Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:3].[Cl:22][CH2:23][CH2:24][CH2:25][OH:26]>C(#N)C>[Cl-:22].[OH:26][CH2:25][CH2:24][CH2:23][N+:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OCCCCl
Reactant: CCCCCCCCCCCCCCCCCCN(C)C
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCO
Product: [Cl-]
Yield: 77.7 %

Procedure:
Employing the procedure of EXAMPLE II, 31.3 g of N,N-dimethyloctadecylamine was reacted with 9.0 g of 3-chloropropanol in 100 ml of acetonitrile to provide a crude product which was recrystallized from acetone to give 29.0 g (70%) of white solids. Proton NMR confirmed the desired structure.
Reaction SMILES: [Br:1]Br.[CH:3]1([C:6]2[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[N:10]=2)[CH2:5][CH2:4]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:8]1[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]([CH:3]2[CH2:4][CH2:5]2)=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncn2)nc1C1CC1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(-c2ccncn2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Bromine was added to a cooled solution of 4-(2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidine (1.36 g, 4.30 mmol) in DCM at 0° C. followed by saturated aqueous Na2CO3 solution (16 mL, 4.30 mmol). The reaction mixture was stirred for 3 hours at room temperature. After the reaction was judged complete by LCMS analysis, the reaction mixture was allowed to stand and partition. The resulting layers were separated and the aqueous layer was extracted with EtOAc (2×). The combine organic layers were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was by flash chromatography using an EtOAc-hexanes gradient (20-80%) to give 4-(5-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidine (1.07 g, 2.71 mmol, 63%) as a yellow oil: LCMS(m/z): 395.0 (MH+), tR=1.09 minutes; 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H) 0.80-1.50 (m, 4H) 2.06-2.25 (m, 1H) 3.49-3.65 (m, 2H) 6.05 (s, 2H) 7.95-8.07 (m, 1H) 8.82-8.94 (m, 1H) 9.27-9.34 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:14]([O:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:8][CH2:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Cn1ccnc1[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cn1ccnc1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of trans-4-(1-Methyl-1H-imidazol-2-yl)cyclohexanol (0.106 g, 0.588 mmol), tert-Butyldimethylsilyl chloride (0.177 g, 1.18 mmol), 4-Dimethylaminopyridine (10 mg, 0.1 mmol), 1H-Imidazole (120 mg, 1.76 mmol) and DCM (3.0 mL, 47 mmol) was stirred at ambient temperature for 1.5 h. The reaction mixture was diluted with DCM to ≈60 mL, washed with sat. NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel [Isco Combiflash, 2.5 g loading column/12 g column, eluting with DCM→4.9% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo overnight, giving the title compound as yellow oil. 1H NMR (CDCl3, 400 MHz): δ=6.97 (brs, 1H), 6.78 (s, 1H), 3.69 (tt, J=10.6, 4.0 Hz, 1H), 3.61 (s, 3H), 2.60 (tt, J=11.8, 3.2 Hz, 1H), 2.04-1.96 (m, 2H), 1.95-1.87 (m, 2H), 1.87-1.72 (brm, 2H), 1.47-1.36 (m, 2H), 0.89 (s, 9H), 0.07 (s, 6H). MS (ES+): m/z=295.24 (100) [MH+]. HPLC: tR=3.20 min (verypolar—5 min, ZQ3). UV: λmax=216 nm.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22](I)[CH:23]=[CH:24][CH:25]=1>>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:23]=[CH:22][CH:21]=1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: COc1cccc(I)c1
Product: COc1cccc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)c1

Procedure:
Reaction of 1.15 g (5 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol and 1.5 ml (12.5 mmol) of 3-methoxy-iodobenzene as described in Example 4 yielded after isolation by chromatography over 60 g of silica gel with methylene chloride and crystallization from ether/hexane 1.05 g (62.5%) of colorless crystals with m.p. 108°-112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]([CH3:25])[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=2)[N:14]=[C:13]([CH3:24])[N:12]=1.[H][H]>CC(O)=O.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]([CH3:25])[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=2)[N:14]=[C:13]([CH3:24])[N:12]=1
Reactant: [H][H]
Reactant: COc1ccc(N(C)c2nc(C)nc3ccc([N+](=O)[O-])cc23)c(F)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(N(C)c2nc(C)nc3ccc(N)cc23)c(F)c1
Reaction time: 3 h

Procedure:
10% Pd—C (10 mg, 0.0094 mmol) was added to a soln of (2-fluoro-4-methoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine (127 mg, 0.371 mmol) in AcOH (3 mL) and this was reacted under 1 atm of hydrogen. After 3 h, the rxn was filtered through a 0.45 μm filter then concentrated. Satd NaHCO3 (10 mL) was added and the product extracted into CHCl3 (2×2 mL). The soln was dried (MgSO4), filtered through a plug of silica with an EtOAc wash then concd to a yellow crystalline solid (104 mg; 90%). 1H NMR (CDCl3) δ 7.61 (d, J=8.8 Hz, 1H), 7.05-6.99 (m, 2H), 6.73 (dd, J=2.8, 12 Hz, 1H), 6.66 (ddd, J=1.2, 3.2, 8.8 Hz, 1H), 6.18 (d, J=2.4 Hz, 1H), 3.82 (s, 3H), 3.51 (s(br), 2H), 3.50 (s, 3H), 2.69 (s, 3H); LC-MS (ESI+; 313 ([M+H]+)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH3:17][NH:18][CH:19]([CH3:22])[CH2:20][OH:21]>C(#N)C.CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:18]([CH3:17])[CH:19]([CH3:22])[CH2:20][OH:21])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CNC(C)CO
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CO)N(C)c1cc(Cl)nc(Cl)n1
Reaction time: 1 h

Procedure:
To a mixture of 2,4,6-trichloropyrimidine (5.0 g, 27 mmol) and triethylamine (11 mL, 82 mmol) in acetonitrile (20 mL) was slowly added a solution of 2-(methylamino)propan-1-ol (2.9 g, 33 mmol) in N,N-dimethylformamide (DMF) (2 mL) at 0° C. The reaction mixture was stirred at same temperature for 1 h, then filtered through a thin pad of celite and concentrated. Purification via silica gel flash chromatography (petroleum ether/ethyl acetate=4/1˜1/1) afforded the title product as an oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2.[OH-].[Na+].CN([CH:21]=[O:22])C>O>[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:21]=[O:22]
Reactant: Fc1cccc2cc[nH]c12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2c(F)cccc12
Reaction time: 1 h

Procedure:
Phosphoryl chloride (2.0 ml) was added to DMF (3 ml) under nitrogen at 0° and to this mixture was added 7-fluoroindole (2.1 g) in dry DMF (4 ml). The mixture was stirred for 1h, 5N sodium hydroxide solution (50 ml) was added, and stirring was continued at 50° for 1h. The mixture was then diluted with water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (2.07 g), m.p. 203°-205°.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[S:10][C:11]([C:15]2[N:16]=[C:17]([CH2:20][C:21]#[N:22])[S:18][CH:19]=2)=[C:12]([CH3:14])[N:13]=1.[CH:23]1[N:27]=[CH:26][N:25]([C:28](N2C=NC=C2)=[O:29])[CH:24]=1.CN(C=O)C>C(Cl)Cl>[C:21]([CH2:20][C:17]1[S:18][CH:19]=[C:15]([C:11]2[S:10][C:9]([NH:8][C:28]([N:25]3[CH:24]=[CH:23][N:27]=[CH:26]3)=[O:29])=[N:13][C:12]=2[CH3:14])[N:16]=1)#[N:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1-c1csc(CC#N)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(CC#N)n1
Temperature: 45 °C

Procedure:
Triethylamine (0.65 ml; 4.69 mmol; 1.49 eq.) is added to a suspension of (2′-amino-4′-methyl-4,5′-bi-1,3-thiazol-2-yl)acetonitrile (1 000 mg; 3.15 mmol; 1 eq.) and CDI (1 372.3 mg; 8.46 mmol; 2.68 eq.) in dry DCM (65 ml). DMF (4 ml) is added and the mixture is heated at 45° C. for one night. The reaction is cooled down to rt. The resulting precipitate is filtered and washed with Et2O, affording N-[2-(cyanomethyl)-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide, which is used in the next step without further purification (822.8 mg; 79%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=C=O)[CH:4]([CH:19]=[CH:20][C:21]=1O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].CN([C:28]([O:32]N1N=NC2C=CC=CC1=2)=[N+:29]([CH3:31])[CH3:30])C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[O:56]=[C:57]1CNC[CH2:59][NH:58]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:28]([N:29]1[CH2:30][CH2:59][NH:58][C:57](=[O:56])[CH2:31]1)=[O:32])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C1CNCCN1
Reactant: O=C=C1C(Cl)=C(O)C=CC1C(=O)NCc1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CCN1
Temperature: 25 °C

Procedure:
0.182 g (0.50 mmol) of 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-hydroxy-carbonylbenzamide is dissolved in 5 mL of N,N-dimethylformamide and 160.5 mg (0.50 mmol) of TBTU and 85.6 μL (0.50 mmol) of diisopropylethylamine are added successively with stirring at ambient temperature. Then a solution of 50 mg (0.50 mmol) of 2-oxopiperazine in 5 mL of N,N-dimethylformamide is added dropwise and the reaction mixture is stirred for 3 hours at ambient temperature. Then the solvent is eliminated in vacuo and the residue purified by chromatography on silica gel (gradient: dichloromethane/methanol=100:0 □93:7). Yield: 99 mg (44%); C20H17C12N5O3 (446.30); mass spectrum: (M+H)+=446/448/450 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.O[NH:35][C:36](=[NH:48])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>C1COCC1>[NH2:48][C:36](=[N:35][O:17][C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:15][CH:14]=1)=[O:18])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCC(=N)NO
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(N)=NOC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h

Procedure:
At 0° C., to a solution of boc-(4-aminomethyl)-benzoic acid (5.000 g, 19.9 mmol), NMM (2.214 g, 21.89 mmol) in anhydrous THF (50 mL) was added dropwise isobutyl chloroformate (2.853 g, 20.89 mmol). The resulting mixture was stirred for 10 min, then N-hydroxydodecanimidamide (Example 23, step a) (6.398 g, 29.85 mmol) was added at once. After 1 h the ice-water bath was removed and the mixture was stirred for 14 h at rt. An aqueous solution of HCl (1N, 50 mL) was added and the mixture was extracted with AcOEt (3×70 mL). The combined organic layers were washed with water (150 mL), dried over MgSO4 and evaporated to give a white solid (9.2 g). This crude product was purified by flash chromatography over silica gel (c-Hex/AcOEt 4/1) to give the title compound as a white solid (7.91 g, 89%). 1H NMR (CDCl3, 300 MHz) δ 7.80 (d, 2H, J=8.0 Hz), 7.50 (t, 1H, J=5.7 Hz) 7.32 (d, 2H, J=8.0 Hz), 6.42 (br s, 1H), 6.27 (br s, 1H), 4.20 (s, 1H), 4.18 (s, 1H), 1.91-2.15 (m, 2H), 1.08-1.66 (m, 27H), 0.86 (t, 3H, J=6.9 Hz). M+(LC/MS(ESI)): 448.4; M−(LC/MS(ESI)): 446.3. HPLC (Condition A), Rt: 5.74 min (HPLC purity: 96.7%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:11](=[O:13])[N:12]=2)[CH2:4][CH2:3]1.[OH:28][C@@H:29]([CH2:42][NH2:43])[CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1>>[OH:28][C@@H:29]([CH2:42][NH:43][CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:14]=[C:10]3[S:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[N:12][C:11]3=[O:13])=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)[CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(=O)CC4)cc3)S2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(NC[C@H](O)COc5cccc6[nH]c(=O)[nH]c56)CC4)cc3)S2)CC1

Procedure:
The title compound was prepared from 1-{4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 29) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a yellowish solid; mp>150° C. (dec.); 1 H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.85-2.00 (m, 2 H), 2.24 (s, 3 H), 2.40-3.00 (m, 11 H), 3.50-4.10 (m, 7 H), 6.56 (d, J=8.1 Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.84 (dd, J=8.1, 8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.48 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H), 10.3-11.0 (brs, 2 H); MS (ES) m/z: 296.5 ((M+2H)2+, 100%); 592.1 (MH+, 20%); HRMS Calcd. for C30H38N7O4S (MH+): 592.2760. Found: 592.2685.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].Cl.Br[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>C(O)(=O)C>[N:28]1[CH:29]=[CH:30][C:25]([N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)=[CH:26][CH:27]=1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Reactant: Brc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(ccc3c2ccn3-c2ccncc2)n1
Temperature: 110 °C

Procedure:
A solution of 7.97 g. of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 500 ml. of dry dimethylformamide is stirred, under nitrogen, with 4.61 g. ca. 50% sodium hydride-mineral oil dispersion for 1.5 hours. Addition of 8.95 g. of p-bromopyridine hydrochloride is followed by heating of the reaction mixture at 110° C. for 5 hours. Glacial acetic acid (10 ml) is added and the solvent is removed in vacuo. The residue is stirred thoroughly with a mixture of excess aqueous potassium carbonate solution and 100 ml. of 1 N sodium hydroxide solution, collected, washed with water and dried. Three crystallizations from methanol and one from dimethylformamide and drying afford 0.61 g. of the title product, m.p. 328.5°-329.5° C., NMR (dDMSO): δ 7.16 (doublet, J=8 Hz, 5H), 7.22 (doublet, J=3 Hz, 9H), 7.88 (doublet, J=3 Hz, 8H), 7.96 (doublet, J=8 cps, 6H), p.p.m. λmax95%EtOH 255 mμ (22,900) and 297 mμ (22,100).
Reaction SMILES: [Zn:1].BrCCBr.C[Si]([Cl:10])(C)C.[Cl:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl>O1CCCC1>[Cl-:10].[Cl:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][Zn+:1]
Reactant: C[Si](C)(C)Cl
Reactant: [Zn]
Reactant: ClCc1cccc(Cl)c1Cl
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Clc1cccc(C[Zn+])c1Cl
Product: [Cl-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under an argon stream, to a suspension of zinc powder (55.1 g, 843 mmol) in tetrahydrofuran (THF; 56 ml) was added 1,2-dibromoethane (2.9 ml, 33.8 mmol) and the mixture was heated under reflux for 5 min. Then, trimethylsilyl chloride (8.6 ml, 67.5 mmol) was added at 0° C. and the mixture was stirred at 0° C. for 5 min, after which a solution of 2,3-dichlorobenzyl chloride (82.4 g, 421.7 mmol) in THF (330 ml) was added dropwise with ice-cooling. After completion of the dropwise addition, the mixture was warmed to room temperature and stirred for 1 hr to give a solution of 2,3-dichlorobenzylzinc chloride in THF.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])#[N:2].C(C1SC=C(C(N2CC3(CCN(CCC4C=CC(CCOCCC(OC(C)(C)C)=O)=CC=4)CC3)OCC2)=O)N=1)(C)C>>[C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])#[N:2]
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(C#N)c1
Agent: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Product: N#Cc1cccc(CCOCCC(=O)O)c1

Procedure:
Prepared by the method of Example 1, step e using tert-butyl 3-(3-cyanophenethoxy)propanoate [Examples 81-175, step a] (7.0 g) in place of tert-butyl 3-(4-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoate. After concentration in-vacuo, the residue was azeotroped with toluene (×2) to afford the subtitled compound. Yield 2.8 g. m/z 218 (M−H)− (APCI).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([N:17]3[CH:21]=[CH:20][C:19]([CH3:22])=[N:18]3)=[C:12]([C:14]([OH:16])=O)[CH:13]=2)[CH:5]=[N:6][CH:7]=1.[CH3:23][N:24]1[C:33]2[C:28](=[CH:29][C:30]([CH2:34][NH2:35])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1.CCCP(O)(O)=O.CCN(C(C)C)C(C)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([N:17]3[CH:21]=[CH:20][C:19]([CH3:22])=[N:18]3)=[C:12]([C:14]([NH:35][CH2:34][C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[N:24]([CH3:23])[CH2:25][CH2:26][CH2:27]4)=[O:16])[CH:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN1CCCc2cc(CN)ccc21
Reactant: Cc1cncc(-c2cnc(-n3ccc(C)n3)c(C(=O)O)c2)c1
Agent: CCCP(=O)(O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(-c2cnc(-n3ccc(C)n3)c(C(=O)NCc3ccc4c(c3)CCCN4C)c2)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 5′-methyl-6-(3-methyl-1H-pyrazol-1-yl)-3,3′-bipyridine-5-carboxylic acid (5-2, 0.025 g, 0.085 mmol) and 1-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methanamine (0.015 g, 0.085 mmol) in ACN (0.85 mL) was added 1-propylphosphonic acid cyclic anhydride (T3P, 0.15 mL, 0.255 mmol) followed by Hunig's base (0.089 mL, 0.51 mmol) and the system was stirred at 40° C. for 1 h in an oil bath. The reaction mixture was cooled and partitioned between EtOAc and water, washed with saturated sodium bicarbonate and dried over magnesium sulfate. The reaction mixture was filtered, concentrated and purified via normal phase chromatography (0→10% MeOH in EtOAc) to afford the title compound (5-3) as a bone powder. 1H NMR (500 MHz, CDCl3) δ 8.68 (m, 1H), 8.51 (m, 1H), 8.29 (m, 1H), 8.22 (m, 1H), 7.72 (m, 1H), 7.12 (m, 1H), 7.0 (m, 1H), 6.90 (m, 1H), 6.54 (m, 1H), 6.27 (m, 1H), 4.46 (m, 2H), 3.22(m, 2H), 2.88 (s, 3H), 2.74 (m, 2H), 2.44 (s, 3H), 2.28 (s, 3H), 1.97 (m, 2H). HRMS [M+H] C27H28N6O calc'd 453.2391, found 453.2397.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=O)OC(C)(C)C.N1(OC2[N:31]=[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH:43]=[CH:42][CH:41]=[N:40]4)=[C:35]([F:44])[CH:34]=3)[C:29]([C:45]([NH2:47])=[O:46])=[CH:28][N:27]=2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:43]=[CH:42][CH:41]=[N:40]3)=[C:35]([F:44])[CH:34]=2)[C:29]([C:45]([NH2:47])=[O:46])=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1Nc1ccc(-n2cccn2)c(F)c1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-n2cccn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A solution of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.30 M in NMP, 2.00 mL, 0.600 mmol) in NMP (2 mL) was added to 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(3-fluoro-4-(1H-pyrazol-1-yl)phenylamino)pyrimidine-5-carboxamide (184 mg, 0.427 mmol). DIEA (0.150 mL, 0.863 mmol) was also added. The mixture was stirred at 90 C overnight. After being cooled to room temperature, water was added to induce precipitation. The precipitate was collected, then dissolved in CH2Cl2 (5 mL) and TFA (4 mL). The solution was stirred at room temperature for 30 min. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (103 mg). MS 411.5 (M+H). UV λ=238.8, 304.8 nm.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.Cl.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31]Cl.C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])=[O:19])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCCOC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 31, piretanide can be reacted with 3-(dimethylamino)propyl chloride hydrochloride, triethylamine and sodium iodide in dimethylformamide (DMF) to yield 3-(N,N-dimethylaminopropyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].O[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].BrC[CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1>CN(C=O)C.O>[O:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:1][O:4][C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:9](=[O:10])[CH3:8]
Reactant: O=C(CO)c1ccccc1
Reactant: BrCC1CCCO1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccccc1OCC1CCCO1
Temperature: 110 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
K2CO3 (4.5 g, 0.032 mol) was added to a solution of 2-hydroxy-acetophenone (4 g, 0.03 mol) and 2-bromomethyl-tetrahydro-furan (10 g, 0.06 mol) in DMF (20 mL). The resulting mixture was vigorously stirred for 16 h at 110° C., cooled and then diluted with water (100 mL), extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×30 mL), filtered over anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chropatography on silica gel (eluent EtOAc-hexane, 1:5) to give 1-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-ethanone (2.22 g; 34%) as brown oil.