Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]([CH2:32][N:33]1[C:37]([NH2:38])=[CH:36][CH:35]=[N:34]1)=[O:31].O>O1CCCC1.C(OCC)(=O)C>[CH3:28][O:29][C:30]([CH2:32][N:33]1[C:37]([NH:38][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:36][CH:35]=[N:34]1)=[O:31]
Reactant: COC(=O)Cn1nccc1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triphenylmethyl chloride (154.98 g) was added to a solution of triethylamine (154.97 ml) and 1-methoxycarbonylmethyl-5-aminopyrazole (71.88 g) in tetrahydrofuran (215.64 ml) and the mixture was stirred for three hours at ambient temperature. The reaction mixture was added to a mixture of water (300 ml) and ethyl acetate (200 ml). The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-methoxycarbonylmethyl-5-triphenylmethylaminopyrazole.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18]>>[OH:18][C@H:17]([C:16]([CH3:20])([CH3:19])[CH3:15])[C@@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CC(C)(C)C=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@H](O)C(C)(C)C

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolone with trimethylacetaldehyde. Slow addition of the aldehyde to the enolate solution over 1 hour at 0° C. gave a 9:1 ratio of the (2R*,3S*) and (2R*,3R*) isomers. The desired isomer was crystallized from 1:1 ether/hexanes, mp=90-2° C. 1H-NMR (CDCl3, 400 MHz) δ 8.04 (m, 1H), 7.23-7.29 (m, 3H), 4.32 (dq, J=3, 7 Hz, 1H), 3.79 (d, J=10 Hz, 1H), 3.41 (dd, J=3,10 Hz, 1H), 1.51 (d, J=7 Hz, 3H), 0.94 (s, 9H). 13C-NMR (CDCl3, 100 MHz) δ 178.2, 150.8, 142.0, 127.6, 125.7, 125.0, 116.3, 110.0, 84.0, 37.4, 36.2, 26.7, 18.1.
Reaction SMILES: C(OC([CH:8]([NH2:23])[CH2:9][O:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN([PH+](N(C)C)N(C)C)C>C(Cl)Cl.CN(C=O)C>[N+:20]([C:18]1[CH:17]=[CH:16][C:12]2[C:13](=[O:14])[NH:23][CH2:8][CH2:9][O:10][C:11]=2[CH:19]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)C(N)COc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CN(C)[PH+](N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1NCCOc2cc([N+](=O)[O-])ccc21
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of 2-(2-tert-butoxycarbonyl amino-ethoxy)-4-nitro-benzoic acid (0.18 g, 0.00055 mol) in DCM (5 mL) was added TFA (0.5 mL) and stirred 1 hr. and evaporated. The residue was treated with anhydrous DMF (1 mL), N-methyl morpholine (0.50 mL 0.0046 mL) and 1-hydroxybenzotriazole hydrate (0.12 g, 0.00088 mol) and stirred 10 min. Benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.39 g, 0.00088 mol) was added, stirred 15 hrs. and evaporated. The residue was purified by ISCO chromatography giving 8-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.032 g, 26%) as a white solid. MP: 208-9° C.; 1H-NMR (DMSO-d6) δ 8.66 (s, 1H), 7.99-8.01 (d, 1H), 7.92-4 (d, 1H), 7.79-80 (d, 1H), 4.39-41 (m, 2H), 3.36-9 (m, 2H); LC/MS (ESI+): 209 (M+H).
Reaction SMILES: P(Cl)(Cl)Cl.[N+:5]([C:8]1[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]([O-])[CH:13]=1)([O-:7])=[O:6]>ClCCCl>[N+:5]([C:8]1[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][CH:13]=1)([O-:7])=[O:6]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[n+]([O-])c1C(=O)OCC
Solvent: ClP(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1cc([N+](=O)[O-])cnc1C(=O)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
88.8 g (0.648 mol) of phosphorus trichloride were added in the course of 30 minutes while stirring at 25° C. to a mixture of 92 g (0.324 mol) of the above N-oxide and 300 ml of 1,2-dichloroethane. After stirring at 25° C. for 12 hours, the reaction mixture was concentrated in vacuo, the residue was taken up again in methylene chloride and the solution was poured into 2.5 l of ice-water. After phase separation, the aqueous phase was extracted with methylene chloride. The organic extract was washed with water, saturated sodium hydrogencarbonate and sodium chloride solution, dried over magnesium sulfate and filtered off with suction through neutral alumina and silica gel. After concentrating, 58.2 g (67% of theory) of the title compound were obtained as a yellowish syrup. 1H-NMR, 400 MHz (CDCl3) δ: Ar 9.0 (d/1H), 9.55 (d, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].[CH:19]([Sn](CCCC)(CCCC)CCCC)=[CH2:20].CCOC(C)=O.O>CS(C)=O>[C:12]1([C:7]2[NH:8][C:9]3[C:4]([C:5](=[O:18])[CH:6]=2)=[CH:3][C:2]([CH:19]=[CH2:20])=[CH:11][CH:10]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1cc(-c2ccccc2)[nH]c2ccc(Br)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: C=Cc1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Temperature: 100 °C
Yield: 97.9 %

Procedure:
To a solution of 6-bromo-2-phenylquinolin-4(1H)-one 1 (1.5 g, 5.0 mmol) in DMSO (60 mL) was added vinyltributyl tin (1.75 mL, 6.0 mmol) and tetrakis-triphenylphosphine palladium (116 mg, 0.1 mmol). The mixture was then heated to 100° C. for 20 h, at which time, LC-MS revealed the disappearance of starting material. The reaction was then poured into a mixture of EtOAc (200 mL) and water (400 mL) which caused a grayish solid to precipitate. This solid was collected and dried under vacuum in a desiccator over night to yield 1.21 g (97% yield) of 2-phenyl-6-vinylquinolin-4(1H)-one which was pure by 1H NMR and LC-MS. 1H NMR (400 MHz, DMSO-d6) ppm: 11.75 (br s, 1H), 8.08 (s, 1H), 7.85 (m, 3H), 7.74 (d, J=8.8 Hz, 1H), 7.59 (m, 3H), 6.88 (dd, J=17.6 Hz, 10.8 Hz, 1H), 6.34 (s, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.30 (d, J=10.8 Hz, 1H). LRMS (CI, [M+H]) Calc'd=248.2. found=248.2. HRMS (APCI, [M+H]+) Calc'd for C15H11BrNO: 248.1070. found: 248.1068.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:20][O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:13])=[CH:7][CH:6]=1.[CH:28](O)=O.[OH-].[Na+]>C=O.O>[ClH:1].[ClH:1].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:28])[CH2:16][CH:15]2[CH2:20][O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:13])=[CH:9][CH:10]=1
Reactant: O=CO
Reactant: COc1ccc(NC(=O)N2CCNCC2COc2cccnc2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NC(=O)N2CCN(C)CC2COc2cccnc2)cc1
Reaction time: 16 h
Yield: 13 %

Procedure:
N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide dihydrochloride (prepared as described in Example 10) (123 mg, 0.295 mmol), was dissolved in formaldehyde (37% aqueous solution, 1 mL) and formic acid (1 mL) and heated to 60° C. After 16 h, the reaction mixture was brought to pH 12 with 1 N NaOH in water and was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by HPLC (5 to 30% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL) and treated with 4M HCl in 1,4-dioxane. The mixture was concentrated under reduced pressure, yielding 16.2 mg (13%) of the desired product as an off-white solid. LC-MS: RT=3.59 min, [M+H]+=357.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15]I)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][N:25]3[CH2:26][CH2:27][CH:22]([CH2:21][C:20]([O:19][CH3:18])=[O:28])[CH2:23][CH2:24]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCC(CI)CC2)cc1
Reactant: COC(=O)CC1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCN(CC2CCN(c3ccc(C#N)cc3)CC2)CC1
Temperature: 130 °C

Procedure:
A suspension of 2.18 g of 1-(4-cyanophenyl)-4-iodomethyl-piperidine (mixture from Example XXV), 1.26 g of methyl-4-piperidyl-acetate-hydrochloride and 1.35 g of triethylamine in 150 ml of dimethylformamide is heated to 130° C. for 24 hours. After cooling, the solvent is removed under reduced pressure and the residue is chromatographed over silica gel with methylene chloride/methanol (30:1). The solvent is removed under reduced pressure and the crude product is used for the next stage of synthesis without any further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:31][CH2:30][CH2:29][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])=[O:7])(C)(C)C>Cl.O1CCOCC1>[OH:28][CH:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:10](=[O:11])[C@@H:9]1[CH2:29][CH2:30][CH2:31][N:8]1[C:6](=[O:7])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 149.7 %

Procedure:
(2S)-1-[N-(tert-Butoxycarbonyl)-L-prolyl]-2-[1-hydroxy-2(4-methoxyphenoxy)ethyl]pyrrolidine (658 mg) was dissolved in 4N hydrochloric acid/1,4-dioxane (8 ml), and the mixture was stirred at room temperature for 0.5 hour. The residue obtained by concentration and drying of the reaction mixture was dissolved in methylene chloride (10 ml), and thereto were added dropwise triethylamine (0.42 ml) and phenoxyacetyl chloride (0.21 ml) under ice-cooling. After stirring the mixture under ice-cooling for 0.5 hour, and then at room temperature for 2 hours, the reaction mixture was treated in the same manner as in Example 46-D) to give 531 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH2:20][CH2:19]2.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([N:21]2[CH2:20][CH2:19][C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:22]2)[N:3]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: Cn1cnc2nc(Cl)nc(Cl)c21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CN(c1nc(Cl)nc3ncn(C)c13)CC2

Procedure:
A solution of 1.44 g of 2,6-dichloro-7-methylpurine, 1.63 g of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride and 1.5 g of triethylamine in 25 ml of methylene chloride was stirred at room temperature under nitrogen for 15 hours. The reaction mixture was washed with a 1N hydrochloric acid solution (3×150 ml), water (3×150 ml) and a brine solution (1×100 ml), and then dried over sodium sulfate. Removal of the solvent left a residue which was chromatographed on 150 g of silica gel, 1.3 g.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:23]1[CH2:24][CH:25]=[C:26]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:27][CH2:28]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Fc1cccnc1Nc1ccc(Oc2nccnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1cccnc1Nc1ccc(Oc2nccnc2C2=CCOCC2)cc1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added N-(4-(3-chloropyrazin-2-yloxy)phenyl)-3-fluoropyridin-2-amine (0.2824 g, 0.892 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.281 g, 1.337 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.050 g, 0.071 mmol), and sodium carbonate (0.473 g, 4.46 mmol) in DME (2.378 mL) and Water (0.594 mL). The reaction mixture was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 100° C. for 20 min (60 watts, Powermax feature on, ramp time 5 min). The crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-3-fluoropyridin-2-amine. MS (ESI, pos. ion) m/z: 365.0 (M+1). IC50 (uM) 0.0.0217.
Reaction SMILES: C(O)CCCCCCCO.FC1C=CC(CBr)=CC=1.[F:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])=[CH:23][CH:22]=1.FC1C=CC(COCCCCCCCC(O)=O)=CC=1.Cl.Cl.[CH2:59]([O:66][C:67](=[O:75])[CH2:68][C@@H:69]([NH2:74])[CH2:70][N:71]([CH3:73])[CH3:72])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH2:59]([O:66][C:67](=[O:75])[CH2:68][C@@H:69]([NH:74][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][C:24]1[CH:23]=[CH:22][C:21]([F:20])=[CH:37][CH:36]=1)[CH2:70][N:71]([CH3:72])[CH3:73])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: OCCCCCCCCOCc1ccc(F)cc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: Fc1ccc(CBr)cc1
Agent: O=C(O)CCCCCCCOCc1ccc(F)cc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)cc1

Procedure:
The title compound, m/e=397.4 ([M+H]+), was produced in analogy with example 1, steps 1-4. Thus, 1,8-octanediol was alkylated in step 1 with 4-fluorobenzyl bromide, leading to 8-(4-fluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(4-fluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(4-fluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][NH:7][C:6]=2[N:16]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>CC(N(C)C)=O>[CH2:17]([N:7]1[CH2:8][C:9]([CH3:14])([CH3:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[N:16][C:6]1=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CN1C(=O)C(C)(C)CNc2nc(Cl)ncc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(C)CN(Cc2ccccc2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
2-Chloro-8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (50 mg, 0.21 mmol) and benzylbromide (30 μl, 0.25 mmol) in DMA (0.5 ml) was treated with sodium hydride 60% oil dispersion (9 mg, 0.23 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc in hexanes, loaded on silica, ˜50 mL silica) to give the title compound as a white solid (63 mg, 91%). NMR DMSO D6 1.00 (6H, s), 3.22 (3H, s), 3.53 (2H, s), 4.91 (2H, s), 7.28-7.39 (5H, m), 8.12 (1H, s); MS (ES+) 331.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.C(=O)(O)O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH2:28])=[NH:27])=[CH:21][CH:20]=1>C(O)(C)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]2[N:28]=[C:5]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)[CH:4]=[CH:3][N:27]=2)=[CH:23][CH:24]=1
Reactant: CN(C)C=CC(=O)c1cccs1
Reactant: COc1ccc(NC(=N)N)cc1
Agent: O=C(O)O
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3cccs3)n2)cc1
Yield: 61.2 %

Procedure:
A mixture of 10.9 g of 3-dimethylamino-1-(2-thienyl)-2-propen-1-one (U.S. Pat. No. 4,374,988) and 11.8 g of 4-methoxyphenylguanidine carbonate in 150 ml of isopropanol was heated at reflux for 48 hours. The solution was cooled, then filtered, giving 9.0 g of the desired product as yellow crystals, mp 158°-160° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-])=O)[C:16](I)=[N:17][CH:18]=1>>[NH2:20][C:15]1[C:16]([C:4]([C:3]2[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])=[O:5])=[N:17][CH:18]=[C:13]([Cl:12])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1I
Reactant: COc1cccc(F)c1C=O
Product: COc1cccc(F)c1C(=O)c1ncc(Cl)cc1N

Procedure:
(3-Amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-methanone was prepared from 2-fluoro-6-methoxybenzaldehyde and 5-chloro-2-iodo-3-nitro-pyridine in three steps according to the General Procedure C. MS m/z: 281.0 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:12]=[CH:11][N:10]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:4]=2[C:5](=[O:9])[N:6](C)[N:7]=1.[H-].[Na+].Br[CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27]>CN(C=O)C.O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[N:10]1[C:4]2[C:5](=[O:9])[NH:6][N:7]=[C:2]([NH:1][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:3]=2[CH:12]=[CH:11]1
Reactant: Cc1cc(C)c(-n2ccc3c(N)nn(C)c(=O)c32)c(C)c1
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)Nc1n[nH]c(=O)c2c1ccn2-c1c(C)cc(C)cc1C
Temperature: 80 °C
Reaction time: 15 h
Yield: 25.9 %

Procedure:
To a solution of 4-amino-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (113 mg, 0.40 mmol) in DMF (1 ml) were added sodium hydride (60% in oil, 48 mg, 1.20 mmol) and 3-bromopentane (0.15 ml, 1.20 mmol). The mixture was stirred at 80° C. for 15 hours, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5:1) to give 35 mg (25%) of the title compound as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]4[CH:25]=[CH:24][CH:23]=[CH:22][C:12]4=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26]1[C:34]2[C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[S:31][C:30]=2[C:29]([C:39]2[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=2)=[CH:28][CH:27]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO.C1(C)C=CC=CC=1.O.C(O)C>[CH:26]1[C:34]2[C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[S:31][C:30]=2[C:29]([C:39]2[CH:40]=[C:41]([C:2]3[CH:3]=[C:4]([C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[C:11]6[CH:25]=[CH:24][CH:23]=[CH:22][C:12]6=[C:13]6[CH:21]=[CH:20][CH:19]=[CH:18][C:14]6=5)[N:9]=4)[CH:5]=[CH:6][CH:7]=3)[CH:42]=[CH:43][CH:44]=2)=[CH:28][CH:27]=1
Reactant: Brc1cccc(-c2ccc3c4ccccc4c4ccccc4c3n2)c1
Reactant: OB(O)c1cccc(-c2cccc3c2sc2ccccc23)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1cc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)cc(-c2ccc3c4ccccc4c4ccccc4c3n2)c1
Yield: 61.5 %

Procedure:
In a 50-mL three-neck flask, 0.56 g (1.5 mmol) of 2-(3-bromophenyl)dibenzo[f,h]quinoline, 0.46 g (1.5 mmol) of 3-(dibenzothiophen-4-yl)phenylboronic acid, 58 mg (0.19 mmol) of tri(ortho-tolyl)phosphine, 15 mL of toluene, 1.5 mL of ethanol, and 1.5 mL of a 2M aqueous solution of potassium carbonate were put. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. Then, 17 mg (77 μmol) of palladium(II) acetate was added to this mixture, and the mixture was stirred at 80° C. for 9 hours under a nitrogen stream. After a predetermined time, water and toluene were added to this mixture, and the resulting solid was collected by suction filtration. A toluene solution of the obtained solid was suction-filtered through alumina and Celite, and the filtrate was concentrated to give a yellow solid. A methanol suspension of the obtained solid was irradiated with ultrasonic waves, and a solid was collected by suction filtration, so that the object of the synthesis was obtained as 0.52 g of white powder in 63% yield.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C@@H:17]1[N:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:52])[C@@H:36]([NH:38][C:39](=[O:51])[C@@H:40]([NH:44][C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:41]([CH3:43])[CH3:42])[CH3:37])=[CH:30][CH:29]=2)=[O:25])[C:22]2[CH:53]=[C:54]([O:59][Si:60]([CH:67]([CH3:69])[CH3:68])([CH:64]([CH3:66])[CH3:65])[CH:61]([CH3:63])[CH3:62])[C:55]([O:57][CH3:58])=[CH:56][C:21]=2[C:20](=[O:70])[N:19]2[CH:71]=[C:72](/[CH:74]=[CH:75]/[CH3:76])[CH2:73][C@@H:18]12.N1C(C)=CC=CC=1C>C(Cl)Cl>[Si:1]([O:8][C@@H:17]1[N:23]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:52])[C@@H:36]([NH:38][C:39](=[O:51])[C@@H:40]([NH:44][C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:41]([CH3:42])[CH3:43])[CH3:37])=[CH:32][CH:33]=2)=[O:25])[C:22]2[CH:53]=[C:54]([O:59][Si:60]([CH:61]([CH3:63])[CH3:62])([CH:67]([CH3:69])[CH3:68])[CH:64]([CH3:65])[CH3:66])[C:55]([O:57][CH3:58])=[CH:56][C:21]=2[C:20](=[O:70])[N:19]2[CH:71]=[C:72](/[CH:74]=[CH:75]/[CH3:76])[CH2:73][C@@H:18]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)N2c3cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc3C(=O)N3C=C(/C=C/C)C[C@H]3[C@@H]2O)cc1)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)N2c3cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc3C(=O)N3C=C(/C=C/C)C[C@H]3[C@@H]2O[Si](C)(C)C(C)(C)C)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
Tert-butyldimethylsilyltrifluoromethane sulfonate (0.46 g, 1.74 mmol, 3.0 eq) was added to a solution of secondary alcohol 16 (0.5 g, 0.58 mmol, 1.0 eq) and 2,6-lutidine (0.25 g, 2.32 mmol, 4.0 eq) in dry DCM (10 mL) at 0° C. under an atmosphere of nitrogen. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for a further 120 mins. The organic phase was then washed successively with water (10 mL), saturated sodium bicarbonate (10 mL) and brine (5 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 50/50 v/v n-hexane/EtOAc) to afford the product as a white solid (0.320 g, 57%). LC/MS (4.415 min (ES+)), m/z: 976.52 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.31 (br s, 1H), 7.48 (d, 2H, J=8.0 Hz), 7.21 (s, 1H), 7.14 (d, 2H, J=8.3 Hz), 6.89 (s, 1H), 6.65 (s, 1H), 6.38 (d, 1H, J=7.3 Hz), 6.25 (d, 1H, J=14.6 Hz), 5.93 (m, 1H), 5.85 (d, 1H, J=8.8 Hz), 5.50 (m, 1H), 5.34 (m, 1H), 5.24 (m, 2H), 5.15 (d, 1H, J=12.5 Hz), 4.86 (d, 1H, J=12.2 Hz), 4.62 (m, 3H), 4.01 (m, 1H), 3.86 (s, 3H), 3.78 (m, 1H), 3.04 (m, 1H), 2.56 (m, 1H), 2.20 (m, 1H), 1.84 (dd, 3H, J=6.6, 0.7 Hz), 1.48 (d, 3H, J=6.8 Hz), 1.20 (m, 3H), 1.05 (d, 9H, J=2.9 Hz), 1.03 (d, 9H, J=2.9 Hz), 0.99 (d, 3H, J=6.8 Hz), 0.95 (d, 3H, J=6.8 Hz), 0.88 (s, 9H), 0.27 (s, 3H), 0.14 (s, 3H).