.48 (d, J=6.0 Hz, 2H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[C:40]1([SH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>[Cu]I>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([S:46][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: Sc1ccccc1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: OCCO
Product: CN1CCN(c2ccc(Nc3ncc4ccc(Sc5ccccc5)n4n3)cc2)CC1
Temperature: 120 °C
Yield: 27.1 %

Procedure:
Into a sealed tube was added (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.120 g, 0.310 mmol), Sodium tert-butoxide (89.5 mg, 0.931 mmol), Copper(I) iodide (4 mg, 0.02 mmol), 1,2-Ethanediol (34.7 uL, 0.623 mmol), N,N-Dimethylformamide (4.4 mL, 56 mmol), and finally Benzenethiol (32.1 uL, 0.313 mmol). The reaction was heated at 120° C. overnight. An HPLC showed 40% starting material remaining The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The Solvent was removed under vacuum. The desired product was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 8% methanol). The collected fractions afforded [4-(4-Methyl-piperazin-1-yl)-phenyl]-(7-phenylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a yellow solid (35 mg, 27%). MP 155-157° C. LCMS (E/I+) 417.13 (M+H). NMR 1H (DSMO-d6)-9.33 (s, 1H), 8.97 (s, 1H), 7.43 (d, 2H, J=9.04 Hz), 7.30 (t, 2H, J=7.57 Hz), 7.18 (t, 1H, J=7.33 Hz), 7.13 (d, 2H, J=8.33 Hz), 7.01 (d, 1H, J=4.60 Hz), 6.92 (d, 1H, J=4.60 Hz), 6.74 (d, 2H, J=9.09 Hz), 3.03 (t, 4H, J=5.96 Hz), 2.44 (t, 4H, J=5.21 Hz), 2.23 (s, 3H).
Reaction SMILES: C(C([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:21]=[C:20]([C:22]3[CH:26]=C(C)N[C:23]=3[CH3:28])[CH:19]=[CH:18][CH:17]=2)[CH:11]=1)(CC#N)C([O-])=O)C.Cl.[CH:30]([O-:32])=O.[NH4+:33]>[Pd].C(O)C>[CH3:14][C:13]1[NH:33][C:10]([CH3:15])=[CH:11][C:12]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([C:22]2[CH:23]=[CH:28][C:17]([CH:18]3[CH2:19][CH2:20][NH:21][C:30]3=[O:32])=[CH:16][CH:26]=2)[N:21]=1
Reactant: O=C[O-]
Reactant: CCC(CC#N)(C(=O)[O-])c1cccc(-c2cccc(-c3cc(C)[nH]c3C)n2)c1
Reactant: [NH4+]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(-c2cccc(-c3ccc(C4CCNC4=O)cc3)n2)c(C)[nH]1
Yield: 16.2 %

Procedure:
To a 125 mL round-bottomed flask equipped with condenser and N2 inlet were added 2.84 g (7.61 mmol) ethyl-3-[2-(2,5-dimethylpyrrolyl)-6-pyridyl]phenyl-3-cyano-propionate, 50 mL ethanol, and 1 mL concentrated hydrochloric acid. The solution was heated as 700 mg 10% palladium-on-carbon and 2.4 g (38.07 mmol) ammonium formate were added, and the reaction heated at 80° C. for 4.75 hours, with additional catalyst and ammonium formate at 1 hour intervals. The reaction was cooled and filtered through Celite, and the filtrate evaporated. The residue was taken up in ethyl acetate, washed with aqueous sodium hydroxide, dried over sodium sulfate, and evaporated. The residue was taken up in 50 mL dry toluene, treated with 5 mL triethylamine, and heated at reflux for 1 hour. The reaction was then cooled, washed with dilute aqueous hydrochloric acid and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/methanol as eluant to afford 204.5 mg (8.1%) of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.Cl.[CH3:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][CH3:13]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: COCCCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCCCNc1c(F)cccc1[N+](=O)[O-]
Temperature: 6 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
To a solution of 1,2-difluoro-3-nitrobenzene (5.15 g) and 4-methoxybutan-1-amine hydrochloride (5.42 g) in acetonitrile (100 ml) was added diisopropylethylamine (17 μl), and the mixture was stirred at 6° C. for 12 hr. 4-Methoxybutan-1-amine hydrochloride (1.00 g) was further added, and the mixture was stirred at 70° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with hexane-ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give the object product (7.70 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=O)[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)[CH2:25][CH3:26].C([O-])([O-])=[O:42].[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:30]2[CH:29]=[N:28][N:27]([CH2:24][CH2:25][CH3:26])[CH:31]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][CH2:18][C:17]1=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C([O-])[O-]
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Na+]
Solvent: COCCOC
Product: CCCn1cc(-c2ccc(N3C(=O)CNS3(=O)=O)c(OCc3ccccc3)c2)cn1
Temperature: 110 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (100 mg, 0.225 mmol), 1-propyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (106 mg, 0.45 mmol), resin-bound PPh3Pd (177 mg, loading 0.13 mmol/g) and aqueous Na2CO3 (0.45 mL of a 2M solution) in DME (3 mL) is heated in a microwave apparatus at 110° C. for 10 min. The mixture is filtered and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([OH:12])[CH3:11]>>[C:2]1([OH:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([O:9][C:11]1[CH:10]=[CH:4][CH:3]=[CH:2][CH:1]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccccc1
Product: O=C(Oc1ccccc1)c1ccccc1
Product: Oc1ccccc1

Procedure:
Following Example 11 but replacing the 1-(H)-tetrazolylacetic acid with benzoic acid, 1.95 g (1.6 cmoles) and the ethanol with phenol, 1.51 g (1.6 cmoles) the ester of the title was obtained with a yield of 94% (2.98 g), m.p.=68°-70° C. IR spectrum: band at 1730 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:6][C@H:7]([CH3:9])[NH2:8].CO[C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1OC)[CH2:20][C@@H:21](C)N.O>C1C=CC=CC=1>[C:19]1([CH:20]([NH:8][CH:7]([CH2:6][C:5]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:9])[CH3:21])[CH:24]=[CH:25][CH:26]=[CH:17][CH:18]=1
Reactant: COc1ccc(C[C@H](C)N)cc1OC
Reactant: COc1ccc(C[C@@H](C)N)cc1OC
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(CC(C)NC(C)c2ccccc2)cc1OC

Procedure:
Said synthesis was developed by D. E. Nichols et al. ("J. Med. Chem.", 1973, 16, 480-48 and U.S. Pat. No. 4,000,197, of 12.28.1976) and was applied to the chiral synthesis of several methoxylated amphetamines, including (S)-3,4-dimethoxy-amphetamine, which is an enantiomer of (3). In U.S. Pat. No. 4,000,197, the synthesis of the iminic intermediate is carried out in benzene under refluxing conditions during 24 hours with formed water being simultaneously azeotroped off; the hydrogenation is carried out with Raney-Nickel as the catalyst, in absolute ethanol under medium-pressure hydrogen (3 atm of H2). The N-α-phenyl-ethyl-3,4-dimethoxy-amphetamine (15) intermediate is isolated as hydrochloride salt, by crystallization in aqueous acetone or acetone/isopropanol blend, in moderate yield (relatively to dimethoxy-phenyl-acetone), of 48%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3-chloro-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 3-(3-Chloro-benzylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine is obtained; m.p. 158-163° C.; HPLC: TRet (Grad20-100)=12.4.
Reaction SMILES: [C:1]1([NH2:12])[C:6](F)=[C:5](F)[C:4](F)=[C:3](N)C=1F.[ClH:13].Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CC[O:67][CH2:66]C1.Cl.CO>CO>[ClH:13].[ClH:13].[NH:12]1[CH2:3][CH2:4][CH:5]([C:66]([N:35]2[CH2:36][CH2:37][N:32]([C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:17]4[C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[NH:15][N:16]=4)=[CH:39][CH:38]=3)[CH2:33][CH2:34]2)=[O:67])[CH2:6][CH2:1]1
Reactant: CN1CCOCC1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(C(=O)C2CCNCC2)CC1
Temperature: 60 °C
Yield: 41 %

Procedure:
The product obtained using dihydrochloride of Compound 18 (200 mg, 0.49 mmol), isonipocotic acid tert-butyl ester (122 mg, 0.49 mmol), 1-hydroxybenzotriazole monohydrate (86 mg, 0.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.69 mmol) and N-methylmorpholine (0.1 mL, 0.98 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 mol/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 142 (0.09 mg, 41%).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:39]=[CH:38][C:28]3[CH2:29][N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][N:33]([CH2:34][CH3:35])[C:27]=3[CH:26]=2)[C:21]([Cl:40])=[CH:20][N:19]=1>>[Cl:40][C:21]1[C:22]([NH:24][C:25]2[CH:39]=[CH:38][C:28]3[CH2:29][N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][N:33]([CH2:34][CH3:35])[C:27]=3[CH:26]=2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(Nc3nc(Cl)ncc3Cl)ccc2C1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc5c(c4)N(CC)CCN(CC)C5)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(1,4-diethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-8-yl)-amine in an analogous manner to example 712.
Reaction SMILES: [CH3:1][C:2]([C:33]#[N:34])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:12][C:11]=1[CH2:31][CH3:32])[CH3:3].Cl.C(N(CC)CC)C.[N-:43]=[N+:44]=[N-:45].[Na+].Cl>CN(C)C=O.O>[CH3:1][C:2]([C:33]1[NH:45][N:44]=[N:43][N:34]=1)([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:12][C:11]=1[CH2:31][CH3:32])[CH3:3]
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)c1nnn[nH]1
Temperature: 125 °C
Yield: 71.1 %

Procedure:
A mixture of 1.44 g of 2-methyl-2-cyano-7-(2-ethyl-4-(4-fluorophenyl)-5-benzyloxyphenoxy)heptane, 4.1 g of triethylamine hydrochloride, and 1.95 g of sodium azide in 40 mL of dimethylformamide was heated in an oil bath at 125° C. for 17 hours, adding an additional 4 g of triethylamine hydrochloride and 2 g of sodium azide after 5 hours. The mixture was cooled, diluted with water, acidified with 1.0N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with water, washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol to provide 1.12 g (72%) of the desired title product. NMR.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]3)[NH:10][C:6]=2[C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27].[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][N:10]1[C:6]2[C:5](=[O:25])[N:4]([CH3:26])[C:3](=[O:27])[N:2]([CH3:1])[C:7]=2[CH:8]=[C:9]1[N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1
Reactant: Cn1c(=O)c2[nH]c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)cc2n(C)c1=O
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O

Procedure:
A solution of tert-butyl [(3R)-1-(1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)piperidin-3-yl]carbamate (60 mg), 2-chlorobenzyl bromide (32 μl) and potassium carbonate (44 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure and purified by a preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain the title compound (10 mg) as a white amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]#[CH:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][OH:5].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[C@H:24]([CH2:31][CH3:32])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]#[CH:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][O:5][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][C@H:24]1[CH2:31][CH3:32])=[O:29]
Reactant: C#CCOc1cc(F)c(CO)c(Cl)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: C#CCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(Cl)c1
Yield: 80 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-prop-2-ynyloxy-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (357 mg; 80%); MS (ISP): 472.3 (M+NH4)+.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[C:9]3[NH:25][N:26]=[CH:27][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].I[CH3:31].O>CC(C)=O>[CH3:31][N:26]1[CH:27]=[C:8]2[C:9]([N:10]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:25]1.[CH3:31][N:25]1[C:9]2=[N:10][C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]2[CH:27]=[N:26]1
Reactant: c1ccc(-c2nc3[nH]ncc3c(-c3ccccc3)c2-c2ccncc2)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cn1cc2c(-c3ccccc3)c(-c3ccncc3)c(-c3ccccc3)nc2n1
Product: Cn1ncc2c(-c3ccccc3)c(-c3ccncc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %
Yield: 47 %

Procedure:
To a suspension of 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.10 g, 0.3 mmol, obtained in example 2) in acetone (1 mL), KOH (21 mg, 0.4 mmol) was added under argon atmosphere. Then, a solution of iodomethane (47 mg, 0.3 mmol) in acetone (0.1 mL) was added and stirred overnight at room temperature. Water was added and extracted with CHCl3. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 47 mg of 2-methyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 47%) and 38 mg of 1-methyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 38%).