Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]CC([NH:5][CH2:6][C:7]1[CH:12]=[C:11](OC(F)(F)F)[CH:10]=[CH:9][C:8]=1[O:18][CH3:19])=O.ClCC(NCC1C=CC(OC(F)(F)[F:34])=CC=1O)=O>>[ClH:1].[F:34][C:11]1[CH:10]=[CH:9][C:8]([O:18][CH3:19])=[C:7]([CH:12]=1)[CH2:6][NH2:5]
Reactant: COc1ccc(OC(F)(F)F)cc1CNC(=O)CCl
Reactant: O=C(CCl)NCc1ccc(OC(F)(F)F)cc1O
Product: COc1ccc(F)cc1CN
Product: Cl

Procedure:
This compound was prepared using the procedure described in Example 74, using 2-chloro-N-(2-methoxy-5-trifluoromethoxy-benzyl)-acetamide, instead of 2-chloro-N-(2-hydroxy-4-trifluoromethoxy-benzyl)-acetamide. 1H NMR (CD3OD) δ=7.15–7.11 (2H, m), 7.06–7.03 (1H, m), 4.06 (2H, s), 3.88 (3H, s).
Reaction SMILES: C([NH:8][CH2:9][CH:10]([CH2:12][S:13][CH:14]([CH3:16])[CH3:15])[OH:11])(OC(C)(C)C)=O.C(Cl)[Cl:18]>>[NH2:8][CH2:9][CH:10]([CH2:12][S:13][CH:14]([CH3:16])[CH3:15])[OH:11].[ClH:18]
Reactant: ClCCl
Reactant: CC(C)SCC(O)CNC(=O)OC(C)(C)C
Product: CC(C)SCC(O)CN
Product: Cl

Procedure:
BOC-NHCH2CH(OH)CH2SCH(CH3)2 (3.74 g, 0.015 mole) was dissolved in 75 ml CH2Cl2 and occasionally purged with HCl gas over two hours. The solvent was removed in vacuo, and the residue was triturated with Et2O. The solvent was decanted and the residue was stripped to a foam, 2.83 g. IR, NMR, and mass spectral analysis confirmed the structure.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:18][C:19]([O:22][C:23]([N:25]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:26]1[N:27](C(OC(C)(C)C)=O)[CH:28]=[C:29]([CH:31](OC)[O:32]C)[N:30]=1)=[O:24])([CH3:21])[CH3:20].O>CC(C)=O>[CH3:21][C:19]([O:22][C:23]([N:25]([C:26]1[NH:27][CH:28]=[C:29]([CH:31]=[O:32])[N:30]=1)[C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])=[O:24])([CH3:18])[CH3:20]
Reactant: COC(OC)c1cn(C(=O)OC(C)(C)C)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C=O)c[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
A catalytic amount of pyridinium p-toluenesulfonate was added to a solution of 1,1-dimethylethyl 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-[bis(methyloxy)methyl]-1H-imidazole-1-carboxylate (1.520 g, 3.32 mmol) in acetone:water/3:2 (25 mL). The mixture was stirred at RT for 3 days. The solvent was evaporated and the residue was purified by chromatography (EtOAc:hexanes) to give 0.680 g of the title compound (0.680 g, 66%). 1H NMR (400 MHz, chloroform-d) δ ppm 10.57 (br. s., 1H), 9.57 (s, 1H), 7.61 (s, 1H), 1.51 (s, 18H). ES MS: m/z 310 (M−H), 334 (M+Na).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:12])[CH:10]=[CH2:11])[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1CCCN(C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution is prepared of 20 g (175 mM) of N-methylhomopiperazine in 100 ml of dichloromethane, to which is added, dropwise, at 0° C., a solution of 15.85 g (175 mM) of acryloyl chloride in 20 ml of dichloromethane. The reaction mixture is agitated for 1 hour at 0° C., and then for 2 hours at ambient temperature, and then hydrolysed with a solution of 12 g of sodium carbonate in 20 ml of water. The mixture is decanted, the organic phase is washed once with water and then dried over magnesium sulphate and concentrated under reduced pressure. 23 g of the compound sought after are thus obtained, as an orangy oil, which is used, without other purification, in the next step.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([OH:10])[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[N:17]=[C:16]([NH:30][CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[N:15]=1>C1C=CC=CC=1>[Cl:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[NH:20][C:18]1[N:17]=[C:16]([NH:30][CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[N:15]=[C:14]([O:10][CH:6]2[CH2:7][CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]2)[N:19]=1
Reactant: CC(=O)N1CCCC(O)C1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OC3CCCN(C(C)=O)C3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of N-acetyl-3-hydroxypiperidine (0.335 g, 2.27 mmol) and sodium hydroxide (95 mg, 2.27 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography to afford the title compound E20 as an off-white solid (0.35 g, 91%). mp 138-140° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 17.20 min, 91.70% purity; MS (CI): m/z 489 (M+, 100).
Reaction SMILES: C[O:2]CO[C:5]1[C:6](CCN)=[C:7]2[C:12](=[C:13](C)[C:14]=1C)[O:11][C:10](C)(C)[CH2:9][CH2:8]2.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>CC#N.C(OC(C)C)(=O)C>[S:29]([OH:31])(=[O:2])(=[O:30])[CH3:28].[O:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1c(C)c(C)c2c(c1CCN)CCC(C)(C)O2
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)C
Product: CS(=O)(=O)O
Product: c1ccc2c(c1)CCCO2
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
A suspension of the hydrochloride salt of 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (100 mg, 300 μmol), prepared as described in Example 1, in 1.5 mL MeCN was charged with pyridine (300 μL) followed by methanesulfonyl chloride (30 μL, 360 μmol). The suspension was stirred at 23° C. for 90 min, then diluted in isopropyl acetate (30 mL) and washed successively with 2.5 M aqueous sodium hydroxide, 1 M aqueous citric acid, and brine (1×15 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a yellowish oil. The oily residue was dissolved in methanol (3 mL), treated with concentrated HCl (approx. 30 μL), and the resulting mixture was warmed to 40° C. After 1 hr, the reaction was judged to be complete by TLC analysis, and was diluted into 50 mL EtOAc. The mixture was washed with 1 M aqueous sodium bicarbonate and brine (1×20 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient elution 20→60% EtOAc/Heptane) produced yellow solid chroman mesylate intermediate (48 mg). 1H NMR (CDCl3, 400 MHz) 3.31 (m, 2H), 2.90 (t, 2H), 2.78 (s, 2H), 2.67 (t, 2H), 2.14 (s, 3H), 2.09 (s, 3H), 1.76 (t, 2H), 1.22 (s, 6H) ppm. The resulting chroman was oxidized with CAN in a manner analogous to that used in Step 4 of Example 1. Silica gel purification (gradient elution 30→80% EtOAc/Heptane) afforded N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)methanesulfonamide as a yellow oil (25 mg). 1H NMR (CDCl3, 400 MHz) 4.82 (t, 2H), 3.26 (q, 2H), 2.92 (s, 3H), 2.78 (t, 2H), 2.61 (m, 2H), 1.99 (s, 6H), 1.59 (m, 2H), 1.26 (s, 6H) ppm.
Reaction SMILES: [Cl-].[NH4+].[C:3]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([F:24])[CH:16]=1)#[N:4]>C(O)C.O.CO.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:6]2[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][NH:9][C:5]=2[C:3]#[N:4])=[CH:16][C:17]=1[F:24]
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccc([N+](=O)[O-])c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(C#N)c1-c1ccc(N)c(F)c1
Temperature: 70 °C
Yield: 94 %

Procedure:
Iron (Alrich cat#20930-9, 24.9 g, 445 mmol) and ammonium chloride (4.80 g, 89.7 mmol) were added to a suspension of ethyl 5-cyano-4-(3-fluoro-4-nitrophenyl)-1H-pyrrole-3-carboxylate (45.0 g, 148 mmol) in ethanol (540 mL) and water (180 mL) equipped with an overhead stirrer. The reaction was warmed (70° C.) for 2 h, and then cooled to rt. The mixture was diluted with methanol (500 mL) and then filtered through a well-packed pad of Celite®. The filter cake was thoroughly rinsed with methanol (1 L) and acetonitrile (2 L) and the combined filtrate was evaporated. The residue was dissolved in ethyl acetate (1.5 L) then washed with water (500 mL) and brine (500 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to afford the desired product (38.0 g, 94%) containing trace impurities (<5%). The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 13.36 (s, 1H), 8.25 (dd, J=12.8, 2.0 Hz, 1H), 6.92-6.97 (m, 1H), 6.72-6.79 (m, 1H), 5.35 (s, 2H), 4.10 (q, J=7.0 Hz, 2H), 1.16 (t, J=7.0 Hz, 3H); ES-MS m/z 274.3 (MH)+; HPLC RT (Method A) 2.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[CH:9][N:10]=2)[N:7]=1.[Br:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[Br:12][CH2:13][CH2:14][CH2:15][C:16]([NH:11][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)=[O:17]
Reactant: Nc1cnc2ccc(Cl)nn12
Reactant: O=C(Cl)CCCBr
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCCBr)Nc1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To 1.0 g (5.930 mmol) of 6-chloroimidazo[1,2-b]pyridazin-3-amine dissolved in 15 mL of THF was added 4-bromobutanoyl chloride (1.21 g, 6.52 mmol) and pyridine (0.96 mL, 11.86 mmol). This mixture was stirred for 1 hr at rt, and then diluted with 30 mL EtOAc and quenched with aq. NaHCO3. The organic layer was separated and washed with brine, dried over MgSO4, and concentrated. The solid obtained (1.39 g, 74% yield) was pure enough to be used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=N)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=C(c2ccccc2)c2ccccc2)[C@H](O)C1
Yield: 87.9 %

Procedure:
tert-butyl-4-amino-3-hydroxypiperidine-1-carboxylate (11.9 g; 55 mmol) and benzophenone imine (10 g; 59 mmol; 1.05 eq.) were dissolved in anhydrous toluene and heated to reflux for 18 hrs. Monitored the reaction by TLC (30% EtOAc/hexanes with 0.1% triethylamine). The crude reaction was concentrated and purified by flash column chromatography. Isolation gave 18.4 g of the title compound in an 86% yield. LC/MS (ES+)[(M+H)+]: 381 for C23H28N2O3.
Reaction SMILES: C1(S([N:10]2[CH2:15][CH:14]([CH2:16][O:17][CH3:18])[N:13]([CH3:19])[CH:12]([CH2:20][O:21][CH3:22])[CH2:11]2)(=O)=O)C=CC=CC=1.C1(C)C=CC=CC=1.[ClH:30]>C1(C)C(C)=CC=CC=1>[ClH:30].[CH3:22][O:21][CH2:20][CH:12]1[CH2:11][NH:10][CH2:15][CH:14]([CH2:16][O:17][CH3:18])[N:13]1[CH3:19]
Reactant: COCC1CN(S(=O)(=O)c2ccccc2)CC(COC)N1C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: COCC1CNCC(COC)N1C
Temperature: 140 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
To a mixture of the above described (2SR,6SR)-4-benzenesulfonyl-2,6-bis-methoxymethyl-1-methyl-piperazine (910 mg, 2.771 mmol) in xylene (20 ml) was added sodium dihydro-bis(2-methoxyethoxy)aluminate in toluene (2.154 ml, 7.065 mmol) and the mixture was stirred at 140° C. for 18 h. Cooled to 23° C., poured into 2 M HCl, extracted twice with tert-butyl methyl ether, the aqueous layer was made alkaline with 10 M NaOH-sol., extracted twice with tert-butyl methyl ether, the combined organic layer was dried over sodium sulfate, filtered, to the filtrate was added ethanol (5 ml) and chlorotrimethylsilane (ca. 0.5 ml) and all volatiles were removed in vacuum to give the title compound as a colorless oil (350 mg, 56%), MS (ISP) m/e=189.3 [(M+H)+].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([F:12])[CH:6]=1)([CH3:3])[CH3:2].[C:13]([NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])[CH2:14][C:15]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16].C([O-])(=O)C.[Na+].Cl.[N:36]([O-])=O.[Na+]>O>[CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][N:36]=[C:28]([CH3:29])[O:27][C:25](=[O:26])[NH:24][C:13](=[O:23])[CH2:14][C:15]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[C:7]([F:12])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)NC(=O)CC(=O)NC(=O)OCC
Reactant: CC(C)Oc1ccc(N)c(F)c1
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)NC(=O)CC(=O)NC(=O)OC(C)=NNc1ccc(OC(C)C)cc1F
Temperature: 10 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
A mixture of 5.92 g (0.035 mole) of 4-isopropoxy-2-fluoroaniline, 10.60 g (0.043 mole) of malonyldiurethane, and 41.02 g (0.500 mole) of sodium acetate was suspended in 1000 mL of water with vigorous stirring. To this suspension was added 25 mL of 12N hydrochloric acid. The reaction mixture was cooled to 10° C., and, while this temperature was maintained, a solution of 2.42 g (0.035 mole) of sodium nitrite in 25 mL of water was slowly added. The reaction mixture was allowed to warm slowly to room temperature where it was stirred under a nitrogen atmosphere for approximately 16 hours. During this period a yellow solid formed and precipitated out. The mixture was filtered, and the yellow solid was washed in succession with water and diethyl ether. After being dried, 9.20 g of 2-(4-isopropoxy-2-fluorophenyl)hydrazonomalonyldiurethane was isolated as a yellow solid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:15])([CH3:14])[CH2:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br-].[CH:17]1(CO)[CH2:19][CH2:18]1.[C:22](=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CCC(C)=O>[CH:17]1([CH2:1][N:2]([CH3:22])[C:3]([CH3:15])([CH3:14])[CH2:4][NH:5][C:6](=[O:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:19][CH2:18]1
Reactant: CNC(C)(C)CNC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: OCC1CC1
Agent: [Br-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CN(CC1CC1)C(C)(C)CNC(=O)c1ccccc1
Yield: 79.6 %

Procedure:
A solution of N-[2-methylamino-2-methyl propyl]benzamide (1 g., 0.0052 mole) in MEK (50 ml.) was added to a solution of cyclopropyl carbinol bromide (0.66 g.,) in MEK (30 ml.) containing sodium carbonate (0.55 g.,) and a few crystals of sodium iodide. The mixture was refluxed for 24 hrs. and then filtered and the excess MEK evaporated under reduced pressure to give a liquid residue. This was passed down an alumina column, eluting with ethyl acetate to give N-[2-[(cyclopropylmethyl)methylamino]-2-methylpropyl]benzamide (0.9 g.).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].[NH2:11][C:12]([NH2:14])=[O:13].S(=O)(=O)(O)O>CS(C)=O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:4]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[N:14]=[C:12]([OH:13])[N:11]=1
Reactant: N#Cc1ccccn1
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Oc1nc(-c2ccccn2)nc(-c2ccccn2)n1
Temperature: 25 °C

Procedure:
1.0 g (approximately 60% dispersion in paraffin oil, about 25 mmol) of sodium hydride is added in portions to a solution of 5.21 g (50 mmol) of 2-cyanopyridine and 1.50 g (25 mmol) of urea in 100 ml of dimethyl sulfoxide. The resulting suspension is maintained at room temperature for 3 hours and then heated at 75° C. for 23 hours, cooled and poured into 100 ml of ice-water. The mixture is rendered neutral with 2N sulfuric acid, and the crude product is filtered off and recrystallised from 55 ml of methanol, yielding 4,6-di-pyrid-2-yl-[1,3,5]triazin-2-ol in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12]
Reactant: ClCCN1CCCC1
Reactant: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1nn(CCN2CCCC2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
A solution of 5-bromo-3-(trifluoromethyl)-1H-indazole (282 mg, 1.07 mmol) in DMSO (15 mL) was treated with Cs2CO3 (1.45 g, 4.45 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (376 mg, 2.21 mmol). After stirring for 16 hours at room temperature, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, MeOH/EtOAc/hexanes, 0:1:1 to 1.49:50) gave the title compound (250 mg, 65%) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.54 (dd, J=8.9, 1.7 Hz, 1H), 7.40 (d, J=8.9, 1H), 4.54 (t, J=7.1 Hz, 2H), 3.01 (t, J=7.1 Hz, 2H), 2.56-2.54 (m, 4H), 1.79-1.75 (m, 4H); ESI MS m/z 362 [M+H]+.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C1(C)C(C)=CC=CC=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][N:20]=1>CCCCCCC>[C:21]([C:18]1[S:17][C:16]([NH:15][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])=[N:20][N:19]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1C
Solvent: CCCCCCC
Product: CC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A two-liter reaction flask with appropriate fittings was charged with 33.6 g (0.4 mole) of diketene, 965 ml of xylene and 59.7 g (0.38 mole) of 2-amino-5-tert butyl-1,3,4-thiadiazole. The stirred mixture was heated to 70° at which time all solids had dissolved. After one hour, the solution was cooled and added to 2500 ml of chilled heptane. Product precipitation was judged complete after two hours. The solids were collected on a vacuum filter and air dried. There was obtained 54 g (58.9%) of white product, m.p. 166°-68°. N.M.R. (CDCl3 -dimethyl-d6 sulfoxide) ∂ 1.5 [C(CH3)3 ], 2.0 (CH3, enol), 2.3 (CH3, keto), 3.6 (CH2), 5.4 (CH, enol).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]2[NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15]O)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:21])=O>>[ClH:21].[C:1]([C:5]1[CH:18]=[CH:17][C:8]2[NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][Cl:21])=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc2[nH]c(CCCCO)nc2c1
Product: CC(C)(C)c1ccc2[nH]c(CCCCCl)nc2c1
Product: Cl
Yield: 100 %

Procedure:
A solution of 4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-butan-1-ol (1.00 g, 4.06 mmol) in thionyl chloride (10 ml) was heated to 80° for 1 h. LCMS analysis shows complete consumption of starting material. The solvent was evaporated and the residue was co-evaporated with toluene (4×10 ml) to afford 1.22 g (100%) of crude product as a beige solid which was used without purification; MS (ESI+) for C15H21ClN2 m/z 1 [M+H]+, 265.15; HPLC purity 99% (ret. time, 1.66 min).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:16](=C)[C:17]([NH2:19])=[O:18])CCCCCCCCC.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[CH2:30])=[CH2:22].O>C(O)C>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:30]([NH:19][C:17](=[O:18])[CH:16]=[CH2:6])[CH2:29][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:23][CH2:21][CH3:22]
Reactant: C=C(CCCCCCCCCC)C(N)=O
Reactant: C=Cc1ccccc1C=C
Agent: C=CC(N)=O
Solvent: O
Solvent: CCO
Product: C=CC(=O)NCCCCCCCCCC

Procedure:
Polystyrenesulfonate (22.5 mmoles, 3.918 g), acrylamide (3.45 mmoles, 0.245 g), n-decylacrylamide (3.45 mmoles, 0.729 g) and divinylbenzene (0.6 mmoles, 85.5 microL) were dissolved in 15 mL ethanol and 5 mL water in a 40 mL vial fitted with a septa cap. The solution was degassed by bubbling nitrogen through and 1 mole % AIBN was added as a solution. The polymerization solution was further degassed and the placed in a heated reaction block at 60° C. for 18 h. A creamy yellow gel formed.
Reaction SMILES: [NH2:1][CH:2](C)[CH:3]([CH3:5])[OH:4].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].[CH2:21](N(CC)CC)C.O>ClCCl>[OH:4][C:3]([CH3:5])([CH3:21])[CH2:2][NH:1][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(N)C(C)O
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Under a nitrogen atmosphere 2-amino-1-methylpropan-1-ol (25.5 g, 0.28 mol) was added over a period of 30 minutes to a chilled (15° C.) solution of 4-chloro-3-nitro[1,5]naphthyridine (54.5 g, 0.26 mol) and triethylamine (39.5 g, 0.39 mol) in dichloromethane (1 L). The temperature of the reaction mixture was maintained below about 30° during the addition. After the addition was complete the reaction mixture was stirred at ambient temperature overnight. The resulting precipitate was isolated by filtration, slurried with water, and again isolated by filtration to provide 40.53 g of N-(2-hydroxy-2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid.
Reaction SMILES: [CH2:1]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16](C3N=CC(O)=CN=3)[CH:17]=2)C1)[CH2:2][CH2:3]CCCCCCC.C(C1C=CC2N=C(C3C=CC(O)=CC=3)SC=2C=1)CCCCCCC.[C:51]1([CH3:70])[CH:56]=[CH:55][C:54]([S:57]([O:60]CCCC2C=CC=CC=2)(=[O:59])=[O:58])=[CH:53][CH:52]=1>>[C:51]1([CH3:70])[CH:52]=[CH:53][C:54]([S:57]([O:60][CH2:3][CH2:2][CH2:1][CH2:11][CH2:19][CH:18]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:58])=[O:59])=[CH:55][CH:56]=1
Reactant: CCCCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccccc2)cc1
Agent: CCCCCCCCc1ccc2nc(-c3ccc(O)cc3)sc2c1
Product: Cc1ccc(S(=O)(=O)OCCCCCC2CCCCC2)cc1
Yield: 62.4 %

Procedure:
An objective product was prepared in the same manner as in Example 2 except that 2-(2-decylindan-5-yl)pyrimidine-5-ol was changed to 4-(6-octylbenzothiazole-2-yl)phenol and 3-phenylpropyl p-toluenesulfonate was changed to 5-cyclohexylpentyl p-toluenesulfonate (Yield: 62.4%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:23][NH:24][O:25][CH3:26]>C(Cl)Cl>[CH3:26][O:25][N:24]([CH3:23])[C:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[O:9]
Reactant: CNOC
Reactant: O=C(O)c1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a suspension of 4-pyridinecarboxylic acid (12.3 g, 100 mmol) over CH2Cl2 (200 mL) a solution of CDI (18.0 g, 111 mmol) in CH2Cl2 (200 mL) was added. After addition, the mixture was stirred for 2 h at room temperature. Following this, N,O-dimethylhydroxyl-amine hydrochloride (13.9 g, 145 mmol) was added and the mixture was stirred overnight. The reaction mixture was quenched with 1N NaOH and the phases separated. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (PE/EtOAc=1:1) to give the title compound as orange oil (10.1 g, 61% yield). LC-MS (Method A): m/z 167 (M+H)+, Rt: 0.49 min. 1H NMR (400 MHz, CDCl3): δ=8.64 (d, J=6.0 Hz, 2H), 7.46 (d, J=6.0 Hz, 2H), 3.47 (s, 3H), 3.30 (s, 3H).