Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]([CH2:9][C:10]([OH:12])=O)[C:4](=[O:13])[N:3]=1.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][CH2:34][CH2:35][CH3:36])[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:23]=2[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1>>[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][CH2:34][CH2:35][CH3:36])[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:10](=[O:12])[CH2:9][N:5]3[CH:6]=[C:7]([CH3:8])[C:2]([OH:1])=[N:3][C:4]3=[O:13])[C:23]=2[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: Cc1cn(CC(=O)O)c(=O)nc1O
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)Cn1cc(C)c(O)nc1=O
Yield: 19.6 %

Procedure:
Using the general method of Example 105 2-(4-hydroxy-5-methyl-2-oxo-1,2-dihydro-1-pyrimidinyl)acetic acid (0.12 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.2 g, 0.64 mmol) to provide 0.06 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-hydroxy-5-methyl-2-oxo-1,2-dihydro-1-pyrimidinyl)acetamide as a solid, m.p. 242-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.I[C:17]1[N:18]=[CH:19][N:20]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].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:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]3[N:18]=[CH:19][N:20]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: C[Si](C)(C)CCOCn1cnc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Cl)c3s2)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 73.2 %

Procedure:
To a solution of 2 (9.4 g, 56.0 mmol) in THF (150 ml) at −78° C. was added n-BuLi (28 ml, 70.0 mmol, 2.5 M soln in hexanes) and the reaction mixture was stirred at −78° C. for 45 mins. A solution of ZnCl2 (140 ml, 70.0 mmol, 0.5M in THF) was added and the reaction mixture was warmed to room temperature. To the warmed mixture a solution of 4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole [Carl J. Lovey et al, Tetrahedron Lett., 2004, 45(28) 5529-5532] (9.0 g, 28.0 mmol) and Pd(PPh3)4 (2.5 g, 2.1 mmol) in THF (50 ml) were added. The reaction mixture was heated to reflux for 3 hrs, cooled to room temperature, quenched with aqueous ammonium hydroxide and made neutral with aqueous HCl. The neutral solution was extracted with EtOAc, the organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (eluent MeOH-EtOAc, 1:20) to afford the title compound 91 (7.5 g, 73% yield) as a brown oil. MS (m/z) 366.0/368.0 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH2:22])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:11]=[C:5]2[CH:4]=1>CN1CCCC1=O>[NH2:22][C:18]1([C:15]2[CH:14]=[CH:13][C:12]([C:10]3[N:11]=[C:5]4[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][N:6]4[C:9]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: COc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Solvent: CN1CCCC1=O
Product: NC1(c2ccc(-c3nc4cc(O)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 160 °C
Reaction time: 0.13 h
Yield: 80.6 %

Procedure:
To a solution of 1-[4-(7-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (408 mg, 1.10 mmol) in N-methylpyrrolidone (16 mL) at 100° C. was added Na2S (431 mg, 5.52 mmol, 5 equiv) in portions. The resulting mixture was heated at 160° C. for 30 min., cooled to room temperature, and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 8 min., gradient to 95% CH2Cl2: 5% MeOH over 5 min.; 95% CH2Cl2: 5% MeOH for 4 min., gradient to 80% CH2Cl2: 20% MeOH over 5 min., 80% CH2Cl2: 20% MeOH for 6.2 min., gradient to 75% CH2Cl2: 25% MeOH over 2.0 min., 75% CH2Cl2: 25% MeOH for 18.2 min.) to give 2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-ol (315 mg, 81%):
Reaction SMILES: B([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])(O)O.[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21](Cl)[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.[Cl-].[Na+].O>[Cl:18][C:19]1[N:20]=[C:21]([C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=2[NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:22]=[N:23][CH:24]=1
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(B(O)O)c1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cncc(Cl)n2)c1
Temperature: 25 °C

Procedure:
To a stirred mixture of the title compound from Example 1 (3.9 g, 0.017 mol), 2,6-dichloropyrazine (10.0 g, 0.067 mol) and tetrakis(triphenylphospine)-palladium(0) (0.05 g) in glyme (ethylene glycol dimethyl ether, 150 mL) was added aqueous 1M sodium carbonate (67 mL), 0.067 mol). The mixture was heated to reflux and for 8 h. After cooling to room temperature, the mixture was poured into brine (300 mL). The layers were separated and the aqueous phase extracted with three 150 mL-portions of ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with 20% ethyl acetate/hexane to furnish 4.0 g (78% of theory) of the title compound as a white solid melting at 80°-83° C. 1H NMR (300 MHz, CDCl3) δ 10.75 (br s, 1H), 8.91 (s, 1H), 8.51-8.56 (m, 1H), 8.39-8.41 (m,1H), 7.46 (s, 1H), 7.29-7.33 (m, 1H), 2.40 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:20][CH2:21][CH3:22])[C:9]([O:18][CH3:19])([O:16][CH3:17])[C:10]([NH:12][CH:13]1[CH2:15][CH2:14]1)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][CH:8]([CH2:20][CH2:21][CH3:22])[C:9]([O:18][CH3:19])([O:16][CH3:17])[C:10]([NH:12][CH:13]1[CH2:14][CH2:15]1)=[O:11]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(OC)(OC)C(=O)NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(N)C(OC)(OC)C(=O)NC1CC1
Reaction time: 1 h

Procedure:
To tert-butyl(1-(cyclopropylamino)-2,2-dimethoxy-1-oxohexan-3-yl)carbamate (prepared from product of Example 19 by saponification and amidation using the conditions described in example 22 and 23) (25 mg, 0.075 mmol) in DCM (1 mL) was added a catalytic amount of TFA and the mixture was stirred for 1 h. The acid was neutralized with solid NaHCO3 and precipitates were filtered off. The solvent was removed under reduced pressure to give 20 mg of the amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([C:15]([O:17]C)=[O:16])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:8]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([C:15]([OH:17])=[O:16])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: COC(=O)c1nn(-c2ccncc2)cc(OC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cn(-c2ccncc2)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of methyl 5-methoxy-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxylate (0.50 g, 1.9 mmol) in MeOH (10 mL) and THF (10 mL) was added 1 M NaOH aqueous solution (3.0 mL, 3.0 mmol), and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. To the residue was added 1 M HCl aqueous solution (3.1 mL). The formed precipitate was collected by filtration, washed with water and dried to give the title compound (0.47 g, 99% yield) as an off-white solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.98 (3H, s), 7.97 (2H, dd, J=4.7, 1.7 Hz), 8.83 (2H, dd, J=4.7, 1.7 Hz), 8.92 (1H, s), 14.63 (1H, brs).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16]>CCOCC>[CH2:1]([O:13][C:19](=[O:20])[NH:18][S:15]([Cl:14])(=[O:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCO
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCOC(=O)NS(=O)(=O)Cl
Reaction time: 2 h
Yield: 101.6 %

Procedure:
A solution of n-dodecyl alcohol (10.7 g, 57.4 mmoles) in 100 mL Et2O was added dropwise to a solution of chlorosulfonyl isocyanate (5.0 mL, 57.4 mmoles) in 100 mL Et2O at ~15° C. under an atmosphere of N2. The resulting mixture was stirred for 2 hours and concentrated in vacuo. The residue was triturated with cold hexanes to give a white solid and collected by filtration to give 19.12 g of a white solid, mp 62°-63° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1.[F:24][CH2:25][C:26](Br)=O.C([O-])(=O)C.[Na+]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]2[N:11]3[C:26]([CH2:25][F:24])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=3)[C:6]=2[CH:22]=1
Reactant: CSc1ccc(C2=NCC(NN)=Nc3c(C)cc(C)cc32)cc1
Reactant: O=C(Br)CF
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CSc1ccc(C2=NCc3nnc(CF)n3-c3c(C)cc(C)cc32)cc1

Procedure:
In the manner given in Example 1, 7,9-dimethyl-5-[p-(methylthio)phenyl]-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with fluoroacetyl bromide and after 1.5 hours with sodium acetate, then the mixture was refluxed to give 8,10-dimethyl-1-(fluoromethyl)-6-[p-(methylthio)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:42])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]5[C:30]6[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[N:35][C:31]=6[N:32]=[CH:33][N:34]=5)[CH:23]=4)[CH:17]=[CH:16][C:15]=3[S:43][C:44]3[CH:49]=[CH:48][C:47]([NH:50]C(=O)OC(C)(C)C)=[CH:46][CH:45]=3)=[N:11][CH:10]=[N:9][C:8]=2[N:58]=1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[NH2:50][C:47]1[CH:48]=[CH:49][C:44]([S:43][C:15]2[CH:16]=[CH:17][C:18]([NH:20][C:21](=[O:42])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]4[C:30]5[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[N:35][C:31]=5[N:32]=[CH:33][N:34]=4)[CH:23]=3)=[CH:19][C:14]=2[NH:13][C:12]2[C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:58][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:45][CH:46]=1
Reactant: CC(C)c1ccc2c(Nc3cccc(C(=O)Nc4ccc(Sc5ccc(NC(=O)OC(C)(C)C)cc5)c(Nc5ncnc6nc(C(C)C)ccc56)c4)c3)ncnc2n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1ccc2c(Nc3cccc(C(=O)Nc4ccc(Sc5ccc(N)cc5)c(Nc5ncnc6nc(C(C)C)ccc56)c4)c3)ncnc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
The product from Example 7C (40 mg, 0.050 mmol) was dissolved in dioxane (2.0 mL) and 4M HCl in dioxane (0.25 mL) was added. This solution was stirred at room temperature overnight. The solid HCl salt of the product was filtered off then dissolved in methanol and added to saturated NaHCO3. Extracted with ethyl acetate and evaporated. Purification by chromatography on silica gel eluting with (0% to 30% methanol in dichloromethane) gave the title compound (13 mg, 37% yield). 1H NMR (300 MHz, DMSO-D6) d ppm 1.36 (dd, J=6.80, 4.23 Hz, 12H) 3.20-3.30 (m, 2H) 6.57 (d, J=8.46 Hz, 2H) 7.04-7.12 (m, 3H) 7.60-7.70 (m, 2H) 7.82-7.95 (m, 3H) 8.00-8.08 (m, 2H) 8.29 (s, 1H) 8.83-8.93 (m, 2H) 9.09 (d, J=12.50 Hz, 1H) 9.17 (d, J=7.72 Hz, 1H) 10.58 (s, 1H) 11.38 (s, 1H) 11.69 (s, 1H). MS (ESI) m/z 693 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([CH:22]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])=[CH:20][CH:21]=1)C(OC(C)(C)C)=O)(C)(C)C.Cl>C(O)C>[ClH:40].[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([S:31]([CH:22]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[C:19]2[N:18]=[CH:17][C:16]([CH2:15][NH2:7])=[CH:21][CH:20]=2)(=[O:33])=[O:32])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 200 %

Procedure:
To an ethanol (2 ml) solution of t-butyl[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-N-(t-butoxycarbonyl)carbamate (70 mg, 0.115 mmol) was added concentrated hydrochloric acid (2 ml). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added ethanol. The resulting mixture was concentrated under reduced pressure to give the title compound (51 mg, 0.115 mmol, 100%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH:8]=1)[OH:7].C(O)(=O)[CH:11]([CH2:13][C:14](O)=O)[OH:12].OS(O)(=O)=O>O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]2[C:8]=1[CH:14]=[CH:13][C:11](=[O:12])[O:7]2
Reactant: O=C(O)CC(O)C(=O)O
Reactant: Cc1cc(O)cc(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)cc2oc(=O)ccc12
Temperature: 0 °C
Yield: 43.9 %

Procedure:
A mixture of 5-methylresorcin (25.0 g), malic acid (26.0 g) and conc.H2SO4 (55 ml) was gently heated with the gaseous development almost ceased. The reaction mixture was then poured with vigorous stirring into a mixture of water and ice (700 ml), and stirred until the gummy mass initially formed was completely dispersed. The precipitate was collected by filtration, washed with water and crystallized twice (Me2CO) producing 5-methyl-7-hydroxycoumarin (I; 15 g; m.p. 256° C.) ##STR4## free from the isomer 5-hydroxy-7-methylcoumarin (II). ##STR5##
Reaction SMILES: [Na].[NH2:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[C:9]([O:11]CC)=O.[C:14](OCC)(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C.O>[OH:11][C:9]1[C:4]2[CH:5]=[N:6][N:7]([CH3:8])[C:3]=2[NH:2][C:14](=[O:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cnn(C)c1N
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(O)c2cnn(C)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of sodium metal (12.7 g, 0.55 mol) in ethanol is treated at room temperature with ethyl 5-amino-1-methyl-4-pyrazolecarboxylate (25 g, 0.148 mol), stirred for 0.5 h, treated dropwise with a solution of diethyl malonate (80 mL, 0.52 mol in ethanol over a 0.5 h period, heated at reflux temperature for 56 h, cooled to room temperature, diluted with water, washed with ethyl acetate, acidified to pH 2 with HCl and filtered. The filtercake is washed sequentially with water, ethanol, ethyl acetate and toluene and dried in vacuo at 40° C. for 16 h to afford the title product as a white solid, 28.7 g (82% yield), identified by HNMR analysis.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].[F:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49]2[C:50]3[C:57]4[CH2:58][CH2:59][NH:60][CH2:61][C:56]=4[S:55][C:51]=3[N:52]=[CH:53][N:54]=2)=[C:44]([O:62][CH:63]2[CH2:68][CH2:67][O:66][CH2:65][CH2:64]2)[CH:43]=1>CN(C=O)C.O>[CH3:34][N:35]([CH3:40])[CH2:36][C:37]([N:60]1[CH2:59][CH2:58][C:57]2[C:50]3[C:49]([NH:48][C:45]4[CH:46]=[CH:47][C:42]([F:41])=[CH:43][C:44]=4[O:62][CH:63]4[CH2:68][CH2:67][O:66][CH2:65][CH2:64]4)=[N:54][CH:53]=[N:52][C:51]=3[S:55][C:56]=2[CH2:61]1)=[O:38]
Reactant: CN(C)CC(=O)O
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)c(OC2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)cc4OC4CCOCC4)c23)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.4 %

Procedure:
HATU (0.285 g, 0.75 mmol) was added into a stirred solution of Hünig's base (0.13 mL, 0.75 mmol) and N,N-dimethylglycine (0.077 g, 0.75 mmol) in DMF (1.0 mL) and the mixture stirred for 20 minutes at ambient temperature. [4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)-phenyl]-(5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-yl)-amine (0.10 g, 0.25 mmol) was added and the mixture stirred for 18 hours. Water (5 mL) was added and the mixture stirred for 20 minutes. The precipitated solid was collect by filtration, washed with water (10 mL), diethyl ether (10 mL), and dried under vacuum to give a colourless solid (0.049 g, 40%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C@@H:9]([OH:42])[CH:10]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:11][C:12]([CH3:29])([CH3:28])[CH2:13][CH2:14][O:15][C:16]([O:18]C1C=CC([N+]([O-])=O)=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:51]>O1CCCC1.C(OCC)C>[CH2:1]([C@H:8]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[C@@H:9]([OH:42])[CH:10]([NH:30][S:31]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)(=[O:33])=[O:32])[CH2:11][C:12]([CH3:28])([CH3:29])[CH2:13][CH2:14][O:15][C:16](=[O:18])[NH2:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)NC(CC(C)(C)CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Reactant: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NC(CC(C)(C)CCOC(N)=O)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
To a solution of the product from step 1 (520 mg, 0.73 mmol) in tetrahydrofuran (10 mL) at 5° C. was added ammonium hydroxyde (30%, 2 mL) and the reaction was stirred at 5° C. for 40 minutes. The mixture was diluted with ethyl ether, washed with saturated sodium bicarbonate, dried (magnesium sulfate), and evaporated to provide the title compound (490 mg) containing p-nitrophenol (˜10%). 1H NMR (DMSO-d6): δ 0.93 (3H, s), 0.96 (3H, s), 1.2 (9H, s), 1.6 (2H, t), 2.45 (1H, dd), 2.78 (1H, d), 2.85-2.95 (2H, m), 3.3-3.6 (3H, m), 3.7 (1H, quartet), 3.8 (3H, s), 3.96 (2H, t), 5.0 (1H, d), 6.4 (2H, br s), 6.6 (1H, d), 7.05 (2H, d), 7.10-7.25 (5H, m), 7.7 (2H, d).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>ClCCl>[CH2:1]([C:3]1[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCN)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylamine (step 4 of EXAMPLE 3, 1.72 g, 5.9 mmol) and triethylamine (2.0 mL, 14.8 mmol) in dichloromethane (60 mL) was added phenyl chloroformate (900 μL, 7.0 mmol) at ambient temperature. After 1 h, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 3:1 to 1:1) to afford 2.0 g (83%) of the title compound as colorless amorphous: MS (ESI) m/z 412 [M+H]+, 1H-NMR (CDCl3)δ1.27 (3H, d, J=7.5 Hz), 2.73 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.1 Hz,) 3.59 (2H, t, J=7.0 Hz), 5.12 (1H, br), 7.12 (2H, d, J=7.5 Hz), 7.18-7.25 (2H, m), 7.29-7.41 (8H, m) 7.80 (2H, dd, J=8.3, 1.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[C:18]([CH2:20]C)[O:17][N:16]=3)[N:4]2[N:3]=1.N1C=CC=C[C:23]=1CO>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[C:19]([CH3:23])=[C:18]([CH3:20])[O:17][N:16]=3)[N:4]2[N:3]=1
Reactant: CCc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: OCc1ccccn1
Product: Cc1onc(-c2nnc3c4ccccc4c(Cl)nn23)c1C

Procedure:
The title-compound was prepared from 6-chloro-3-(5-ethylisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine and 2-pyridylcarbinol using the procedure given for Example 1, 1H NMR (360 MHz, CDCl3) δ 1.42 (3H, t, J=7.6 Hz, Me), 2.93 (2H, q, J=7.5 Hz, CH2), 5.78 (2H, s, CH2O), 6.83 (1H, s, Ar—H), 7.29 (1H, m, Ar—H), 7.75-7.85 (3H, m, 3 of Ar—H), 7.99 (1H, m, Ar—H), 8.33 (1H, d, J=7.8 Hz, Ar—H), 8.64-8.72 (2H, m, Ar—H); MS (ES30) m/e 373 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:3]=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CC(O)C>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([O:45][CH:2]([CH3:3])[CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c2c1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1ccc2[nH]c(C(=O)OC(C)C)c(Sc3ccc(Cl)cc3)c2c1
Yield: 58 %

Procedure:
Following the method used to prepare 24a, 1b (0.21 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with 2-propanol (2 mL) provided 44 mg (58%) of product 12 as a white solid, mp 172-174° C. 1H NMR (300 MHz, DMSO-d6) δ 1.18-1.24 (m, 6H), 2.35 (s, 3H), 5.09-5.12 (m, 1H), 7.04 (dd, J=2, 9 Hz, 2H), 7.19 (d, J=8, 1H), 7.25-7.30 (m, 3H), 7.46 (dd, J=2, 9 Hz, 1H), 12.34 (s, 1H). LC-MS (CI): m/z 360.0 [(M+H)+ C19H18ClNO2S requires 359.07]. Purity (100%). Calcd for C19H18ClNO2S: C, 63.41; H, 5.04; N, 3.89; S, 8.91; Cl, 9.85. Found: C, 63.59; H, 4.97; N, 3.90; S, 9.04; Cl, 9.85.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[OH:17])[N:9]=[C:5]2[CH:4]=1.[CH2:22]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:23]1[O:25][CH2:24]1.O.C(OCC)(=O)C>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C(C)=CC=CC=1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:24][CH:23]([OH:25])[CH2:22][O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][C:11]=3[OH:17])[N:9]=[C:5]2[CH:4]=1
Reactant: Oc1ccc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c1
Reactant: CCCCOCC1CO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCOCC(O)COc1ccc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c1

Procedure:
A mixture of 2.3 g of 5-trifluoromethyl-2-(2,4-dihydroxyphenyl)-2H-benzotriazole prepared in Example 31, 1.3 mL of butyl glycidyl ether and 100 mg of ethyl triphenylphosphonium bromide in 50 mL of xylene is heated to reflux under nitrogen for 14 hours. Water (25 mL) and 25 mL of ethyl acetate are added and 3 g of the crude product is isolated. Recrystallization from heptane give 2.1 g of the title compound whose structure is confirmed by nmr.