Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][S:12](=[S:24])([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br)=[O:13].[Cl-].[Cs+]>>[CH3:11][S:12](=[S:24])([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:8])=[O:13]
Reactant: CS(=O)(=S)OCCOCCOCCBr
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Cl-]
Agent: [Cs+]
Product: CS(=O)(=S)OCCOCCOCCOC(=O)c1ccc(N)cc1
Yield: 70.6 %

Procedure:
In a manner analogous to that above, the reaction of p-aminobenzoic acid (473 mg; 4.90 mmol), 1-(8-bromo-3,6-dioxaoctyl) methanethiosulfonate (1.04 g, 3.39 mmol) and CsCl (1.17 g, 3.6 mmol) yielded 10-(4-aminophenyl)-10-oxo-3,6,9-trioxadecyl methanethiosulfonate (870 mg). 1H NMR (500 MHz, (CD3)2SO) δ 7.62 (d J=8.6 Hz, 2H), 6,55 (d, J=8.6 Hz, 2H), 5.94 (s, 2H), 4.25 (t, J=4.8 Hz, 2H), 3.72-3.67 (m, 4H), 3.58 (s, br., 4H). 3.51 (s, 3H), 3.35 (t, J=5.9 Hz, 2H).
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[NH2:37][C@@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1>COCCOC.CCOC(C)=O>[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:37][C@@H:38]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39]3)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: N[C@H]1CCc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(Cl)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N[C@H]3CCc4ccccc43)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
To a mixture of [1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl](chloro)[(2,3-η)-(1Z)-1-phenylprop-1-ene-2,3-diyl]palladium(2+) (7.8 mg, 0.000012 mol) and potassium tert-butoxide (73.7 mg, 0.000656 mol) under an atmosphere of argon was added 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-2-chloropyridine (281.8 mg, 0.0005968 mol) in 1 ml DME. The solution was stirred for 5 mins, then (S)-(+)-1-aminoindane (0.10 mL, 0.000776 mol) in 1.0 ml DME was added dropwise over 15 min. The solution was stirred overnight, then dissolved in 50 mL EtOAc, washed with water, and concentrated. The residue was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.3219 g, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15](=[O:24])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15](=[O:24])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]1)=[O:5]
Reactant: COC1CCNCC1
Reactant: COc1cccc2c(=O)[nH]nc(Cc3ccc(F)c(C(=O)O)c3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)[nH]nc(Cc3ccc(F)c(C(=O)N4CCC(OC)CC4)c3)c12
Yield: 54 %

Procedure:
2-fluoro-5-((8-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (125) and 4-methoxypiperidine were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.163 mL, 0.91 mmol) and then HBTU (347 mg, 0.91 mmol). The solvent was removed and the residue was dissolved in acetonitrile. A white solid precipitated, which was filtered and dried to afford the desired material as a white crystalline solid (140 mg, 54.0% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.49-1.60 (1H, m), 1.62-1.83 (2H, m), 1.86-1.96 (1H, m), 3.07-3.19 (1H, m), 3.32-3.36 (3H, m), 3.41-3.62 (3H, m), 3.78-3.82 (3H, m), 3.94-4.04 (1H, m), 4.36-4.46 (2H, m), 6.93-7.00 (1H, m), 7.10-7.30 (3H, m), 7.64-7.72 (1H, m), 8.00-8.12 (1H, m), 9.98-10.07 (1H, m); m/z (ES+) (M+H)+=426.4; HPLC RT=1.71 min.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[C:13]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N+:3]([O-:5])=[O:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1[N+](=O)[O-])c1ccccc1
Reaction time: 0.17 h

Procedure:
1.58 g of sodium hydride (60% content) was suspended in 19.80 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 19.83 g of a tetrahydrofuran solution containing 2.50 g of 2-nitroaniline was dropwise added over 1 hour, stirred for 10 minutes, allowed to stand at room temperature and stirred for 30 minutes. To the obtained mixture, 2.77 g of benzoyl chloride was added dropwise over 0.5 hr at room temperature and stirred for 2 hours. The reaction mixture was added to water and separated. The separated organic layer was washed with sodium hydroxide solution and saline to obtain an organic layer, which was analyzed by high performance liquid chromatography to find the yield of the desired product was 82%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:35]1[C:44]2[C:39](=[CH:40][C:41]([O:47][CH3:48])=[C:42]([O:45][CH3:46])[CH:43]=2)[N:38]=[CH:37][N:36]=1>C1COCC1>[CH3:46][O:45][C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][C:41]=1[O:47][CH3:48])[N:38]=[CH:37][N:36]=[C:35]2[O:27][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:24])([F:25])[F:26])[CH:13]=2)=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C(Nc1ccc(F)c(O)c1)Nc1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)ccc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
After a mixture of 1-(4-fluoro-3-hydroxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (0.22 g, 0.58 mmol) and Cs2CO3 (0.325 g, 1 mmol) in THF (10 mL) was stirred at room temperature for 1 hour, to it was added 4-chloro-6,7-dimethoxyquinazoline (0.13 g, 0.58 mmol). It was stirred at 40° C. for 14 hours. The mixture was quenched by water and extracted with DCM. Extracts were dried over MgSO4 and concentrated. It was purified on a silica gel column using a mixture of EtOAc-hexane as eluent to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (0.064 g, 19% yield). 1H NMR (300 MHz, DMSO-d6) 3.99 (s, 3H), 4.00 (s, 3H), 6.87 (s, 1H), 7.24 (m, 1H), 7.36 (t, 1H), 7.42 (s, 1H), 7.59 (m, 6H), 7.67 (dd, 1H), 8.56 (s, 1H), 8.83 (s, 1H), 9.32 (s, 1H); LC-MS (ESI) m/z 569 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[NH2:16])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[C:17](O)(=O)C.C(N)=N>COCCO>[NH:16]1[C:15]2[CH:14]=[CH:13][C:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])=[CH:5][C:4]=2[N:3]=[CH:17]1
Reactant: Nc1ccc(CCOCCO)cc1N
Reactant: CC(=O)O
Agent: Cl
Agent: N=CN
Solvent: COCCO
Product: OCCOCCc1ccc2[nH]cnc2c1
Yield: 56.6 %

Procedure:
In 10 mL of ethylene glycol monomethyl ether is dissolved 1.2 g of 2-[(3,4-diaminophenethyl)oxy]-1-ethanol dihydrochloride, to which is added 0.93 g of formamidine acetate. The mixture is heated under reflux for 30 minutes. Then, the solvent is distilled off under reduced pressure, water and methylene chloride are added to the residue, pH is adjusted to 9 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The aqueous layer is salted out and extracted with methylene chloride. The organic layers are collected, washed with saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1) to obtain 0.52 g of 2-[2-(1H-benzo[d]imidazol-5-yl)ethoxy]-1-ethanol as an oily product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][C:8]3[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:3]1.[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][CH:2]2[CH2:5][N:4]([C:6]3[S:7][C:8]4[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][C:9]=4[N:10]=3)[CH2:3]2)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(N3CC(N)C3)sc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cccc2nc(N3CC(NC(=O)c4nc(Cl)c(CC)[nH]4)C3)sc12
Yield: 85.4 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-(3-aminoazetidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (224b) (273 mg, 0.98 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (166 mg, 0.95 mmol), WSC hydrochloride (547 mg, 2.85 mmol), 1-hydroxybenzotriazole (128 mg, 0.95 mmol) and N-methylmorpholine (0.21 mL, 1.90 mmol), to obtain 352 mg of the title compound as a pale yellow solid (85%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: C[C@H]1CCCCN1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.84 mmol) in DMSO (2 mL) was added (S)-2-methylpiperidine (166 mg, 1.7 mmol) and DIEA (217 mg, 1.7 mmol). The resulting solution was stirred at 70° C. for 3 h and then quenched by water (10 mL), the solids were collected by filtration to afford (S)-methyl 3-(2-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (200 mg, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1I)[CH3:2].[CH3:14][C:15]([CH3:26])=[CH:16]B1OC(C)(C)C(C)(C)O1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH:14]=[C:15]([CH3:26])[CH3:16])[CH3:2]
Reactant: CCOC(=O)c1cccc(C)c1I
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(C)c1C=C(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A suspension of the 2-iodo-3-methylbenzoic acid ethyl ester (289) (2.9 g-0.01 mol) and 2-methyl-1-propenylboronic acid pinacol ester (3.64 g-0.02 mol-2 eq) in dry DMF (50 mL) and saturated NaHCO3 (10 mL) is degassed for 10 minutes and then treated with tetrakis(triphenylphosphine)palladium(0) (400 mg). The mixture is stirred at 110° C. overnight. The reaction is cooled and the DMF removed in vacuo and the residue diluted with water (120 mL). The aqueous is filtered through hyflo and extracted with EtOAc (3×75 mL). The organic extracts are washed with water (2×50 mL) and brine (2×50 mL), and dried over MgSO4. The organic extracts are concentrated in vacuo and purified by flash chromatography (400 g silica gel, 5% EtOAc in heptane) to give the product as pale yellow oil (1.85 g, 85%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[SH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH3:22][C:16]([S:13][C:9]1[N:10]=[N:11][S:12][C:8]=1[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Sc1nnsc1Cc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Sc1nnsc1Cc1ccccc1

Procedure:
A solution of 1.99 g of 5-(phenylmethyl)-1,2,3-thiadiazole-4-thiol, sodium salt in 30 ml of ethanol was stirred overnight with 1.96 g of ethyl 2-bromoisobutyrate and then concentrated in vacuo. The residue was taken up in ether, filtered, and evaporated in vacuo. The oily residue was purified as described in Example 50, giving a yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 1.22 (t, 3H); 1.67 (s, 2 CH3 's); 4.12 (q, 2H); 4.31 (s, CH2); 7.30 (6s, SH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].Cl>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][O:10][CH:18]2[C:17]2[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: OCCc1ccc(Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(C2OCCc3ccc(Br)cc32)cc1

Procedure:
20.1 g (100 mM) of 2-(4-bromophenyl)-ethanol and 15.1 g (100 mM) of 4-nitrobenzaldehyde were dissolved in 300 ml of anhydrous benzene, then 13.6 g (100 mM) of anhydrous zinc chloride were added and dry hydrochloric acid gas was led into the stirred mixture for 4 hours. Then the process described under Examples 1-7, Step a) was applied. The crude product was recrystallized from ethyl acetate.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].N[CH2:15][CH2:16][OH:17].N>O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C.C(O)CCC>[CH2:1]([C:12]1[O:17][CH2:16][CH2:15][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: N
Agent: [Cd+2]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCCC1=NCCO1
Temperature: 125 °C
Yield: 88 %

Procedure:
The reaction was carried out under nitrogen atmosphere in a three neck flask equipped with a magnetic stirring bar, reflux condenser, addition funnel and thermometer. 50 ml of 1-butanol and 667 mg (2.5 mmoles) of cadmium acetate dihydrate was introduced and the catalyst was dissolved by slight warming. 18.13 g (100 mmoles) of undecyl cyanide was added and the solution was heated to 125° C. 7.33 g (120 mmoles) of 2-aminoethanol was then added dropwise controlling the evolution of ammonia. At the end of the reaction (ca. 48 hrs.) the solvent was removed under vacuo. The residue was treated with 100 ml of petroleum ether and filtered after keeping for several hours. The filtrate was washed with water, dried over anhydrous magnesium sulfate, concentrated and the residue was distilled 114° C./0.5mm to give 19.83 g (88%) of 2-undecyl-2oxazoline.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[F-:23].[Cs+].CS(C)=O>CCOC(C)=O>[F:23][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[N:3]=1
Reactant: [F-]
Reactant: CC(C)Oc1ccc(-c2cc(-n3cccn3)cc(Cl)n2)cc1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2cc(-n3cccn3)cc(F)n2)cc1
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a 2 dram vial equipped with a stir bar and charged with 2-chloro-6-(4-isopropoxyphenyl)-4-(1H-pyrazol-1-yl)pyridine (41 mg, 0.13 mmol) was added CsF (199 mg, 1.31 mmol), then DMSO (0.7 mL). The vial was placed in a 140° C. heating block with vigorous stirring for 18 hours. The reaction mixture was transfered to a separatory funnel and was diluted with EtOAc (50 mL). The organic solution was washed twice with brine:water (25 mL:25 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford 2-fluoro-6-(4-isopropoxyphenyl)-4-(1H-pyrazol-1-yl)pyridine as a yellow solid (25 mg, 63%). 1H-NMR (500 MHz, CDCl3) δ 8.07 (dd, J=2.6, 0.4 Hz, 1H), 8.03-7.99 (m, 2H), 7.95 (t, J=1.4 Hz, 1H), 7.81 (d, J=1.4 Hz, 1H), 7.09 (t, J=1.6 Hz, 1H), 7.01-6.97 (m, 2H), 6.57 (dd, J=2.7, 1.7 Hz, 1H), 4.65 (spt, J=6.1 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H); MS: MS m/z 298.2 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][C:14]1[N:18]=[CH:17][NH:16][N:15]=1.[OH-].[K+].Cl>CS(C)=O.O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH:17]=[N:18][C:14]([CH3:13])=[N:15]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1nc[nH]n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Reaction time: 0.75 h
Yield: 6.3 %

Procedure:
A solution of 2-chloro-5-nitroanisole (1.0 g, 5.2 mmol), 3-methyl-1H-1,2,4-triazole (1.74 g, 20.9 mmol) and potassium hydroxide (0.44 g, 7.8 mmol) in dimethyl sulfoxide (5 ML) was heated to 80° C. under an atmosphere of nitrogen for two days. Water and 1M aqueous hydrogen chloride solution was added and the reaction was stirred for 45 minutes. The precipitate was filtered off, washed with water, dissolved in dichloromethane. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound as a yellow solid (77 mg, 6%). MS ISP (m/e): 235.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.88 (s, 1H), 8.10 (d, 1H), 7.96-8.02 (m, 2H), 4.10 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:36]1[N:41]=[C:40]([NH2:42])[C:39]([N+:43]([O-:45])=[O:44])=[CH:38][CH:37]=1>C(#N)C>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:7]1[C:8]([CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:9][CH:10]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:36]2[N:41]=[C:40]([NH2:42])[C:39]([N+:43]([O-:45])=[O:44])=[CH:38][CH:37]=2)[CH:6]=1
Reactant: NCCNc1ccc(CN2CCOCC2)c(-c2ccc(Cl)cc2Cl)c1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2ccc(CN3CCOCC3)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
The amine hydrochloride salt 10 (35 mg) in acetonitrile (2 ml) is treated with N,N-diisopropylethylamine (54 eq) and 6-chloro-3-nitro-2-pyridylamine 11 (1.2 eq) and stirred at 90° C. for 2 h. The mixture is concentrated under reduced pressure and dried under vacuum. The crude product is purified by chromatography starting with 3% MeOH in methylene chloride and finishing with, 5% MeOH in methylene chloride to provide 12 as yellow solid (50–70%). The material is acidified with 2 equivalents of HCl and lyophilized to a dry powder.
Reaction SMILES: C[C:2](C)([C:6]([O-:8])=O)[C:3]([O-:5])=O.[CH3:10][O:11][C:12]([NH2:14])=[NH:13].Cl.C[O-].[Na+]>>[CH3:10][O:11][C:12]1[N:14]=[C:3]([OH:5])[CH:2]=[C:6]([OH:8])[N:13]=1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: COC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1nc(O)cc(O)n1

Procedure:
Under a nitrogen atmosphere 3.10 mL (27.0 mmol) dimethylmalonate, 3.00 g (27.1 mmol) o-methylisourea hydrochloride and 15.0 mL (80.8 mmol) sodium methoxide solution (30%) were refluxed for 1.25 h with stirring. The reaction mixture was cooled. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:5][C:4]2[C:13]([CH2:21][CH2:22][CH3:23])=[C:14]3[C:19](=[CH:20][C:3]1=2)[CH2:18][CH2:17][CH2:16][CH2:15]3.[N+:24]([O-])([OH:26])=[O:25].O>S(=O)(=O)(O)O>[N+:24]([C:20]1[C:3]2[C:2](=[O:1])[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:5][C:4]=2[C:13]([CH2:21][CH2:22][CH3:23])=[C:14]2[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]2)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: CCCc1c2c(cc3c(=O)cc(C(=O)OCC)oc13)CCCC2
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1c2c(c([N+](=O)[O-])c3c(=O)cc(C(=O)OCC)oc13)CCCC2
Temperature: 25 °C
Yield: 79 %

Procedure:
Ethyl 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (9.4 g) was dissolved in concentrated sulphuric acid (100 ml) and cooled to room temperature, and fuming nitric acid (3 ml) was added dropwise, with stirring. The resulting mixture was stirred for a further 3 hours and then poured into water (2 l). The resulting yellow semi-solid was extracted into ether. The organic layer was washed with water, dried (sodium sulphate) and evaporated to give a yellow solid of moderately pure ethyl 6,7,8,9-tetrahydro-5-nitro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (3.5 g; 79%). An analytically pure sample (5 g) was obtained on recrystallisation from cyclohexane, mp 140°-2°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][N:6]=1)=[O:4].S(Cl)([Cl:16])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([Cl:16])=[O:13])=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)Cl)cn1
Temperature: 70 °C

Procedure:
14.5 g (80 mmol) of 2-methoxycarbonylpyridine-5-carboxylic acid are treated with 6.48 ml of thionyl chloride and 2 ml of anhydrous N,N-dimethylformamide in 200 ml of anhydrous toluene. The mixture is heated at 70° C. for 3 h with stirring. It is then concentrated in vacuo and the residue is dissolved in 150 ml of tetrahydrofuran.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[C:25]([N:29]=[C:30]=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:30]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Brc1cnc2ccc(NC[C@@H]3CCCN3)nn12
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of (S)-3-bromo-N-(pyrrolidin-2-ylmethyl)imidazo[1,2-b]pyridazin-6-amine (400 mg, 1.2 mmol) and triethylamine (0.5 mL, 3.5 mmol) in DCM (10 mL) was added t-butyl isocyanate (0.2 mL, 1.75 mmol) dropwise. After stirring at it for 2 h, the reaction mixture was concentrated and purified by ISCO column chromatography (10% MeOH/DCM) to give (S)-2-(((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)-N-(tert-butyl)pyrrolidine-1-carboxamide (360 mg, 76% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.58 (d, J=9.60 Hz, 1H), 7.42 (s, 1H), 6.72 (d, J=9.85 Hz, 1H), 5.07 (s, 1H), 4.26 (dd, J=6.57, 1.77 Hz, 1H), 3.35-3.48 (m, 4H), 2.09-2.20 (m, 1H), 1.90-2.05 (m, 3H), 1.26 (s, 9H); LRMS (ESI) m/e 395.2 [(M+H)+, calcd for C16H24BrN6O 396.3].