Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:22])=O>C1C=CC=CC=1.CN(C)C=O>[Cl-:22].[CH2:1]([O:8][C:9](=[O:18])[CH:10]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(C)CC(C(=O)O)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
9.7 grams of the thus-obtained isobutylmalonic acid monobenzyl ester were dissolved in 120 ml of absolute benzene. The solution was treated with 40 drops of dimethylformamide and subsequently, at 0°, with 6.64 ml of oxalyl chloride. After stirring at 0°-5° for 1 hour and for 30 minutes at 20°, the mixture was evaporated under reduced pressure and the residue re-evaporated once with benzene to yield isobutylmalonic acid monobenzyl ester chloride as an orange-red oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O>>[OH:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C=O)cc1O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(OC)c(O)c2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 3-hydroxy4-methoxybenzaldehyde gave the title compound as a yellow solid m.p.:140°-148° C.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[CH2:6]([N:9]1[C:17]2[C:12](=[N:13][C:14]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]5[CH2:30][NH:31][CH2:32][C:27]5=[N:26]4)=[CH:21][CH:20]=3)=[C:15]([Cl:18])[CH:16]=2)[N:11]=[C:10]1[O:33][C@H:34]1[C@H:38]2[O:39][CH2:40][C@@H:41]([OH:42])[C@H:37]2[O:36][CH2:35]1)[CH:7]=[CH2:8].[NH4+].[OH-].CO.C(Cl)Cl>O1CCOCC1.CO.C(Cl)Cl>[CH2:6]([N:9]1[C:17]2[C:12](=[N:13][C:14]([C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[C:28]5[CH2:30][N:31]([CH2:1][C:2]([OH:5])([CH3:4])[CH3:3])[CH2:32][C:27]5=[N:26]4)=[CH:23][CH:24]=3)=[C:15]([Cl:18])[CH:16]=2)[N:11]=[C:10]1[O:33][C@H:34]1[C@H:38]2[O:39][CH2:40][C@@H:41]([OH:42])[C@H:37]2[O:36][CH2:35]1)[CH:7]=[CH2:8]
Reactant: CC1(C)CO1
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-n4cc5c(n4)CNC5)cc3)c(Cl)cc21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-n4cc5c(n4)CN(CC(C)(C)O)C5)cc3)c(Cl)cc21
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Isobutylene oxide (17 μl, 0.191 mmol) was added to a stirred solution of (3R,3aR,6R,6aR)-6-[1-allyl-6-chloro-5-[4-(5,6-dihydro-4H-pyrrolo[3,4-c]pyrazol-2-yl)phenyl]imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (83.4 mg, 0.160 mmol) in dioxane (0.64 ml). The reaction mixture was a pale yellow solution that was heated to 80° C. After 3 days, additional isobutylene oxide (8 μl, 0.090 mmol) was added. After stirring an additional 16 h, the reaction mixture was cooled to room temperature. The reaction mixture was then diluted with MeOH/DCM and loaded onto two 500 micron 20 cm×20 cm silica gel plates, which were developed twice using 10% (10% NH4OH/MeOH)/DCM. The silica containing the product band was collected and eluted with 10% (10% NH4OH/MeOH)/DCM (80 ml). The solvent was evaporated under reduced pressure to give the desired product as a yellow residue. LC-MS: calculated for C30H33ClN6O5 592.22 observed m/e: 593.25 (M+H)+ (Rt 1.00/2 min)
Reaction SMILES: [OH:1][C:2]1C=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])C=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=C(Cl)C(F)=CN=1.C(N)C1OC=CC=1>>[CH2:4]([NH:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:21]2[O:22][CH:18]=[CH:19][CH:20]=2)[C:12]([F:23])=[CH:11][N:10]=1)[C:5]1[O:1][CH:2]=[CH:7][CH:6]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: Fc1cnc(Cl)nc1Cl
Agent: NCc1ccco1
Product: Fc1cnc(NCc2ccco2)nc1NCc1ccco1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and furfurylamine were reacted to yield N2,N4-bis(furfuryl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.72 (bs, 1H), 7.38 (dd, 2H, J=1.8 and 7.5 Hz), 6.34-6.30 (m, 2H), 6.22 (dd, 2H, J=2.4 and 9.9 Hz), 5.163 (bs, 2H), 4.63 (d, 2H, J=6.0), 4.54 (d, 2H, J=6.0); 19F NMR (CDCl3): −48621 ; LCMS: ret. time: 97.27 min.; purity: 97%; MS (m/e): 289 (MH+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[S:11][CH2:12][CH2:13][NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[C:22](=[O:23])[C:21](=[O:24])[C:20]=1OC>CO>[NH2:18][C:19]1[C:22](=[O:23])[C:21](=[O:24])[C:20]=1[NH:14][CH2:13][CH2:12][S:11][C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1
Reactant: COc1c(N)c(=O)c1=O
Reactant: NCCSc1cccc(CN2CCCCC2)c1
Solvent: CO
Product: Nc1c(NCCSc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.2 %

Procedure:
The crude amine prepared in Step E (1.4 g, 4.05 mmoles) in 40 mL of methanol was added to a suspension of 1-amino-2-methoxycyclobutene-3,4-dione (0.515 g, 4.05 mmoles) in 100 mL of methanol. The mixture was stirred for 20 hours at ambient temperature and then filtered to give 0.8136 g of product. A second crop was obtained from the concentrated mother liquor and the combined lots were recrystallized from methanol to yield 0.786 g (56%) of the title compound, m.p. 228°-230° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:13]=[C:12]([S:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:13]=[C:12]([S:14][C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(SC(=O)N(C)C)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(SC(=O)N(C)C)cc(C(=O)O)c1
Reaction time: 11 h
Yield: 79.3 %

Procedure:
To a solution of 5-dimethylcarbamoylsulfanyl-isophthalic acid dimethyl ester (D56) (6 g, 20.2 mmol, 1 equiv) in THF (100 ml) at room temperature was added 2N aqueous NaOH solution (9.6 ml, 19.2 mmol, 0.95 equiv). The resulting mixture was stirred for 11 h and then partitioned between AcOEt and H2O. The two layers were separated and the aqueous phase extracted with AcOEt. After acidification to pH 1, the aqueous phase was extracted twice with AcOEt. The organic solution was dried over MgSO4 then concentrated in vacuo to give 5-dimethylcarbamoylsulfanyl-isophthalic acid monomethyl ester (D57) (4.54 g, 79%) as a white solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C1COCC1.[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([CH:20]([C:22]3[C:23]([O:39][CH3:40])=[C:24]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)=[O:37])[CH:31]=4)[C:25]([CH3:29])=[C:26]([Cl:28])[CH:27]=3)[CH3:21])[N:18]=[CH:19][C:12]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([CH:20]([C:22]3[C:23]([O:39][CH3:40])=[C:24]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:4][CH2:3][CH2:1][OH:2])=[O:37])[CH:31]=4)[C:25]([CH3:29])=[C:26]([Cl:28])[CH:27]=3)[CH3:21])[N:18]=[CH:19][C:12]=12
Reactant: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)O)c1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)NCCO)c1
Reaction time: 1 h

Procedure:
Ethanolamine (2.0 M) in THF (0.14 mL, 0.28 mmol) was added to a solution of 4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid (from Example 38, Step 2) (18.6 mg, 0.042 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperature followed by adding triethylamine (8.8 μL, 0.064 mmol). The reaction was stirred for 1 hour, then quenched with water. The mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C23H25ClN7O3 (M+H)+: m/z=482.2; Found: 482.2.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH:12]1([C:18]2([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])(=O)=O>O1CCCC1.O>[CH3:36][N:35]([CH2:34][CH2:33][C:19]1[C:18]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=1)[CH3:37]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Reactant: C1=CC(C2CCCCC2)(C2CCCCC2)C=C1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CCC1=CC=CC1(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, a solution of n-butyllithium in hexane (18.7 mL; 1.6 mol/L; 30 mmol) was added dropwise to a cooled (0° C.) solution of dicyclohexyl-cyclopentadiene (Example IV) (6.90 g; 30.0 mmol) in dry tetrahydrofuran (125 ml) in a 250 mL three-necked round-bottomed flask provided with a magnetic stirrer and a dropping funnel. After 24 hours of stirring at room temperature, 30.0 mmol of 2-dimethylaminoethyl tosylate prepared in situ were added. After 18 hours of stirring, the conversion was found to be 88%, and water (100 ml) was carefully added dropwise to the reaction mixture and the tetrahydrofuran was then distilled off. The crude product was extracted with ether, and the combined organic phase was then dried with sodium sulphate, and evaporated to dryness. The residue was purified on a silica gel column, which resulted in 7.4 g of (dimethylaminoethyl)dicyclohexylcyclo-pentadiene.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH:15]C(=O)OC(C)(C)C)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 1,1-dimethylethyl [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (113 mg, 0.20 mmol) and trifluoroacetic acid (500 μL) in dichloromethane (2 mL) was added stirred at room temperature for one hour then was partitioned between saturated aqueous sodium bicarbonate, and dichloromethane. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a colorless residue which was purified by column chromatography eluting with 10% methanol in dichloromethane to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (85 mg, 95% yield) as a white foam. 1H NMR (400 MHz, CDCl3): 8.53 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.46-4.39 (m, 2H), 3.98-3.75 (br m, 4H); MS (EI) for C16H13F3IN3O: 448 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH2:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[O:18][CH3:17])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:16]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)c3ccccc3OC)ccc21

Procedure:
3-Amino-9-ethylcarbazole (5.6 g; 0.027 mol) was reacted with 2-methoxybenzoyl chloride (4.35 ml; 0.029 mol) by working in a manner similar to that described in Example 4.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:29][CH2:28][C:9]2[N:10]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)(O)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1.C(=O)(O)[O-].[Na+]>S(Cl)(Cl)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:29][CH2:28][C:9]2[N:10]([CH:18]=[C:19]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1
Reactant: COCCCN1CCc2c(c3cc(C)ccc3n2CC(C)(O)c2ccncc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COCCCN1CCc2c(c3cc(C)ccc3n2C=C(C)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
1-[2-(3-Methoxy-propyl)-8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl]-2-pyridin-4-yl-propan-2-ol (550 mg, 1.39 mmol) was dissolved in thionyl chloride (5 mL), stirred at RT for 1 h. Progress of the reaction was monitored by TLC/LCMS. After completion of the reaction, excess thionyl chloride was evaporated under vacuum. The solid mass obtained was neutralized with aqueous sodium bicarbonate and the desired compound extracted with EtOAc (100 mL×2). The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum to obtain crude product, which was purified by silica gel column chromatography (100-200 mesh) using MeOH:DCM (0-10%) as eluent followed by reverse phase HPLC to obtain 35 mg of 2-(3-Methoxy-propyl)-8-methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm): 8.62 (d, 2H), 7.42 (d, 2H), 7.22 (s, 1H), 7.10 (s, 1H), 7.0 (s, 2H), 3.80 (s, 2H), 3.50 (t, 2H), 3.36 (s, 3H), 2.92 (m, 2H), 2.78 (m, 4H), 2.42 (s, 3H), 2.02 (s, 3H), 1.95 (m, 2H). 1H NMR (CD3OD oxalate salt) δ (ppm): 8.82 (d, 2H), 8.30 (d, 2H), 7.80 (s, 1H), 7.38 (s, 1H), 7.16 (s, 2H), 4.40 (m, 1H), 3.98 (m, 1H), 3.60 (m, 4H), 3.50 (t, 2H), 3.40 (s, 3H), 3.25 (m, 2H), 2.42 (s, 3H), 2.20 (m, 2H), 2.18 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C[Si]([C:25]#[CH:26])(C)C.CCN(CC)CC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:25]#[CH:26])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccc(-c2cc(C3CC3)n3ncc(I)c3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-7-cyclopropyl-3-iodo-pyrazolo[1,5-a]pyrimidine (example C.5, step 4) (1.58 g, 4.0 mmol), trimethylsilylacetylene (0.78 mL, 6.0 mmol), and Et3N (12.0 mL, 45 mmol) in N,N-dimethylformamide (12 mL) was stirred for 10 min at 20° C. while being purged with Argon. Then, PdCl2(PPh3)2 (56 mg, 2 mol %), PPh3 (42 mg, 4 mol %) and CuI (15 mg, 4 mol %) were added and stirring was continued at 75° C. for 15 h in an atmosphere of argon. The mixture was cooled to 20° C. and partitioned between EtOAc and water. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue (2.2 g) was dissolved in a mixture of THF (8 mL) and MeOH (20 mL), potassium carbonate (0.11 g, 0.8 mmol) was added, and the solution was stirred for 2 h at 0° C. followed by 1 h at 20° C. The mixture was partitioned between EtOAc and 10% sodium chloride solution. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel using EtOAc/cyclohexane (1:5 v/v) as eluent and crystallization from EtOAc/cyclohexane gave 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (0.47 g, 40%) as a yellow solid; mp 181-182° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([NH:19][C:20](=[O:21])[O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: O=C=NCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccccc1)OCc1ccccc1[N+](=O)[O-]
Yield: 67.9 %

Procedure:
10 ml of toluene, 5.75 g of 2-nitrobenzyl alcohol and 5 g of benzyl isocyanate were heated to reflux for 3 hours in a nitrogen atmosphere. Following cooling of the mixture, 50 ml of toluene was added. This reaction solution was washed several times with water, and was then dehydrated with sodium sulfate. The sodium sulfate was then filtered out, and the solvent was removed from the filtrate by means of a rotary evaporator. The solid obtained was recrystallized from a hexane-toluene mixed solvent, producing 7.3 g of o-nitrobenzyl benzylcarbamate in the form of plate yellow crystals. This compound had a melting point of 110° to 111° C., and the infrared absorption spectrum was 3308 cm-1 : N--H, 1696 cm-1 : C=O, 1520 cm-1 : N--O.
Reaction SMILES: Br[C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH2:25]([NH2:27])[CH3:26]>CN1C(=O)CCC1.O>[CH2:25]([NH:27][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1)[CH3:26]
Reactant: CCN
Reactant: O=Cc1ccc(-c2nc3nc(Br)nn3cc2-c2ccccc2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCNc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Temperature: 100 °C

Procedure:
To 90 mg 4-(2-bromo-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described above) in 2 mL NMP were added 0.71 mL ethylamine. The mixture was heated under microwave irradiation to 100° C. for 80 min and then overnight at 100° C. under conventional heating. On cooling the reaction was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated in vacuo to give the crude title compound as an orange oil which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:27]=[CH:26][C:22]2[N:23]=[CH:24][NH:25][C:21]=2[CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:23]1[C:22]2[CH:26]=[CH:27][C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])=[CH:20][C:21]=2[N:25]=[CH:24]1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc2nc[nH]c2c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]cnc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 159.8 mg (1.2 mmol) of 5-aminobenzimdazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed for 1 hr. The work up gave 233.6 mg (67.7%) of the product as a brown solid, m.p. 230°0 C. (dce.), mass (electrospray, m/e): M+H 345.9. HRCIMS: calcd 346.1304 for C19H15N5O2 (M+), obsd 346.1325.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])=[C:10]([CH3:31])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:31])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1nc(Cc2ccccc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (5-{[(3-Benzyl-[1,2,4]oxadiazole-5-carbonyl)-amino]-methyl}-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (65 mg, 0.09 mmol), 2 mL TFA and 4 mL DCM was stirred of room temperature for 1 h. The mixture was evaporated in vacuo and the residue was purified by prep HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). Aq. NaHCO3-solution was added to the product containing fractions and after evaporation the aq. layer was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to give the title compound. 1H-NMR (DMSO-d6, 400 MHz) 9.43 (t, 1H), 7.25-7.36 (m, 5H), 6.10 (s, 1H), 5.70 (s, 2H), 4.35 (d, 2H), 4.18 (s, 2H), 2.29 (s, 3H), 2.16 (s, 3H); LCMS (method A) RtA=1.024 min; [M+H]+=338.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH2:31][CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH2:31][CH2:32][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[CH:9]=[CH:8]2)[CH2:5][CH2:6]1
Reactant: NC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Reactant: COc1ccc2ccccc2c1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2ccccc2c1CCN1CCC(n2ccc3ccc(C(N)=O)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
70 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide and 115 mg of (2-methoxynaphthalen-1-yl)acetaldehyde were dissolved in 2 ml of tetrahydrofuran. Thereafter, 0.03 ml of acetic acid and 91 mg of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then extracted with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol), so as to obtain 72 mg of the subject compound.
Reaction SMILES: C[O:2][CH2:3][C:4]1[N:39]=[C:7]2[N:8]([CH:35]([CH3:38])[CH2:36][CH3:37])[C:9](=[O:34])[C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]2[N:5]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+].Cl>ClCCl>[OH:2][CH2:3][C:4]1[N:39]=[C:7]2[N:8]([CH:35]([CH3:38])[CH2:36][CH3:37])[C:9](=[O:34])[C:10]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:20][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]2[N:5]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)CC)c2nc(COC)nn12
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)CC)c2nc(CO)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of 2-(methoxymethyl)-4-(1-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.07 g), boron tribromide (1.0 M dichloromethane solution, 0.4 mL) and dichloromethane (5 mL) was stirred at room temperature for 2 hr, saturated aqueous sodium hydrogen carbonate (10 mL) was added, and the mixture was further stirred for 1 hr. The reaction mixture was adjusted to pH 5 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.02 g, 29%).