Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:11]3[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=3)[C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)N3CCOCC3)c12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c(Oc3ccc(F)cc3)ncc(C(=O)N3CCOCC3)c12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (1-chloro-5-methylisoquinolin-4-yl)(morpholino)methanone Intermediate-11a (1 equiv) in dry DMF (5 mL) was added, 4-fluorophenol (1.1 equiv), CuI (1.1 equiv) and K2CO3 (2 equiv) in a sealed tube. The reaction mixture was degassed for 20 min and then stirred at 150° C. for 2 h. It was allowed to reach RT and then diluted with EtOAc. The slurry was filtered through celite, and then washed with EtOAc. The solvent was then removed, and the residue was purified by column chromatography (15% EtOAc:Hexane) to afford the title compound; 1H NMR (400 MHz, CDCl3) δ 2.61 (s, 3H), 3.23-4.13 (m, 8H), 7.15-7.20 (m, 4H), 7.55-7.61 (m, 2H), 7.82 (s, 1H), 8.39-8.41 (m, 1H); MS m/z 367 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:19](O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[C:13]1([CH2:12][CH2:11][CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:19]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:26])[N:3]=[CH:4]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccnc1
Reactant: NC(=O)c1c(N)ncn1CCCc1ccccc1
Product: NC(=O)c1c(NC(=O)c2cccnc2)ncn1CCCc1ccccc1

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.00 g (8.19 mmol) of 4-amino-1-(3-phenylpropyl)-5-imidazolecarboxamide prepared in the same manner as in Example 114 and nicotinic acid instead of 3-pyridylacetic acid hydrochloride to obtain crude 1-(3-phenylpropyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:43][Mg]Br.C(OCC)(=O)C>O1CCCC1>[O:42]=[C:17]1[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=[CH:26][CH:27]=[C:19]2[N:18]1[C@H:28]1[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](=[O:37])[CH3:43])[CH2:30][CH2:29]1
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (1.3 g) in tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 1.3 mL) at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.12 g, 94%).
Reaction SMILES: [Br:1][C:2]1[C:12]([OH:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][CH2:25][CH2:26]Cl.[I-].[K+]>CN(C)C=O>[Br:1][C:2]1[C:12]([O:13][CH2:26][CH2:25][O:24][CH3:23])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COCCCl
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(OCCOC)c1Br
Temperature: 70 °C
Yield: 93.5 %

Procedure:
Using a procedure similar to that of Example 2, 0.2 moles of ethyl 2-bromo-3-hydroxy-4-nitrobenzoate and an excess of potassium carbonate (0.35 moles) and 2-chloroethyl methyl ether (0.35 moles) along with a catalytic amount of potassium iodide (7.2 g, 0.045 m) were combined with 350 ml of dimethylformamide. After heating at 70° C. for 4 hours, normal workup gave 0.187 moles of ethyl 2-bromo-3-(2-methoxyethoxy)-4-nitrobenzoate as a viscous oil. This ester can be readily hydrolyzed to its acid using the procedure of Example 8.
Reaction SMILES: ClC1C=C2C(C)(C)/C(=C\C=C(/C3C=CC=C(CCCCC(O[N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=O)C=3)\C=C\C3C(C)(C)C4C5C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=5C=CC=4[N+]=3CCCCS([O-])(=O)=O)/N=C2N(CCCCS([O-])(=O)=O)C=1.[Na+:77].[Na+].[Na+].[C:80]([CH2:83][CH2:84][C:85]1[CH:86]=[C:87](/[C:91](=[CH:125]\[CH:126]=[C:127]2/[C:128]([CH3:146])([CH3:145])[C:129]3[C:130](=[N:144]/2)[N:131]([CH2:136][CH2:137][CH2:138][CH2:139][S:140]([O-:143])(=[O:142])=[O:141])[CH:132]=[C:133]([Cl:135])[CH:134]=3)/[CH:92]=[CH:93]/[C:94]2[C:102]([CH3:104])([CH3:103])[C:101]3[C:100]4[CH:105]=[C:106]([S:113]([O-:116])(=[O:115])=[O:114])[CH:107]=[C:108]([S:109]([O-:112])(=[O:111])=[O:110])[C:99]=4[CH:98]=[CH:97][C:96]=3[N+:95]=2[CH2:117][CH2:118][CH2:119][CH2:120][S:121]([O-:124])(=[O:123])=[O:122])[CH:88]=[CH:89][CH:90]=1)([OH:82])=[O:81].[Na+].[Na+].[Na+]>>[Cl:135][C:133]1[CH:134]=[C:129]2[C:128]([CH3:146])([CH3:145])/[C:127](=[CH:126]\[CH:125]=[C:91](/[C:87]3[CH:88]=[CH:89][CH:90]=[C:85]([CH2:84][CH2:83][C:80]([O:82][N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=[O:81])[CH:86]=3)\[CH:92]=[CH:93]\[C:94]3[C:102]([CH3:103])([CH3:104])[C:101]4[C:100]5[CH:105]=[C:106]([S:113]([O-:116])(=[O:114])=[O:115])[CH:107]=[C:108]([S:109]([O-:112])(=[O:110])=[O:111])[C:99]=5[CH:98]=[CH:97][C:96]=4[N+:95]=3[CH2:117][CH2:118][CH2:119][CH2:120][S:121]([O-:124])(=[O:123])=[O:122])/[N:144]=[C:130]2[N:131]([CH2:136][CH2:137][CH2:138][CH2:139][S:140]([O-:143])(=[O:142])=[O:141])[CH:132]=1.[Na+:77].[Na+:77].[Na+:77]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCC(=O)O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCC(=O)ON2C(=O)CCC2=O)c1

Procedure:
Compound 31 is prepared analogously to compound 29 (Example 38), except that compound 30 is used as a starting material.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18].CC[OH:24]>O.C(OC)(C)(C)C.[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])=[O:24]
Reactant: C[Si](C)(C)CNC(=O)c1ccc(C(Br)Br)c(C(F)(F)F)c1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: COC(C)(C)C
Product: C[Si](C)(C)CNC(=O)c1ccc(C=O)c(C(F)(F)F)c1
Yield: 100 %

Procedure:
4-(dibromomethyl)-3-(trifluoromethyl)-N-[(trimethylsilyl)methyl]benzamide (22.0 g, 49.1 mmol) and AgNO3 (16.7 g, 98.3 mmol) in EtOH and H2O were refluxed for 2 hours, then diluted with t-BuOMe and washed with brine. Dried over MgSO4 and evaporation yielded the product (15.0 g, 100%).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1([C:24]([OH:28])([C:26]#[CH:27])[CH3:25])[CH2:23][CH2:22]1>>[F:19][C:3]1[C:2]([C:27]#[C:26][C:24]([OH:28])([C:21]2([CH3:20])[CH2:23][CH2:22]2)[CH3:25])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)C1(C)CC1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C1(C)CC1
Yield: 8 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1-methylcyclopropyl)but-3-yn-2-ol to give the titled compound as a light brown solid (7.8 mg, 8%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1I)[CH3:2].[CH3:14][N:15]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:34]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:34])[N:15]([CH3:14])[CH:24]=1)[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CCc1ccc(S(C)(=O)=O)cc1I
Product: CCc1ccc(S(C)(=O)=O)cc1-c1cn(C)c(=O)c2ccccc12

Procedure:
The the title compound of Example 312, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 312, step 4 to give the title compound. 1H NMR (400 MHz, CDCl3): δ 1.10 (3H, t, J=8.0 Hz), 2.51-2.56 (2H, m), 3.10 (3H, s), 3.67 (3H, s), 6.97-7.02 (2H, m), 7.52-7.59 (3H, m), 7.80 (1H, s), 7.97 (1H, d, J=8.0 Hz), 8.54 (1H, d, J=8.0 Hz). LCMS: 342 (M+1)+
Reaction SMILES: Cl.[N:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([OH:11])=[CH:8][CH:7]=[N:6]2.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][C:9]2[C:10]3[N:5]([CH:4]=[CH:3][N:2]=3)[N:6]=[CH:7][CH:8]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccnn2ccnc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccnn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of imidazo[1,2-b]pyridazin-8-ol hydrochloride (D-5) (4 g, 23.3 mmol, 1.0 eq) and triethylamine (7.1 g, 70.0 mmol, 3.0 eq) in DCM (50 mL), 4-toluenesulfonyl chloride (5.3 g, 28.0 mmol, 1.2 eq) is added in portions and the resulting mixture is stirred at RT for 1 h. The mixture is washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (10-50% ethyl acetate-petro ether) to afford the product, imidazo[1,2-b]pyridazin-8-yl 4-methylbenzenesulfonate (D-6).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[CH:3]=[C:4]([OH:9])[CH:5]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(O)cc(Br)c1
Product: COc1ccc(S(=O)(=O)Nc2cc(O)cc(Br)c2)cc1
Yield: 86.8 %

Procedure:
3-Amino-5-bromophenol (0.75 g, 3.99 mmol, prepared according to WO 2011119704 A1 20110929) was treated with 4-methoxybenzene-1-sulfonyl chloride (1.61 g, 7.79 mmol) according to the method described In Preparation 15b to give 1.24 g (77% yield) of the title compound as an oil. Purity 89%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])#[N:11].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:20].Cl>O1CCCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([CH2:18][CH:12]([C:10]#[N:11])[C:13]([O:15][CH3:16])=[O:14])=[O:20])=[CH:22][CH:23]=1
Reactant: COC(=O)CC#N
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C#N)CC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
Diisopropylethyl amine (15.5 g, 0.12 mol) is added to dry tetrahydrofuran (60 mL) followed by a solution of methyl cyanoacetate (5.4 g, 0.055 mol) in tetrahydrofuran (10 mL). Finally, a solution of α-bromo-p-chloroacetophenone (11.0 g, 0.05 mol) in tetrahydrofuran (50 mL) is added. After three hours at room temperature, TLC (75/25 hexanes/ethyl acetate) indicates very little starting material. The reaction mixture is then heated at 50° C. for fifteen minutes, cooled and filtered. The filtrate is concentrated in vacuo to obtain an oil which solidifies when treated with dilute hydrochloric acid. The supernatant is decanted and the residue is taken up in ethyl acetate and dried. Work-up leaves a brown waxy solid (8.0 g, 64% crude yield) which on recrystallization from methanol gives the title compound as a white solid (4.3 g, mp 75°-79° C.).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([C:16]([O:18]CC)=[O:17])[CH:7]=1)(=[O:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[N:9]=[C:8]([C:16]([OH:18])=[O:17])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(COC(C)=O)nc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCc1cc(C(=O)O)nc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 6-[(acetyloxy)methyl]-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.95 g, 3.2 mmol, from Step B) in tetrahydrofuran (8.7 mL) at 0° C. was treated with Lithium hydroxide, monohydrate (140 mg, 3.2 mmol) in water (1.3 mL). The reaction was stirred for 15 minutes, then was treated with 1N HCl to pH˜4 while still in the ice bath. THF was removed from the mixture in vacuo. The product was extracted first with ethyl acetate, then with several portions of 10% isopropanol in CHCl3, including periodic adjustment of pH as necessary. The extracts were combined and dried over sodium sulfate, filtered and concentrated to afford a yellow oil, which was used without further purification.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[O:20])[CH:16]=[N:17][CH:18]=1.O>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=2)[OH:20])[CH:16]=[N:17][CH:18]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: Cn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccnc1C(O)c1cncc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
At −78° C., under N2 protection, n-BuLi (0.16 mL, 1.6 M, 1.0 mmol) was added to a solution of 1-methyl-1H-imidazole (82 mg, 1.0 mmol) in THF (10 mL) and the reaction mixture was stirred at −78° C. for 0.5 hour; then, 5-bromo-pyridine-3-carbaldehyde (186 mg, 1.0 mmol) was added to the above solution and stirring continued at −78° C. for additional 2 hours. The reaction mixture was poured into water (5.0 mL) and extracted with EtOAc (2×50 mL). The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (210 mg, 78.4%) as white solid. MS: 268.1 & 270.1 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]([O:37][CH3:38])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([O:37][CH3:38])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1cc(O)ccc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1OC
Yield: 59.1 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (330 mg) in acetonitrile (8.0 mL) were added ethyl 3-(5-hydroxy-2-methoxyphenyl)propanoate (216 mg) and cesium carbonate (647 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (290 mg) as a white solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12].[F-].[K+]>CN(C=O)C>[CH3:9][C:10]([CH3:15])([CH2:14][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]([OH:13])=[O:12]
Reactant: CC(C)(CBr)C(=O)O
Reactant: Sc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CSc1ccccc1)C(=O)O
Temperature: 120 °C

Procedure:
To a solution of thiophenol (5 g, 45 mmol) in DMF (100 mL) is added 3-bromo-2,2-dimethyl-propionic acid (CAS#2843-17-6, 3.98 g, 22 mmol), and potassium fluoride (1.56 g, 27 mmol). The reaction is heated at 120° C. overnight. The reaction is then cooled to room temperature and poured into ice water. A white precipitate is filtered and washed with ice water. The solid is then dissolved in 1M aqueous NaOH and is washed with dichloromethane. The aqueous solution is acidified with 1M HCl and the resulting precipitate is collected to provide 2,2-dimethyl-3-phenylsulfanyl-propionic acid; 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (s, 6 H), 2.72 (br. s., 1 H), 3.19 (s, 2 H), 7.09-7.21 (m, 1 H), 7.21-7.32 (m, 2 H), 7.40 (d, J=7.8 Hz, 2 H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)(=O)=O)=CC=1.[Cl:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[NH:25][N:24]=[N:23]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[Cl:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[N:25]([CH2:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[N:24]=[N:23]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Reactant: O=c1[nH]nnn1CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(CCCl)nnn1CCc1cccs1
Temperature: 70 °C
Yield: 46.5 %

Procedure:
A mixture of 19.6 parts of [2-(2-thienyl)ethyl] 4-methylbenzenesulfonate, 10 parts of 1-(2-chloroethyl)-1,4-dihydro-5H-tetrazol-5-one, 10 parts of sodium carbonate and 90 parts of N,N-dimethylformamide is stirred and heated overnight at 70° C. The reaction mixture is cooled, 100 parts of water are added and the product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and petroleumether (70:30 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 15 parts (46.5%) of 1-(2-chloroethyl)-1,4-dihydro-4-[2-(2-thienyl)ethyl]-5H-tetrazol-5-one as a residue.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2].[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[OH:40].C([O-])([O-])=O.[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:40][C:34]2[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=2[Cl:32])=[CH:7][C:6]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2]
Reactant: CCOC(=O)CN(Cc1cc(OC)ccc1OC)Cc1cc(Br)ccc1C(=O)OCC
Reactant: Oc1ccc(F)cc1Cl
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CN(Cc1cc(OC)ccc1OC)Cc1cc(Oc2ccc(F)cc2Cl)ccc1C(=O)OCC
Temperature: 130 °C
Yield: 53.2 %

Procedure:
To a mixture of 4-bromo-2-{[(2,5-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-benzoic acid ethyl ester (3.44 g, 6.96 mmol) and 2-chloro-4-fluorophenol (2.04 g, 13.9 mmol) in NMP (6.8 mL) was added Cs2CO3 (4.53 g, 13.9 mmol). The resultant mixture was degassed and re-filled with N2 gas prior to the addition of 2,2,6,6-tetramethyl-heptane-3,5-dione (128 mg, 0.70 mmol) and Cu(I)Cl (344 mg, 3.48 mmol). It was de-gassed and filled with N2 gas again. The resultant mixture was heated in a 130° C. oil bath for 24 h. Reaction mixture was filteredthrough a pad of celite and washed with EtOAc until no UV active spot was detected from the filtrate. Filtrate was washed with 1 N HCl (100 mL and 50 mL), water and brine. It was dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with CH2Cl2, to provide the title compound 2.07 g (3.70 mmol) in 44% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 7.80 (d, J=8.4 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.20 (m, 1H), 7.03 (m, 3H), 6.73 (dd, J=8.4, 2.6 Hz, 1H), 6.38 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 4.18 (s, 2H), 4.11 (q, J=7.0 Hz, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.70 (s, 2H), 3.28 (s, 2H), 1.4-1.2 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13].FC1C=CC=C(F)C=1N.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:12]([NH2:13])=[N:32][N:31]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1c(F)cccc1F
Agent: Nc1c(F)cccc1F
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1c(F)cccc1F
Yield: 37 %

Procedure:
This compound was prepared using 103 mg (0.5 mmol) of 2-[(2,6-difluorophenyl)-hydrazono]malononitrile, which was derived from 2,6-difluoroaniline (108 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 44 mg (37%) of the title compound as an orange solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 44 g (0.2 mol) 4-iodophenol, 34 g (0.2 mol) 1-(2-chloro-ethyl)-pyrrolidine-hydrochloride, 110.56 g (0.8 mol) K2CO3 and 800 mL DMF is stirred for 48 h at RT. The reaction mixture is filtered and the filtrate is evaporated down. The residue is taken up in water and extracted with EtOAc. The organic phase is extracted with saturated NaCl solution and dried over Na2SO4. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 85:15:1.5).