Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28]2[S:32][C:31]([C:33]3([O:37][CH2:38][O:39][CH3:40])[CH2:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:8]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:5]2=[N:6][CH:7]=1.[O:41]1[CH2:45][CH2:44][CH:43](O)[CH2:42]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:28]2[S:32][C:31]([C:33]3([O:37][CH2:38][O:39][CH3:40])[CH2:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:43]4[CH2:44][CH2:45][O:41][CH2:42]4)=[CH:13][CH:12]=3)[N:8]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: OC1CCOC1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(O)cc3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(OC5CCOC5)cc3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol (Example 69A) (60 mg, 0.101 mmol), tetrahydrofuran-3-ol (12 mg, 0.131 mmol), and triphenylphosphine (34.3 mg, 0.131 mmol) in anhydrous tetrahydrofuran (1 mL) was treated with diisopropyl azodicarboxylate (0.025 mL, 0.131 mmol). The reaction was stirred for 16 hours at ambient temperature. The reaction treated with more tetrahydrofuran-3-ol (12 mg, 0.131 mmol), diisopropyl azodicarboxylate (0.025 mL, 0.131 mmol) and triphenylphosphine (34.3 mg, 0.131 mmol), and the reaction was warmed to 70° C. for 5 hours. The reaction was cooled, diluted with ethyl acetate, and washed with water and brine. The organic layer dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 30 to 40% ethyl acetate in hexanes, to give the title compound. MS ESI(+) m/z 666.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[N:3][C:2]([C:21]3[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=3)=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)N1CCN(c2ccc(Cl)nn2)CC1
Product: CC(C)N1CCN(c2ccc(-c3ccc(O)cc3)nn2)CC1

Procedure:
4-[6-(4-Isopropyl-piperazin-1-yl)-pyridazin-3-yl]phenol was prepared by the general procedure I similar to that described in Example 71, starting from 3-chloro-6-(4-isopropyl-piperazin-1-yl)-pyridazine and (4-hydroxyphenyl)boronic acid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]=[CH:27][C:26]3[CH:25]=[CH:24][C:23]([O:22][CH:17]4[CH2:18][CH2:19][CH2:20][CH2:21][O:16]4)=[CH:30][CH:29]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=Cc1ccc(OC2CCCCO2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C(=Nc1ccc(OCCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (6.92 g, 33.5 mmol) and 4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (7.25 g, 35.2 mmol) in 110 mL methylene chloride was added magnesium sulfate (14.2 g, 117.3 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen. The reaction was filtered and concentrated to afford 13.3 g of the crude title compound of Step A which was used without further purification. MS 395.2 (M+1)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.[CH2:15]([O:17][P:18]([O-:22])[O:19][CH2:20][CH3:21])[CH3:16].C(N(CC)CC)C.C(Cl)Cl.CO>CO>[CH2:15]([O:17][P:18]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=2)[CH:3]=1)(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16]
Reactant: CCOP([O-])OCC
Reactant: Brc1ccnc(-c2cc(Br)ccn2)c1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccnc(-c2cc(Br)ccn2)c1
Temperature: 98 °C
Reaction time: 0.17 h

Procedure:
2.0 g of 4,4'-dibromo-2,2-bipyridine (6.4 mmol), 0.9g of palladium tetrakistriphenylphosphine (0.8 mmol), 3.14 g of diethylphosphite (23 mmol) and 2.34 g of triethylamine (23 mmol) are measured into an argon filled 50 ml round bottom. flask, equipped with a cold finger (10 cm) and magnetic stirrer. This is heated on a 98° C. oil bath for 3 hours. The reaction is monitored with TLC on silica gel plates, DCM: MeOH (10:1), Rf-Lb=0.73. This is then cooled back to room temperature, and then the solidified mixture is added to 25 mls of methanol, stirred for 10 min. and evaporated to dryness under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[OH-:17].[Na+]>O1CCOCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:17])[N:7]=2)=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: Clc1ccc(COc2ccnc(Cl)n2)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1nc(OCc2ccc(Cl)cc2)cc[nH]1
Temperature: 0 °C
Yield: 5 %

Procedure:
To a stirred solution of 2-chloro-4-((4-chlorobenzyl)oxy)pyrimidine (2.8 g) in dioxane and water (1:4, 30 ml) was added NaOH (440 mg), and the mixture was heated at reflux for 3 h. The reaction mixture was then cooled to 0° C. and the product was precipitated out from the reaction medium. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound (130 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[Cl:9].[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)#[N:11].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl>C1(C)C=CC=CC=1>[C:10]([C:12]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([Cl:9])[CH:4]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Fc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 1,2-dichloro-4-fluorobenzene (1.64 g, 10 mmol) in toluene (25 mL) was added tert-butyl 4-cyanopiperidine-1-carboxylate (2.10 g, 10 mmol) and KHMDS (0.5 M in toluene) (2.99 g, 15.00 mmol). The reaction mixture was stirred at 60° C. for 16 hours and cooled to room temperature. After the addition of 1N HCl (25 mL), the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by Prep-TLC (eluted with ethyl acetate:petroleum ether=1:5) to provide Example 140A. LCMS: 255 [M−100]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10]O)=[CH:7][O:8][C:4]=2[CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[N:36]1([C:42]2[CH:43]=[CH:44][CH:45]=[C:46]3[C:51]=2[N:50]=[CH:49][CH:48]=[CH:47]3)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>N1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][N:39]3[CH2:40][CH2:41][N:36]([C:42]4[CH:43]=[CH:44][CH:45]=[C:46]5[C:51]=4[N:50]=[CH:49][CH:48]=[CH:47]5)[CH2:37][CH2:38]3)=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: OCCc1coc2cc(Cl)ccc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2c(CCN3CCN(c4cccc5cccnc45)CC3)coc2c1
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(6-chloro-1-benzofuran-3-yl)ethanol (980 mg, 5 mmol) in anhydrous pyridine (20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at 0° C. for 48 hrs and quenched with ice cold water. The reaction mixture was extracted with chloroform, washed well with water and dried over anhydrous MgSO4. It was filtered and concentrated. The crude product obtained was taken to next step without any purification. A mixture of tosylate (350 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino-quinoline (213 mg, 1 mmol) was heat at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetate:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a yellow oil. Yield: 120 mg (30%); (M+H): 392; 1HNMR (400 MHz, CDCl3):δ 8.82˜8.81 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H); 8.40˜8.20 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.46˜6.92 (m, 8H); 3.50˜2.70 (m, 12H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Br[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17]2>>[C:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[CH2:18][CH2:17]3)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: O=C1CCc2cc(Br)ccc21
Product: CC(=O)c1cccc(-c2ccc3c(c2)CCC3=O)c1

Procedure:
The title compound was prepared from 3-acetylphenyl boronic acid and 5-bromo-1-indanone according to the coupling procedure as described in example 6. MS (ESI) m/z 251; HRMS: calcd for C17H14O2+H+, 251.10666; found (ESI, [M+H]+), 251.1077.
Reaction SMILES: CS(OC(C1C=NC(NC(C2(C3C=CC4OCOC=4C=3)CC2)=O)=CC=1)C1C=CC=C[C:8]=1[O:13][CH3:14])(=O)=O.N1CCC[CH2:38][CH2:37]1.[O:42]1[C:46]2[CH:47]=[CH:48][C:49]([C:51]3([C:54]([NH:56][C:57]4[CH:62]=[CH:61][C:60]([CH:63]([N:72]([CH3:74])[CH3:73])[C:64]5[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=5[O:70][CH3:71])=[CH:59][N:58]=4)=[O:55])[CH2:53][CH2:52]3)=[CH:50][C:45]=2[O:44][CH2:43]1>>[O:42]1[C:46]2[CH:47]=[CH:48][C:49]([C:51]3([C:54]([NH:56][C:57]4[CH:62]=[CH:61][C:60]([CH:63]([N:72]5[CH2:73][CH2:38][CH2:37][C@H:74]5[CH2:8][O:13][CH3:14])[C:64]5[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=5[O:70][CH3:71])=[CH:59][N:58]=4)=[O:55])[CH2:53][CH2:52]3)=[CH:50][C:45]=2[O:44][CH2:43]1
Reactant: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Reactant: C1CCNCC1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COC[C@@H]1CCCN1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)c1ccccc1OC

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and piperidine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6][N:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:4](=[O:21])[C:3]=1[C:22](OCC)=[O:23].[H-].[Na+].[N+:29](C1C=CC=CC=1CBr)([O-])=O.Cl.CC[O:43][C:44]([CH3:46])=[O:45]>CN(C)C=O.O>[OH:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[N:6][N:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:4](=[O:21])[C:3]=1[C:22]([NH:29][CH2:46][C:44]([OH:43])=[O:45])=[O:23]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)c1c(O)c(C(C)C)nn(Cc2ccccc2[N+](=O)[O-])c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(Cc2ccccc2[N+](=O)[O-])c(=O)c(C(=O)NCC(=O)O)c1O
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Ethyl 5-hydroxy-6-(1-methylethyl)-2-[(2-nitrophenyl)methyl]-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. Sodium hydride (88 mg, 2.21 mmol) was added to a solution of the compound from example 14a) (200 mg, 0.88 mmol) in N,N-Dimethylformamide (DMF) (3.5 mL) at 0° C. The reaction was brought to room temperature and stirred for 30 minutes. The temperature was then reduced to 0° C. and 2-nitrobenzyl bromide (191 mg, 0.88 mmol) was added. The reaction was brought to room temperature and stirred for 3 h followed by the addition of 1N HCl. The solution was diluted with EtOAc and H2O and the layers separated. The aqueous layer was backextracted with EtOAc several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, 30-60% EtOAc/Hexanes) to give the title compound (206 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (s, 1H) 8.07 (dd, J=8.21, 1.14 Hz, 1H) 7.72 (td, J=7.58, 1.26 Hz, 1H) 7.54-7.62 (m, 1H) 7.29 (dd, J=7.71, 1.14 Hz, 1H) 5.46 (s, 2H) 4.27 (q, J=7.07 Hz, 2H) 3.13 (sept, J=6.78 Hz, 1H) 1.25 (t, J=7.20 Hz, 3H) 1.09 (d, J=6.82 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[C:14]([F:15])=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:18].[K+].Cl.O1CCOC[CH2:22]1.O>O>[CH2:2]([CH2:1][NH:8][C:9]1[C:14]([F:15])=[CH:13][N:12]=[C:11]([OH:18])[N:10]=1)[C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:22]=1
Reactant: C1COCCO1
Reactant: CN(Cc1ccccc1)c1nc(Cl)ncc1F
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Oc1ncc(F)c(NCCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 72 h
Yield: 23 %

Procedure:
To a suspension of N-benzyl-2-chloro-5-fluoro-N-methylpyrimidin-4-amine (0.075 g, 0.30 mmol) in dioxane/H2O (1:1, 2 mL total volume) was added potassium hydroxide (KOH; 0.17 g, 3.0 mmol). The mixture was warmed to 100° C. and stirred for 72 h. The reaction mixture was diluted with H2O (5 mL), and the pH was adjusted to 7 with 2 N HCl. The resulting white precipitate was collected by vacuum filtration, but the majority of the product remained in the aqueous phase. The solid and filtrate were combined and the solvent was removed by azeotropic distillation with CH3CN in vacuo. The residue was dissolved/suspended in CH2Cl2 (25 mL), adsorbed onto Celite (3.0 g) and purified by normal phase chromatography (24 g SiO2; gradient, MeOH/CH2Cl2) to give 4-(benzylmethylamino)-5-fluoropyrimidin-2-ol (0.016 g, 23%) as a white solid: mp 122.8-123.6° C.; 1H NMR (300 MHz, CDCl3) δ 12.72 (s, 1H), 7.42-7.14 (m, 6H), 4.88 (s, 2H), 3.20 (d, J=3.2, 3H); ESIMS m/z 235 (M+2)+, 232 (M−H)−.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24](O)=[O:25])=[CH:22][N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1.Cl.C([N:49]=C=NCCCN(C)C)C.CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([NH2:49])=[O:25])=[CH:22][N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1
Reactant: COc1cc(COc2nn(Cc3ccc(Oc4ccccc4)cc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(Cc3ccc(Oc4ccccc4)cc3)cc2C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (0.80 g), 1H-1,2,3-benzotriazol-1-ol ammonia complex (0.22 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.28 g), and N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carbamide (0.75 g, yield 94%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from acetone-hexane. Melting point: 105–106° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[O:26]=[C:27]1[N:36]([CH:37]([CH3:41])[C:38]([OH:40])=O)[CH:35]=[CH:34][C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]1=2.[F:42][C:43]1[C:44]([NH:55][NH2:56])=[N:45][CH:46]=[C:47]([C:49]2[CH:50]=[N:51][N:52]([CH3:54])[CH:53]=2)[CH:48]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:42][C:43]1[C:44]([NH:55][NH:56][C:38](=[O:40])[CH:37]([N:36]2[CH:35]=[CH:34][C:33]3[N:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]2=[O:26])[CH3:41])=[N:45][CH:46]=[C:47]([C:49]2[CH:50]=[N:51][N:52]([CH3:54])[CH:53]=2)[CH:48]=1
Reactant: Cn1cc(-c2cnc(NN)c(F)c2)cn1
Reactant: CC(C(=O)O)n1ccc2ncccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C(=O)NNc1ncc(-c2cnn(C)c2)cc1F)n1ccc2ncccc2c1=O
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
HATU (1053 mg, 2.7 mmol), 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (470 mg, 1.8 mmol) and 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (421 mg, 2 mmol) (step 1 of General Method K) were taken up in 6 mL of acetonitrile. DIPEA (967 μl, 5.5 mmol) was added and the reaction was stirred for 30 minutes, until reaction was complete. The crude material was concentrated and then purified via MPLC with a gradient 100% DCM to 90% DCM/10% MeOH/1% NH4OH) to yield N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide (500 mg, 67% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[CH:10](O)=[O:11].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH:10]([NH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[OH:8])=[O:11]
Reactant: O=CO
Reactant: Cc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c(NC=O)c1

Procedure:
To 2-amino-p-cresol (8.01 g, 65 mmol) was added formic acid (5.98 g, 130 mmol) and the mixture was refluxed for 1 hour. The reaction mixture was allowed to stand for cooling. After the addition of ethyl acetate, the mixture was poured into ice-cold water. The aqueous layer was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel and recrystallized from ethyl acetate-hexane to give the title compound (1). Yield 8.59 g (88%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[N:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[N:16]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(Cl)Cl.O.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>[F:30][C:27]([F:28])([F:29])[O:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[CH:18]=[N:19][C:15]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[N:16]2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 100 °C
Yield: 52.5 %

Procedure:
A microwave vial was charged with (4-(methoxycarbonyl)phenyl)boronic acid (70.1 mg, 0.390 mmol), 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (100 mg, 0.325 mmol), aqueous Na2CO3 (1 M, 1.298 mL, 1.298 mmol), and Pd(PPh3)4 (37.5 mg, 0.032 mmol). The reaction vial was capped and evacuated/backfilled with nitrogen gas (3×). DME (2 mL) was added, the vial was capped, heated at 100° C. for 15 minutes (min) in a Biotage Initiator® microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and diluted with CH2Cl2 (3 mL) and water. The organic and aqueous phase was separated with a phase separator, and the organics were concentrated in vacuo. Purification via flash column chromatography using EtOAc/hexanes as eluent yielded the title compound as a white solid (62 mg, 52%): 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.28 (m, 2H), 8.15 (m, 2H), 7.81 (m, 2H), 7.41 (m, 2H), 3.96 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 364 ([M+H]+).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:16])[CH:4]=1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br-:1].[CH2:14]([O:13][C:11](=[O:12])/[CH:10]=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P+:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:4][C:5]=1[CH3:16])[CH3:15]
Reactant: CCOC(=O)/C=C/c1ccc(CBr)cc1C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Product: [Br-]

Procedure:
A solution of ethyl(2E)-3-[4-(bromomethyl)-2-methylphenyl]prop-2-enoate (intermediate 20, 1.494 g) in toluene (30 ml) was stirred and treated with triphenylphosphine (1.52 g) and then heated at reflux for 2 hours then at 21° C. overnight. More triphenylphosphine (0.5 g) was then added and the reaction heated at reflux for a further 5 hours. The mixture was then allowed to cool and filtered to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:29])([CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:30]([O-])=O)C1C=CC=CC=1>[H][H].[Pd]>[CH3:1][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:29])([CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])=[CH:11][C:10]=1[NH2:30]
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(Cc2nnn[nH]2)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Product: CNc1ccc(C(C)(Cc2nnn[nH]2)C(=O)N2CCCC2)cc1N

Procedure:
Prepared analogously to Example 1f from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one and hydrogen/palladium on activated charcoal.