Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.O[S:12]([OH:15])(=[O:14])=[O:13].[O:16]=[S:17](=[O:19])=[O:18].[C:20]1([S:38]([OH:41])(=[O:40])=[O:39])[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([S:30]([OH:33])(=[O:32])=[O:31])[C:24]=2[CH:23]=[C:22]([S:34]([OH:37])(=[O:36])=[O:35])[CH:21]=1>>[C:20]1([S:38]([OH:41])(=[O:40])=[O:39])[C:29]2[C:24](=[CH:25][C:26]([S:17]([OH:19])(=[O:18])=[O:16])=[CH:27][CH:28]=2)[CH:23]=[C:22]([S:34]([OH:37])(=[O:36])=[O:35])[CH:21]=1.[C:25]1([S:30]([OH:33])(=[O:32])=[O:31])[C:24]2[C:29](=[CH:20][CH:21]=[C:22]([S:34]([OH:37])(=[O:36])=[O:35])[CH:23]=2)[CH:28]=[C:27]([S:12]([OH:15])(=[O:14])=[O:13])[CH:26]=1
Reactant: O=S(=O)=O
Reactant: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c2c1
Reactant: O=S(=O)(O)O
Solvent: c1ccc2ccccc2c1
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cc(S(=O)(=O)O)ccc2c1
Product: O=S(=O)(O)c1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1
Reaction time: 7 h
Yield: 21 %
Yield: 4 %

Procedure:
Naphthalene is introduced at 30° to 35° C. into monohydrate (=100% strength H2SO4), 65% strength oleum being run in at the same time. The reaction mixture is kept at 50° C. for one hour, at 70° C. for one hour and at 90° C. for seven hours, until everything has dissolved. With this process the yield of naphthalene-1,3,5-trisulphonic acid is about 68%, based on the naphthalene employed. In addition, about 21% of naphthalene-1,3,6-trisulphonic acid and about 4 to 5% of naphthalene-1,3,7-trisulphonic acid are formed (see Example 6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18](N(OC)C)=[O:19])=[N:10]1.[CH3:24][Mg+].[Br-]>C1COCC1>[C:18]([C:11]1[C:12](=[O:17])[C:13]([O:15][CH3:16])=[CH:14][N:9]([C:3]2[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=2[F:1])[N:10]=1)(=[O:19])[CH3:24]
Reactant: COc1cn(-c2cc(I)ccc2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cc(I)ccc2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a mixture of 1-(2-fluoro-5-iodophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (4.33 g, 10.0 mmol) in THF (1.0 L) was added MeMgBr (1.0 M in THF, 20.0 mL, 20.0 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 h. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 0/100) and triturated with EtOAc/hexane to yield the title compound (3.58 g, 92% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.5.0 (3H, s), 3.80 (3H, s), 7.38 (1H, dd, J=11.0, 8.7 Hz), 7.95 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 8.15 (1H, dd, J=7.2, 2.3 Hz), 8.52 (1H, d, J=1.5 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH3:16]>>[NH2:16][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: N
Reactant: CC(C(N)=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CC(C(N)=O)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
By an original process, 2-(4'-chloro-3'-nitro-phenyl) propionamide (I), thus obtained, is treated with ammonia in an alcohol solution to furnish 2-(4'-amino-3'-nitro-phenyl) propionamide (II) which, when hydrolyzed in an acid medium, is transformed into 2-(4'-amino-3'-nitro-phenyl) propionic acid (III). This, when treated with 2,5-dimethoxytetrahydrofuran (a mixture of cis/trans isomers) produces 2-(3'-nitro-4'-[1"-pyrrolyl] phenyl) propionic acid (A). Catalytic hydrogenation of the latter in the presence of palladium on activated charcoal produces 2-(3'-amino-4'-[1"-pyrrolyl] phenyl) propionic acid (B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[NH:12][C:11]3=[O:16])[C:9](=[O:17])[N:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:5]2=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.O1CCCC1.C(OCC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12]([CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[C:30]([Cl:29])[CH:31]=4)[C:11]3=[O:16])[C:9](=[O:17])[N:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)CN1C(=O)C2(CC(=O)NC2=O)c2cc(Cl)ccc21
Reactant: Clc1cccc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(CC(=O)N(Cc3cccc(Cl)c3)C2=O)c2cc(Cl)ccc21
Yield: 52 %

Procedure:
Following the general procedure (Route A) as outlined above for the synthesis of intermediate 16, methyl (5-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetate, intermediate 47, (2.94 g, 9.11 mmol) was reacted with potassium tert-butoxide (1.07 g, 9.57 mmol) and 3-chlorobenzyl bromide (1.25 ml, 9.57 mmol) in anhydrous N,N-dimethylformamide (90 ml) at ambient temperature for two hours to give the title compound (2.10 g, 52%) as slightly pink powder after trituration from tetrahydrofuran/diethyl ether. The compound was isolated in several fractions (HPLC purity: 96-99%). MS (ESI+): 447.3; MS (ESI−): 445.3
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=5)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.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.[C:60](O)(=[O:62])[CH3:61]>CN(C=O)C>[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]5[CH2:22][CH2:23][N:24]([C:60](=[O:62])[CH3:61])[CH2:25][CH:26]=5)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: CC(=O)O
Reactant: C1=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CC1
Reaction time: 0.5 h

Procedure:
(1H-Indazol-5-yl)-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine hydrochloride (60 mg, 0.137 mmol), HATU (63 mg, 0.164 mmol) and Hunigs base (100 μL, 0.576 mmol) were combined in DMF (4 mL) and stirred for 30 min. Acetic acid (8 μL, 0.168 mmol) was added and the solution was stirred overnight. Another portion of acetic acid (8 μL, 0.168 mmol) was added and the stirred for a further 4 h. The DMF was removed in vacuo and the residue was loaded onto silica. Purification on silica by elution with dichloromethane:methanol (95:5) yielded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.03 & 2.07 (2s, rotamers, 3H), 2.44 & 2.53 (2s, rotamers, 2H), 3.62-3.67 (m, 2H), 4.11 & 4.18 (2s, rotamers, 2H), 6.39 (s, 1H), 6.72 & 6.76 (2s, rotamers, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 8.24 (s, 1H), 8.33 (brs, 1H), 9.35 (brs, 1H), 11.90 (brs, 1H). MS (ES+): m/z 374.5 (100) [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CN.C1COCC1.[CH3:29][N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:30][CH3:29])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(F)cc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 3 (50 mg, 0.18 mmol) was reacted with methyl amine 2M in THF (0.18 mL, 0.35 mmol), HATU (103 mg, 0.6 mmol) and DIPEA (0.15 mL, 0.88 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-methylbenzamide 5. LC/MS (ESI+): m/z 298 (M+H). 1H NMR (400 MHz, DMSO) δ 8.71 (d, J=4.5 Hz, 1H), 8.59 (dd, J=7.4, 4.0 Hz, 2H), 8.54 (d, J=8.9 Hz, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 2.87 (d, J=4.5 Hz, 3H).
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[CH2:9]([O:11][C:12](=[O:18])[CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[CH3:10].C(N(CC)CC)C.CCOCC>C(Cl)Cl>[CH2:9]([O:11][C:12]([CH2:13][C:14]([N:17]=[C:2]=[O:3])([CH3:16])[CH3:15])=[O:18])[CH3:10]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CC(C)(C)N=C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of trichloromethyl chloroformate (4.1 g) in methylene chloride (15 ml) is slowly added to a stirred mixture of ethyl-3-amino-3-methylbutanoate (3 g), triethylamine (6.6 g) and methylene chloride (30 ml) at 5° C. The mixture is stirred overnight at room temperature, refluxed for 3 hours, cooled and anhydrous ether added thereto. The precipitated triethylamine hydrochloride is filtered and the filtrate evaporated to yield 2-ethoxycarbonyl-1,1-dimethylethylisocyanate as an oil (3.5 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([C:9]2[S:31][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][N:8]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NCC(=O)c1cccs1)c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2ncc(-c3cccs3)s2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a dry nitrogen atmosphere N-[2-(thien-2-yl)-2-oxoethyl]-4-trifluoromethylbenzamide (5.6 g of the solid from Step D) was added to a stirred suspension of [2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (3.6 g, 0.0090 mole) in 150 ml of toluene. The resultant mixture was heated at reflux for four hours, then was allowed to cool to room temperature, and was stirred for approximately 18 hours. The mixture was heated at reflux for three hours and then was cooled. The solvent was removed from the mixture by evaporation under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (3:1) to yield 2.84 g of 2-(4-trifluoromethylphenyl)-5-thien-2-ylthiazole, as a solid, mp 153.5°-155° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#[N:2].C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1.[OH-].[Na+].Cl>C1COCC1.C(Cl)Cl>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCCCOC(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)C(C#N)C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
Butyl cyanoacetate (6.35 g; 0.05 mol) and triethylamine (20.9 ml; 0.15 mol) were dissolved in dry THF (100 ml) under dry nitrogen, and 4-chloro-2-nitrobenzoyl chloride (11.0 g; 0.05 mol) in dry THF (100 ml) added dropwise over 45 min. The mixture was stirred at room temperature under dry nitrogen for 18 hours, during which time a precipitate was formed. The solution was filtered and evaporated, giving a residue which was treated with 2M sodium hydroxide solution (200 ml) and CH2Cl2 (100 ml). This formed three layers. The middle layer was treated with 2M hydrochloric acid (50 ml) and extracted into CH2Cl2 (3×50 ml). The extracts were combined, dried (Na2SO4), filtered and evaporated, giving butyl 2-(4-chloro-2-nitrobenzoyl)-2-cyanoacetate (10.27 g; 63%) as a yellow solid, m.p. 56°-58° C., (Found, C: 52.01; H: 4.05; N: 8.70; Cl: 10.97. C14H13ClN2O5 requires C: 51.77; H: 4.01; N: 8.63; Cl: 10.94%), d (CDCl3 ; 60 MHz) 0.8-2.1 (7H, m), 4.4 (2H, t, J=6 Hz), 7.65 (2H, m), 8.15 (1H, d, J=2 Hz) and 13.0 (1H, br, s), vmax (nujol) 2230, 1660, 1610, 1590 and 1540.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:5]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:4]=1[C:33]([O:35]C)=[O:34])#[N:2].[OH-].[Na+].Cl>O1CCCC1.CO>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:5]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:4]=1[C:33]([OH:35])=[O:34])#[N:2]
Reactant: COC(=O)c1c(C#N)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cccc2c1c(C#N)c(C(=O)O)n2CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 133A (16 mg) and sodium hydroxide (200 μl) in tetrahydrofuran (0.5 ml) and methanol (0.5 ml) was stirred overnight, neutralized with diluted HCl, and concentrated. The residue was purified by RPHPLC to provide the desired product. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 14.24 (s, 1H), 8.14 (d, J=8.54 Hz, 1H), 7.86 (dd, J=7.48, 5.65 Hz, 2H), 7.35-7.61 (m, 5H), 7.18-7.36 (m, 3H), 7.12 (d, J=7.32 Hz, 1H), 7.06 (d, J=7.02 Hz, 1H), 6.89 (d, J=7.32 Hz, 1H), 4.77-5.18 (m, 2H), 4.24 (t, J=5.03 Hz, 2H), 2.30-2.47 (m, 2H), 1.99 (s, 3H).
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:12][C:13]([F:25])([F:24])[C:14]1[S:15][CH:16]=[C:17]([C:19](OCC)=[O:20])[N:18]=1>O.C(OCC)(=O)C>[F:25][C:13]([F:12])([F:24])[C:14]1[S:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=1
Reactant: CCOC(=O)c1csc(C(F)(F)F)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: OCc1csc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
To anhydrous ether (40 ml) was added lithium aluminium hydride (0.33 g). To this mixture was added dropwise an anhydrous ether (20 ml) solution of ethyl 2-trifluoromethyl-4-thiazole carboxylate (2 g). The mixture was stirred for 3 hours at room temperature. To the reaction mixture was added dropwise water (20 ml) under cooling with ice to decompose excess amount of the reducing agent. To the resultant reaction mixture were added ethyl acetate (50 ml) and water (25 ml), which was subjected to extraction with ethyl acetate. The organic layer was washed with water (25 ml) and a saturated aqueous solution of sodium chloride (25 ml) successively, followed by drying over magnesium sulfate. The solvent was distilled off, and the residue was subjected to a silica gel chromatography (2.5×30 cm), eluting with ethyl acetate-hexane (3:1). The desired fraction was concentrated to give 2-trifluoromethyl-4-hydroxymethylthiazole (1.1 g) as a pale yellow oily product.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1>>[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=[C:15]2[C:14]3[N:10]([C:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:13]=3)[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[O:28])[C:16]2=[O:17])=[CH:38]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Reactant: O=Cc1c[nH]c2ccccc12
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 77.2 %

Procedure:
Following the procedure described for Example 1(A), Step A, N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (293 mg, 0.608 mmol) was condensed with 1H-indole-3-carbaldehyde (106 mg, 0.729 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (2% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) yielded 286 mg of 2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.25 (s) and 7.90 (s, total 1H), 8.16 (s, 1H), 7.58-7.67 (m, 4H), 7.37-7.53 (m, 6H), 7.07-7.17 (m, 3H), 6.94 (m, 2H), 4.90 (m, 1H), 4.55 (m, 1H), 4.25 (m, 1H), 3.96 (m, 4H), 1.10 (m, 6H); MS 610.8 (M+1), 608.5 (M−1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.[C:21](=[O:24])([O-])[O-].[K+].[K+].Br[CH2:28]C>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][CH2:21][OH:24])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: O=C([O-])[O-]
Reactant: CCBr
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(OCCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 100 °C
Yield: 38.9 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (40 mg, 0.15 mmol), potassium carbonate (42 mg, 0.30 mmol) and bromoethane (30 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 100° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using 2% methanol in dichloromethane afforded 18 mg (39%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-hydroxyethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3/MeOD), δ (ppm): 8.80 (d, 1H), 8.27 (d, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 8.00 (t, 1H), 7.58 (m, 1H), 7.53 (s, 1H), 4.24 (t, 2H), 3.99 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:4][N:3]=1.[CH:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:18])[CH3:17]>>[ClH:1].[ClH:1].[F:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:23][CH2:24][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21]2)=[N:3][CH:4]=1
Reactant: Fc1cccc(F)c1-c1ccc(Cl)nc1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(c2ccc(-c3c(F)cccc3F)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(2,6-difluorophenyl)pyridine and 1-isopropylpiperazine.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].[CH3:6][O-].[Na+].C[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19](OC)=[O:20]>CO>[ClH:1].[CH3:6][NH:4][C:3]([NH2:5])=[N:2][C:19]([C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:20]
Reactant: COC(=O)c1cc2ccccc2n1C
Reactant: N=C(N)N
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
After 8.58 g (89.8 mmol) of guanidine hydrochloride was added to 70 ml of a methanol solution of 4.85 g (89.8 mmol) of sodium methoxide, the mixture was stirred at room temperature. The precipitated sodium chloride was filtered off to obtain the solution. Then 1.70 g (8.97 mmol) of methyl 1-methyl-2-indole-carboxylate was added to the thus obtained solution. Subsequently methanol was distilled off under reduced pressure. The resulting residue was heated at 130° C. for 5 minutes and then allowed to stand at room temperature for an hour. Thereafter water was poured onto the reaction solution and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography to give the desired 1-methyl-2-indoloylguanidine. The compound was dissolved in chloroform and treated with hydrogen chloride/ether. Thus 0.70 g (30.8%) of 1-methyl-2-indoloylguanidine hydrochloride was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([O:15][CH3:16])=[CH:9][CH:10]=[C:11]([CH2:13][OH:14])[CH:12]=1.O1CCCC1.[H-].[Na+].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>O>[F:24][C:25]([F:34])([F:35])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:14][CH2:13][C:11]1[CH:12]=[C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([O:15][CH3:16])=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COc1ccc(CO)cc1-c1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COCc2cccc(C(F)(F)F)c2)cc1-c1ncccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet was added 3.24 gm of the 5-pyrimidyl-4-methoxyphenylcarbinol and 70 ml of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.45 gm of sodium hydride was added. The system was stirred for an additional 20 minutes and 2.8 ml of 3-trifluoromethylbenzylchloride added. The system was allowed to come to room temperature and was then heated to reflux for 20 hours at this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride was washed with water and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 4.13 gm of the 5-pyrimidyl-4-methoxyphenylcarbinol 3-trifluoromethylbenzylether as an orange oil and listed as Compound No. 7 in Table I.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(N(CC)CC)C.O>CS(C)=O>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:14]([CH3:13])[CH2:19]2)=[N:3][N:4]=1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)OC(C)(C)C
Yield: 45.7 %

Procedure:
Heat a mixture of 1,4-dichlorophthalazine (7.80 g, 39.2 mmol), (S)-tert-butyl 2-methylpiperazine-1-carboxylate (4.98 g, 24.9 mmol) and triethylamine (10.3 mL, 73.9 mmol) in DMSO (110 mL) at 80° C. for 18 h. Pour the reaction mixture into water, rinsing with EtOAc. Extract with EtOAc. Wash the organic layer with water (2×) and brine, and dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 20% to 80% EtOAc in hexanes) to provide the title compound (4.13 g, 46%). ES/MS m/z (35Cl) 363.0 (M+1).