Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Cl>C1(C)C=CC=CC=1.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:5]2[CH:4]=[CH:3][CH:2]=[CH:11][C:6]=2[CH3:7])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cccc2ccccc12
Yield: 184.8 %

Procedure:
The Grignard solution was subsequently added dropwise to a solution of 118 g (0.57 mol) of 1-bromonaphthalene and 3.5 g of bis(triphenylphosphine)nickel dichloride in 800 cm3 of toluene at such a rate that the internal temperature did not exceed 50° C. The mixture was subsequently refluxed for a further 3 hours, 500 ml of 10% strength aqueous HCl were added, the phases were separated, and the organic phase was freed from solvent in vacuo. Filtration through silica gel (hexane) gave 115 g (92%) of 18 as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([OH:14])[N:11]([CH3:15])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH:28]([F:30])[F:29]>CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH:28]([F:30])[F:29])[N:11]([CH3:15])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: FC(F)Cl
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ncc(Cl)cc2F)cc1OC(F)F
Temperature: 85 °C

Procedure:
46.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-hydroxy-1-methyl-[1H]-pyrazole (Example H14) and 84 g of potassium carbonate are initially introduced into 250 ml of dry dimethylformamide and the mixture is heated up to 85° C. Freon 22 (chlorodifluoromethane) is then passed in over a period of 2 hours, with thorough stirring. TLC analysis of a worked-up sample (silica gel 60 F254; n-hexane/ethyl acetate/glacial acetic acid 20/20/1, UV) shows that no further starting material is present. The reaction mixture is partitioned between water and diethyl ether (foaming on addition of water). After extraction by shaking and separation of the phases, the ether phase is washed twice with water and once with brine. After the organic phase has been dried over sodium sulfate and filtered, the filtrate is concentrated in vacuo and the residue is purified by means of flash chromatography (silica gel; eluting agent: n-hexane/ethyl acetate 2/1 (v/v)). 22.0 g of the desired title compound are obtained as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([CH:16]=[CH:15][CH:14]=[C:12](O)[CH:11]=1)[OH:10].Cl.NC1C=CC(C)=CC=1.[OH-].[Na+]>C(OCC)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[CH:11]=[C:9]([OH:10])[CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(Nc2cccc(O)c2)cc1
Temperature: 160 °C
Yield: 74.1 %

Procedure:
A reaction mixture of p-toluidine (13.4 g, 126.2 mol), resorcinol (10 g, 90.8 mmol) and p-toluidine HCl (1.3 g, 9.0 mmol) was heated at 160° C. for 48 h with an oil bath. After cooling to room temperature, the reaction mixture in 500 mL of diethyl ether was treated with 2N NaOH to give precipitated materials and filtered under reduced pressure. The collected solid was treated with glacial acetic acid until completely dissolved, and the solution was extracted with diethyl ether (2×200 mL). The ether layer was washed with water (2×150 mL), dried over MgSO4, and concentrated under reduced pressure to give a dark-brown oil, which was purified by flash column chromatography using EtOAc/hexane (40:60). The resulting oil was crystallized from CH2Cl2/hexane to yield 13.4 g (74%) of the title compound as a dark brown solid. Mp 86-88° C. (lit 91° C. )
Reaction SMILES: [F:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>[Cu](Cl)Cl.C(Cl)Cl>[F:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH:3]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: O=CC(F)c1ccccc1
Reactant: CC(C)(C)[S@](N)=O
Agent: Cl[Cu]Cl
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/C(F)c1ccccc1
Temperature: 23 °C
Reaction time: 0.03 h
Yield: 30.1 %

Procedure:
To a 500 mL RBF containing 2-fluoro-2-phenylacetaldehyde (320.00 mg, 2316.5 μmol) was added DCM (10 mL) and the mixture was allowed to stir at 23° C. for 2 min. At this time, (R)-2-methylpropane-2-sulfinamide (364.99 mg, 3011.5 μmol) was added in one portion to the mixture followed by copper(II) chloride (856.51 mg, 6370.4 μmol) at 5:30 μm. The reaction was allowed to stir overnight and then filtered through a plug of celite over silica gel. The solvent was removed and the crude residue was purified on a silica gel column (15 to 35% EtOAc in hexanes) to give the product (168 mg, 30%).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH3:7]CO.[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([O:20][CH3:21])=[CH:13][C:12]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]SC)[CH2:24][CH2:23]1>O.CCOC(C)=O>[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([O:20][CH3:21])=[CH:13][C:12]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][S:3]([CH3:7])(=[O:5])=[O:2])[CH2:24][CH2:23]1
Reactant: COc1cc(N2CCC(CCSC)CC2)c(C)cc1[N+](=O)[O-]
Reactant: CCO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To OXONE® (155 g, 253 mmol) in H2O (425 mL) and EtOH (250 mL) at 0° C. was added 1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylthio)ethyl]piperidine (32.8 g, 101 mmol) in EtOAc (250 mL) via addition funnel over the period of an hour. The reaction was warmed to rt and allowed to stir for 30 min at which time it was determined to be complete by LCMS. The reaction was diluted with H2O and EtOAc. The resultant precipitate was filtered and washed with EtOAc. The layers of the filtrate were separated and the aqueous layer was washed with EtOAc (3×). The filtered solids were dissolved with DCM and H2O and the layers were separated. The organic layer was washed with DCM (2×). The combined organic layer was dried (MgSO4), filtered, and rotovapped down. The resultant solid was triturated with diethyl ether, filtered, and dried under vacuum to provide the title compound of Step I (26.1 g, 73.2 mmol, 73%). 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 6.67 (s, 1H), 3.88 (s, 3H), 3.27 (d, J=12.3 Hz, 2H), 3.10-3.20 (m, 2H), 2.96 (s, 3H), 2.68 (t, J=11.3 Hz, 2H), 2.17 (s, 3H), 1.79 (d, J=11.2 Hz, 2H), 1.62-1.73 (m, 2H), 1.46-1.60 (m, J=10.7, 7.0, 3.5, 3.5 Hz, 1H), 1.31 (qd, J=11.9, 3.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20]C)=O)=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>>[CH3:22][O:23][CH2:24][CH2:25][NH:26][C:18]([C:15]1[CH:14]=[CH:13][C:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[CH:17][N:16]=1)=[O:20]
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2ccc(F)cc2)cn1
Reactant: COCCN
Product: COCCNC(=O)c1ccc(NS(=O)(=O)c2ccc(F)cc2)cn1

Procedure:
0.5 g (1.61 mmol) of methyl 5-[(4-fluorophenylsulfonyl)amino]pyridine-2-carboxylate (compound from Example 4a) is stirred at 70° C. for 3 h in 5 ml of 2-methoxyethylamine. The mixture is concentrated, the residue is dissolved in water, the solution is acidified with conc. HCl, the solid is filtered off with suction and washed with water and 0.53 g of the title compound is obtained in the form of colorless crystals, M.p. 154° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][O:6][C:7]1[N:12]=[C:11]([C:13](=O)[CH2:14]Br)[CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:12]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: O=C(O)CCOc1cccc(C(=O)CBr)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc(OCCC(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(2-carboxyethoxy)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(2-carboxyethoxy)-2-pyridyl]thiazole.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:7]2[C:12]=1[CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2.[O:21]=[CH:22][C:23](Cl)(Cl)Cl.S([O-])([O-])(=O)=[O:28].[Na+].[Na+].Cl.NO>O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:6]2[C:7]3[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][C:12]=3[C:3]3[NH:2][C:22](=[O:21])[C:23](=[O:28])[C:4]=3[CH:5]=2)=[CH:19][CH:18]=1
Reactant: CN1CCc2c(-c3ccc(Cl)cc3)ccc(N)c2C1
Reactant: O=S(=O)([O-])[O-]
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Product: CN1CCc2c(-c3ccc(Cl)cc3)cc3c(c2C1)NC(=O)C3=O
Temperature: 100 °C

Procedure:
A mixture of 8-Amino-5-(4-chlorophenyl)-N-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloric acid salt (3.1 g, 10 mmol), chloral (1.5 ml, 15 mmol), sodium sulphate (14 g, 98.6 mmol), hydroxylamine hydrochloride (2.4 g, 15 mmol) and water (70 ml) was heated at reflux for 0.5 h. The mixture was allowed to reach room-temperature. The crystals were filtered and washed with water, followed by recrystallisation from ethanol (96%). The crystalline intermediate (2.0 g) was combined with methanesulphonic acid (20 ml) and heated for 15 min at 100° C. The crude mixture was poured out on ice and sodium hydroxide (25 ml, 10 M) was added. The crystalline product was recrystallized from ethanol (96%). Yield 0.54 g (29%). Mp decomp. 225° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](Cl)=[N:12][CH:13]=1.[CH2:15]([OH:18])[CH2:16][CH3:17].O>C1COCC1.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:15][CH2:16][CH3:17])=[N:12][CH:13]=1
Reactant: CCCO
Reactant: Clc1ccc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCOc1ccc(Br)cn1
Temperature: 120 °C
Yield: 96.6 %

Procedure:
Potassium tert-butoxide (1.85 g, 16.5 mmol) was added to a mixture of 5-bromo-2-chloropyridine (2.89 g, 15.0 mmol) and 1-propanol (1.230 mL, 16.5 mmol) in THF (15 mL). The reaction mixture was heated at 120° C. for 30 minutes in a microwave reactor. The mixture was poured into a mixture of water (50 mL) and EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4 and evaporated to dryness. Flash chromatography (silica, 0-20% EtOAc in heptanes) gave the title compound as a yellow oil (3.13 g, 97%) sufficiently pure for the next step.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][CH2:6][CH:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[Br:2][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH3:5]
Reactant: CCCCCC(O)CC
Reactant: BrP(Br)Br
Product: CCCCCC(Br)CC
Temperature: 100 °C
Yield: 106.2 %

Procedure:
To 8 ml (23 g, 85.3 mmol) of phosphorus tribromide was added dropwise 15 g (115.4 mmol) of 3-octanol over a 1/2 hr period. The resulting solution was heated at 100° C. (oil bath) for 2 hr, after which time the reaction mixture was cooled and poured into 200 ml ice-water which was extracted with CHCl3 (3×120 ml). The combined organic extracts were washed with 5% Na2S2O3 (2×200 ml), H2O (200 ml), sat'd aq. NaHCO3 (2×200 ml), H2O (200 ml), and sat'd aq. NaCl (200 ml), and dried over MgSO4. After the removal of the solvent under reduced pressure, the residue was distilled (bp 78°-80° C./18 Torr, lit. bp 84.4°-85.1° C./20 Torr (18)) to give 17.5 g (78.58%) of pure 3-bromooctane which exhibited C-Br band at 797 cm-1 in the IR spectrum (18). NMR(CDCl3): δ1.0 (6H, t, CH3), δ1.31 (6H, broad singlet, --CH2), δ1.75 (4H, q, ##STR13## δ3.90 (1H, m, >CHBr).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH:2]1[C:5]([OH:7])=[O:6].S(Cl)([Cl:10])=O.[CH3:12]O>>[ClH:10].[CH3:12][O:6][C:5]([CH:2]1[CH2:3][CH2:4][NH:1]1)=[O:7]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN1
Product: COC(=O)C1CCN1
Product: Cl
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of azetidine-2-carboxylic acid (1 eq.) in MeOH at 0° C. was added dropwise thionyl chloride (2.5 eq.). The reaction was stirred at 20° C. for 15 h. The crude was concentrated under reduced pressure and used as such without further purification.
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]1[CH2:12][N:11]([CH2:13][CH2:14][N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][C:16]2=[O:26])[CH2:10][C@@H:9]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:8]1)(C)C.[ClH:38].O1CCOCC1>C(Cl)Cl.CO>[ClH:38].[NH2:28][CH2:27][C@H:9]1[CH2:8][C@@H:7]([OH:6])[CH2:12][N:11]([CH2:13][CH2:14][N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][C:16]2=[O:26])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(CCn2c(=O)ccc3ccc(F)cc32)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: NC[C@H]1C[C@@H](O)CN(CCn2c(=O)ccc3ccc(F)cc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To cis-1,I-dimethylethyl ({(3RS,5RS)-5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-[2-(7-fluoro-2-oxo-1(2H)-quinolinyl)ethyl]-3-piperidinyl}methyl)carbamate (410 mg; 0.78 mmol) in DCM (9 ml) and MeOH (1 ml) was added 4N HCl in 1,4-dioxane (1 ml; 4.0 mmol) and the reaction was allowed to stir at room temperature under nitrogen for 2 hours. The reaction was concentrated under reduced pressure to give the desired compound (270 mg; 100%) as a yellow solid which was used in the next reaction without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:32])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:31])[CH:18]=2)[CH:13]=1.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34].C(N(CC)CC)C>ClCCl>[CH3:8][O:9][C:10](=[O:32])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:27][CH2:26]2)=[O:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:31])[CH:18]=2)[CH:13]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)N2CCNCC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(C(=O)c2c(C)c(CC(=O)OC)cc3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of [6-fluoro-3-methyl-4-(piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid methyl ester trifluoroacetate (45.8 mg, 0.10 mmol) and ethanesulfonyl chloride (14 μL, 0.15 mmol) in dichloromethane was added triethylamine (306 μL, 2.2 mmol). The resulting mixture was stirred at room temperature overnight, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 20-40% ethyl acetate in petroleum ether) to afford [4-(4-ethanesulfonyl-piperazine-1-carbonyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (38 mg, 87%) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[CH3:20][C:21]([OH:26])([C:24]#[CH:25])[CH2:22][OH:23]>CS(C)=O.C(N(CC)CC)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:26][C:21]([CH3:20])([CH2:22][OH:23])[C:24]#[C:25][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1
Reactant: C#CC(C)(O)CO
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)CO

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (200 mg, 0.58 mmol, 1.00 equiv), 2-methylbut-3-yne-1,2-diol (200 mg, 2.00 mmol, 3.50 equiv) and Pd(PPh3)2Cl2 (40 mg, 0.06 mmol, 0.10 equiv) in DMSO (1 mL) and triethylamine (1 mL). The final reaction mixture was irradiated with microwave radiation for 1 h at 70° C. The resulting solution was diluted with 20 mL, of water. The solids were collected by filtration and washed by acetonitrile (10 mL). This resulted in 30 mg (14%) of 9-(3,4-Dihydroxy-3-methyl-but-1-ynyl)-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a light brown solid. LC-MS (ES, m/z): 363[M+H]+; 1H-NMR (300 MHz, DMSO-d6, ppm) δ 8.64 (d, 1H), 8.438 (br s, 1H), 7.873 (br s, 1H), 6.997 (d, 1H), 5.397 (s, 1H), 4.971 (t, 1H), 4.383 (t, 2H), 3.510-3.380 (m, 4H), 1.426 (s, 3H).
Reaction SMILES: [CH2:1](OC([N:11]1[CH2:22][CH2:21][N:20]2[CH2:23][CH2:24][CH2:25][N:14]([CH2:15][CH2:16][N:17](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:19]2)[CH2:13][CH2:12]1)=O)[C:2]1C=CC=C[CH:3]=1>CCO>[CH2:1]=[CH:2][CH3:3].[N:14]12[CH2:25][CH2:24][CH2:23][N:20]([CH2:21][CH2:22][NH:11][CH2:12][CH2:13]1)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2
Reactant: O=C(OCc1ccccc1)N1CCN2CCCN(CC1)CCN(C(=O)OCc1ccccc1)CC2
Solvent: CCO
Product: C1CN2CCNCCN(C1)CCNCC2
Product: C=CC

Procedure:
The synthetic intermediate 3 was deprotected by catalytic hydrogenation in EtOH solvent to give propylene cross-bridged cyclen 4. The precursor, propylene cross-bridged cyclen (1,4,7,10-tetraazabicyclo[5.5.3]pentadecane) with bis(t-butyl ester) pendant arms, being dialkylated with t-butyl bromoacetate and convenient to handle, was produced with high yield (85%) enough to be quantitated. The synthetic intermediate 5 was deprotected with trifluoroacetic acid in dichloromethane to give PCB-DO2A 6 as a bis(trifluoroacetic acid) salt. This synthesis procedure of PCB-DO2A according to an embodiment of the present disclosure is remarkably improved over the existing cross-bridged cyclen synthesis method in terms of overall yield (57%), simple procedure, selectivity, or the like.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8](N1C=CN=C1)(N1C=CN=C1)=[O:9].[CH3:20][C:21]1[C:22]([CH2:28][N:29]([CH2:36][C:37]2[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:8]([N:33]2[CH2:34][CH2:35][CH:30]([N:29]([CH2:28][C:22]3[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=3)[CH2:36][C:37]3[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:40]=[CH:39][N:38]=3)[CH2:31][CH2:32]2)=[O:9])[N:3]=1
Reactant: Nc1cccnn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C(=O)Nc3cccnn3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.2 %

Procedure:
To a solution of 3-aminopyridazine (62 mg, 0.65 mmol) (Wermuth, C.-G. J. Het. Chem. 1998, 35, 1091-1100) in CH2Cl2 (5 mL) was added 1,1′carbonyldiimidazole (128 mg, 0.79 mmol). After stirring at room temperature for 1.5 h, the mixture was heated to 50° C. After 45 min, (3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidine-4-yl-amine (115 mg, 0.33 mmol) was added and stirring was continued for 50° C. After 2 h, the reaction mixture was cooled, diluted with CH2Cl2 (20 mL), and washed with saturated NaHCO3 (3×20 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a pale yellow oil. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2/MeOH/NH4OH; 50:1:1) afforded COMPOUND 315 as a pale yellow oil (44 mg, 28%). 1H NMR (CDCl3) δ 0.93 (d, 6H, J=6.0 Hz), 1.64-1.75 (m, 2H), 1.96-1.99 (m, 2H), 2.16 (s, 3H), 2.28 (s, 3H), 2.75-2.84 (m, 4H), 3.78 (s, 2H), 3.84 (s, 2H), 4.21 (s, 1H), 4.26 (s, 1H), 7.15-7.17 (m, 1H), 7.38-7.42 (m, 1H), 7.50 (dd, 1H, J=6.0, 3.0 Hz), 7.99 (s, 1H), 8.18 (s, 1H), 8.32 (d, 1H, J=3.0 Hz), 8.33 (d, 1H, J=3.0 Hz), 8.80 (s, 1H). 13C NMR δ 18.30, 18.46, 23.61, 27.46, 44.89, 53.83, 54.34, 57.27, 118.83, 123.22, 128.28, 132.33, 133.19, 133.88, 139.08, 144.40, 146.12, 146.70, 147.89, 153.74, 154.38, 156.21, 156.96. ES-MS m/z 496 [M+H]+. Anal. Calcd. for C27H35N7O.1.4CH2Cl2.0.5H2O: C, 56.71; H, 6.50; N, 16.30. Found: C, 56.48; H, 6.32; N, 16.54.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:10]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].Cl[C:35]([O:37][CH3:38])=[O:36]>CC(C)=O>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][N:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:23][CH2:22]2)[C:10]=1[CH3:27]
Reactant: COC(=O)Cl
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: COC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Cl)c2C)CC1
Temperature: 80 °C

Procedure:
The 4-chloro-5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinoline 2,2,2-trifluoroacetate (150 mg, 0.37 mmol), potassium carbonate (360 mg, 2.60 mmol) and methyl chloroformate (0.11 mL, 1.50 mmol) were added to acetone (3.0 mL). The slurry was heated in a microwave reactor at 80° C. for 3 h. The reaction mixture was cond and the residue was partitioned between water and EtOAc. The aq. layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×30 mL) and dried over magnesium sulfate to give crude methyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate. Mass Spectrum (ESI) m/e=356.2 (M+1).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1)[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([NH2:16])[N:10]=1.CCN(CC)CC>CC#N>[Cl:8][C:9]1[CH:14]=[C:13]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[CH2:1][CH3:2])[N:12]=[C:11]([NH2:16])[N:10]=1
Reactant: CC[C@@H]1CCCN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@@H]1CCCN1c1cc(Cl)nc(N)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A mixture of (2R)-2-ethylpyrrolidine (80 mg, 0.59 mmol), 4,6-dichloro-2-pyrimidinamine (119 mg, 0.726 mmol) and Et3N (0.25 mL, 1.77 mmol) in CH3CN (6 mL) was stirred overnight at 80° C. The mixture was poured onto water (˜150 mL), sonicated and filtered to afford the title compound (94 mg, 70%) as a white solid. LC-MS (ES) m/z=227, 229 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]=O.[OH:15][C:16]1[C:17]([C:26]([NH:28][NH2:29])=[O:27])=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]=[N:29][NH:28][C:26]([C:17]1[C:16]([OH:15])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)=[O:27]
Reactant: NNC(=O)c1cc2ccccc2cc1O
Reactant: O=Cc1c(O)c(O)cc2ccccc12
Product: O=C(NN=Cc1c(O)c(O)cc2ccccc12)c1cc2ccccc2cc1O
Yield: 18 %

Procedure:
Following the general procedure of Example 1, condensation of 2, 3-dihydroxy-1-naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide yielded a yellow crystal (18%) [recrystallized from dioxane/H2O (1:1, v/v)]: mp>285° C.; 1H NMR d 13.16 (br s, 1 H), 12.27 (br s, 1 H), 11.30 (br s, 1 H), 9.74 (br s, 1 H), 9.57 (s, 1 H), 8.53 (s, 1 H), 8.17 (d, 1 H, J=8.2 Hz), 7.95 (d, 1 H, J=8.2 Hz), 7.79 (d, 1 H, J=8.0 Hz), 7.70 (d, 1 H, J=7.7 Hz), 7.54 (t, 1 H, J=7.4 Hz), 7.42-7.25 (m, 5 H); HRMS Calcd for C22H16N2O4 :372.1110, found 372.1103; Anal. (C22H16N2O4H2O) C, H, N.