Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].[CH2:28]1[O:30][CH2:29]1.B(F)(F)F.CCOCC>CCOCC>[CH:19]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[CH2:28][CH2:29][OH:30])([CH3:21])[CH3:20]
Reactant: C1CO1
Reactant: CC(C)[Si](Oc1ccc2ccccc2c1Br)(C(C)C)C(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc2ccccc2c1CCO)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
n-Butyllithium (16.4 mL of 1.6 M soln in hexanes, 26.3 mmol) was stirred with Et2O (60 mL) at −78° C. in an argon-purged, round-bottom flask. A solution of (1-bromo-naphthalen-2-yloxy)-triisopropyl-silane (7.10 g, 18.8 mmol) in Et2O (˜5 ml) was added dropwise to the stirring n-BuLi solution. The reaction was stirred at −78° C. for ten minutes and then a solution of ethylene oxide (1.41 mL, 28.2 mmol) and BF3-Et2O (3.81 mL, 31.0 mmol) in Et2O (˜5 ml) was added via syringe. The reaction was stirred at −78° C. for one hour and then at room temperature for two hours. The reaction was carefully quenched with H2O and was extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated. The crude product was purified by gradient elution flash chromatography (SiO2, 100% hexanes to 10% EtOAc-hexanes) to give 2-(2-triisopropylsilanyloxy-naphthalen-1-yl)-ethanol (3.41 g, 9.91 mmol) as a colorless oil in 53% yield. MS (APCI) m/z 343.2 (M−1).
Reaction SMILES: [C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:18][C:19]([C:21]2([CH2:26][C:27]([O:29]CC3C=CC=CC=3)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[C:9]2[N:13](CCC#N)[N:12]=[N:11][N:10]=2)=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:18][C:19]([C:21]2([CH2:26][C:27]([OH:29])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:5][CH:6]=1
Reactant: N#CCCn1nnnc1[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)OCc2ccccc2)CCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)c2nnn[nH]2)CCCC1
Reaction time: 0.5 h
Yield: 8.6 %

Procedure:
(S)-benzyl 2-(1-(2-(biphenyl-4-yl)-1-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)ethylcarbamoyl)cyclopentyl)acetate (39 mg, 0.069 mmol) in MeOH (6 mL) was hydrogenated in H-Cube (Cartridge; 10% Pd/C) at room temperature for 0.5 hour. The reaction mixture was concentrated in vacuo. This was treated with 2M NaOH aqueous solution (1 mL) and MeOH (1 mL) and stirred for 0.5 hour. The reaction mixture was acidified with 1M HCl and the mixture was purified by reverse phase HPLC (column; Sunfire C-18, eluent; 0.1% TFA-H2O/CH3CN) to give {1-[(S)-2-biphenyl-4-yl-1-(1H-tetrazol-5-yl)-ethylcarbamoyl]-cyclopentyl}-acetic acid (2.5 mg). LCMS (condition C): 420 (M+1); retention time=1.70 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.54 (m, 6H), 1.87-1.98 (m, 2H), 2.59 (s, 3H), 2.59 (s, 2H), 3.22-3.66 (m, 2H), 5.39-5.48 (m, 1H), 7.29-7.37 (m, 3H), 7.44 (t, J=8.08 Hz, 2H), 7.55 (t, J=8.34 Hz, 2H), 7.59-7.64 (m, 2H), 8.17 (d, J=8.08 Hz, 1H); HRMS (ES+) m/z for C23H25N5O3 [M+H]+ calcd 419.2. found 419.2
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9]2)[CH2:5]1>CO.[Pd]>[ClH:1].[ClH:1].[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:5]1
Reactant: CN1CCC2(CCN(Cc3ccccc3)C2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CCC2(CCNC2)C1

Procedure:
A solution of 2-methyl-7-(phenylmethyl)-2,7-diazaspiro-[4.4]nonane dihydrochloride in 150 ml of methanol with 1.0 g 20% palladium on carbon catalyst was hydrogenated at 50 psi for two days. After filtration, the filtrate was concentrated to a thick syrup which crystallized on addition of acetonitrile to give 11.50 g of 2-Methyl-2,7diazaspiro[4.4]nonane dihydrochloride, softened at 164° C. and melted at 168°-170° C. EXAMPLE I
Reaction SMILES: [CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17](OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:35].[Li+].CN(C)C=O>O>[CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@@H:17]([Cl:35])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1Cl
Temperature: 75 °C
Reaction time: 9 h
Yield: 48.9 %

Procedure:
A mixture of 553 g of 2-benzyl-6-((3R,4R)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidine-1-yl]-3-iodopyridine, 79 mg of lithium chloride and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 9 hours. After cooling as it was, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (5:1), to give 391 mg of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:16][C:4]1[C:3]([CH3:17])=[C:2]([N:23]2[CH2:22][CH2:21][NH:20][C@H:19]([CH3:18])[CH2:24]2)[N:7]=[N:6][C:5]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1c(Cl)nnc(C(=O)c2ccccn2)c1C
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)c2ccccn2)nnc(N2CCN[C@H](C)C2)c1C
Yield: 97.1 %

Procedure:
(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-pyridin-2-yl-methanone (550 mg, 2.22 mmol), (R)-2-methyl-piperazine (320 mg, 3.20 mmol) are added into a microwave vial followed by NMP (6 mL) and triethylamine (0.92 mL, 6.66 mmol). The vial is sealed and irradiated in the microwave at 180° C. for 1 h. The crude material is directly purified via flash chromatography on silica gel (20-70% methanol in CH2Cl2) to afford the title compound (671 mg, 97%).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[C:3]1([CH3:26])[CH3:25].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:4]1[C:3]([CH3:25])([CH3:26])[CH2:2][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5]1
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccccc1[N+](=O)[O-])N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Temperature: 0 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
To a mixture of (E)-methyl 4-(2-nitrobenzylideneamino) benzoate (3.26 g, 11.5 mmol) and yttrium(III) trifluoromethanesulfonate (140 mg, 0.27 mmol) in tetrahydrofuran (28 mL) was added isobutylaldehyde (1.9 mL, 20.6 mmol) at room temperature under nitrogen, then the resultant mixture was stirred at room temperature overnight. Thin layer chromatography and LC-MS showed the starting material was completely consumed. The reaction was quenched with water and separated. The aqueous layer was extracted with ethyl acetate twice and the combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford 1.34 g of methyl 4-hydroxy-3,3-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. Yield: 32.7%. To an ice-cooled mixture of methyl 4-hydroxy-3,3-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.5 g, 4.2 mmol) and triethylsilane (1.48 g, 12.6 mmol) in dichloro methane (150 mL) was added dropwise a solution of trifluoroacetic acid (1.92 g, 16.8 mmol) in dichloromethane (50 mL) over 45 min under nitrogen. The mixture was kept at 0° C. at room temperature for 12 h. Thin layer chromatography and LC-MS showed the starting material was completely consumed. Solid sodium carbonate (2.0 g) was added to the reaction mixture and stirred for 10 min., filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford 1.26 g of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. Yield: 86%.
Reaction SMILES: C([NH:8][C@@:9]([CH3:37])([CH2:35][CH3:36])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)[C:21]([C:23]2[NH:27][N:26]=[C:25]([Cl:28])[CH:24]=2)=[O:22])=[C:15]([F:34])[CH:14]=1)=[O:11])(OC(C)(C)C)=O.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(#N)C>[NH2:8][C@@:9]([CH3:37])([CH2:35][CH3:36])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:29][CH:30]2[CH2:31][CH2:32][CH2:33]2)[C:21]([C:23]2[NH:27][N:26]=[C:25]([Cl:28])[CH:24]=2)=[O:22])=[C:15]([F:34])[CH:14]=1)=[O:11]
Reactant: CC[C@](C)(NC(=O)OC(C)(C)C)C(=O)Oc1ccc(CN(CC2CCC2)C(=O)c2cc(Cl)n[nH]2)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC[C@](C)(N)C(=O)Oc1ccc(CN(CC2CCC2)C(=O)c2cc(Cl)n[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a solution of (S)-4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl 2-(Boc-amino)-2-methylbutanoate (0.020 g, 0.037 mmol) in ACN 2 mL was added 0.5 mL Et3SiH and 0.5 ml TFA, and then stirred at r.t. for overnight. After removed the solvent, chromatography on silica gel with 0-40% methanol in DCM give the crude product. Then, the crude product was purified one more time by preparative HPLC (Water/ACN, 5-100%, 15 mins, then 100%, 5 mins.) gave pure product (S)-4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl 2-amino-2-methylbutanoate (0.010 g, 0.023 mmol, 62% yield).
Reaction SMILES: N#N.C(OC([C@@:13]1([C:23]([NH2:25])=[O:24])[CH2:17][C@@H:16]([OH:18])[CH2:15][N:14]1[C:19]([CH3:22])([CH3:21])[CH3:20])=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:19]([N:14]1[CH2:15][C@H:16]([OH:18])[CH2:17][C@H:13]1[C:23]([NH2:25])=[O:24])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)N1C[C@H](O)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)N1C[C@H](O)C[C@H]1C(N)=O
Yield: 108.6 %

Procedure:
0.224 g of N2 -(benzyloxycarbonyl)-N1 -tert.butyl-4(R)-hydroxy-L-prolinamide was dissolved in 20 ml of ethanol and hydrogenated over 50 mg of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 2 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.13 g of N1 -tert.butyl-4(R)-hydroxy-L-prolinamide which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CCO>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCc1cc(Nc2ccc(CCO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 85 °C
Yield: 69.5 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g, 0.59 mmol) and 2-(4-aminophenyl)ethanol (0.134 g, 0.89 mmol) and 4M HCl in dioxane (0.222 mL, 0.89 mmol) in EtOH was heated for 2.5 h at 85° C. After this time, the mixture was neutralized with NaHCO3 at 0° C. and purified by silica gel chromatography eluting with methylene chloride and methanol to afford the title compound (0.145 g, 70%) as a yellow solid. MW=353.85. 1H NMR (DMSO-d6, 500 MHz) δ 9.53 (s, 1H), 8.33-8.28 (m, 2H), 7.62-7.55 (m, 4H), 7.22 (d, J=8.4 Hz, 2H), 6.58 (s, 1H), 4.62 (t, J=5.2 Hz, 1H), 3.63-3.59 (m, 2H), 2.72-2.64 (m, 4H), 1.26 (t, J=7.6 Hz, 3H); ESI MS m/z 354 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:18](=[O:21])[O:19][CH2:20][C:13]=12.Cl>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:13]2[N:12]=[CH:17][CH:16]=[CH:15][C:14]=2[C:18]([OH:21])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1OCc2ncccc21
Reactant: Oc1ccc(Br)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccnc1COc1ccc(Br)cc1
Temperature: 165 °C

Procedure:
32 g (185 mmol) of 4-bromophenol are treated in methanol with 33.32 g (185 mmol) of 30% solution of sodium methoxide in methanol. The solvent is eliminated and the residue mixed with 5.0 g (37.00 mmol) of furo[3,4-b]pyridin-5(7H)-one (prepared according to Synthesis, 1997, 113-116). The system is stirred at 165° C. for 30′ (at first the mixture melts, afterwards solidifies). Once at room temperature, the solid is dissolved in excess water, adjusted at pH 7-8 with 2N HCl and extracted two times with dichloromethane. The aqueous layer is adjusted at pH 5-6 with more 2N HCl and the solid that precipitates is filtered, washed with water and dried. The yield is 6.6 g (58%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13](O)=[O:14])[C:6]2=[CH:5][C:4]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)=[N:3]1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]([NH:30][CH2:27][CH2:28][CH3:29])=[O:14])[C:6]2=[CH:5][C:4]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)=[N:3]1
Reactant: CCCN
Reactant: O=C(O)CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O
Product: CCCNC(=O)CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(6-oxo-8-((3,4,5-trifluorobenzyl)oxy)-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl) acetic acid and propan-1-amine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH:16]=[O:17].C[O-].[Na+].[C:21](O)(=[O:23])C.C(Cl)Cl>CO>[CH:16]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]=1[O:23][CH3:21])=[O:17]
Reactant: COC(=O)c1cc(C=O)c(Cl)nc1C(=O)OC
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)c(OC)nc1C(=O)OC
Temperature: 90 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
A solution of dimethyl 6-chloro-5-formylpyridine-2,3-dicarboxylate (1.0 g, 0.0039 mol) in methanol (10 mL) is added to sodium methoxide (0.42 g, 0.0078 mol) in methanol (2 mL). The resulting mixture is stirred for 15 hours at 90° C. After cooling to room temperature, the reaction mixture is acidified to pH 3.0 with acetic acid. The reaction is poured into methylene chloride, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound (0.62 g, 63%) as an orange oil, identified by IR and NMR spectral analyses.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C)C=O>[N:12]([CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCCOCc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCc1c[nH]cn1
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A stirred suspension of 4-(2-chloroethoxymethyl)imidazole hydrochloride (14.7 g.) and sodium azide (9.8 g.) in dry dimethylformamide (103 ml.) was maintained at 95° for 5 hours and then set aside overnight at room temperature. Following dilution with water and filtration, the filtrate was concentrated and the residue purified by chromatography on a dry column of alumina using ethanol. The product was basified with potassium carbonate (6.5 g.) in water (3 ml.) and the anhydrous residue was extracted with isopropyl alcohol (3×50 ml.). Concentration of the extracts afforded 4-(2-azidoethoxymethyl)imidazole (7.2 g.). Hydrogenation of the azido compound (7.2 g.) in isopropyl alcohol (142 ml.) over platinum oxide catalyst (3.0 g.) gave 4-(2-aminoethoxymethyl)imidazole (6.48 g.). A sample of the monopicrate monohydrochloride had m.p. 139°-140° (from nitromethane). (Found: C, 35.4; H, 3.8; N, 20.5; Cl, 8.8. C12H15ClN6O8 requires: C, 35.4; H, 3,7; N, 20.7; Cl, 8.7).
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][C:11]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C.C(=O)(O)[O-].[Na+]>[O:1]([CH2:8][CH2:9][N:10]1[C:11](=[O:24])[CH2:12][N:13]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][CH:15]1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)CC(=O)N1CCOc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CN(Cc2ccccc2)CC(O)N1CCOc1ccccc1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
1-(2-Phenoxyethyl)-4-benzyl-2,6-piperazinedione (2.24 g) in ethanol (60 ml) and saturated sodium bicarbonate solution (15 ml) was cooled to 5° and sodium borohydride (0.4 g) added. The mixture was stirred at 5° for 1 h, water (150 ml) added and the mixture extracted with chloroform (3×75 ml). Evaporation of the chloroform gave the title compound as an off-white solid (2.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C([O-])([O-])=O.[Na+].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](OB(O)O)=[CH:22][CH:21]=1>O1CCOCC1.CO>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[CH:22][CH:21]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=c1ccc2cc(-c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 110 °C

Procedure:
A solution of 22.7 g (0.101 mol) 6-bromo-1H-quinolin-2-one in 380 mL 1,4-dioxane and 380 mL MeOH is combined with 141.5 ml (0.283 ml) 2 M Na2CO3 solution and saturated with argon. Then 3.735 g (3.23 mmol) tetrakis-triphenyl-phosphane-palladium and 4-chlorophenylboric acid are added successively. The reaction mixture is heated to 110° C. for four hours and then evaporated down to a volume of 300 mL. 1.2 L water are added and the precipitate is filtered off. The solid is dried at 55° C. in the drying cupboard, washed with diisopropylether and dried again.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:16])=O>N1C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][Cl:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCOCCCC1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: ClCCOCCCC1CCCCC1
Temperature: 0 °C

Procedure:
110.4 g of 2-(3-cyclohexylpropyloxy)-ethanol, 2 ml of pyridine and 112 ml of thionyl chloride are boiled under reflux for 30 minutes. The reaction mixture is allowed to cool and is then poured onto 500 g of ice. The mixture is extracted with twice 500 ml of methylene chloride. The combined organic phases are washed with water, with sodium hydrogen carbonate solution, with water again and are then concentrated. The residue is distilled. 119.6 g of 2-(3-cyclohexylpropyloxy)-ethyl chloride are obtained [bp 68°-69° C. at 0.01 mm Hg (1.3 Pa)].
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.C(N(CC)C(C)C)(C)C.[CH2:40]([NH:47][CH2:48][C:49]#[C:50][CH3:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:40]([N:47]([CH2:48][C:49]#[C:50][CH3:51])[C:8](/[N:9]=[C:10]1\[S:11][C:12]([CH3:29])=[CH:13][N:14]\1[C:15]1[CH:28]=[CH:27][C:18]2[O:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[O:22][C:17]=2[CH:16]=1)=[O:30])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC#CCNCc1ccccc1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCN(Cc1ccccc1)C(=O)/N=c1\sc(C)cn1-c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-3-methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide (Example 81A, 0.75 mL of 0.14 M in acetonitrile, 58 mg, 0.1 mmol) was added to a 20 mL vial followed by N,N-diisopropylethylamine (0.75 mL of 0.14 M in acetonitrile, 18 mg, 0.13 mmol). Subsequently, N-benzylbut-2-yn-1-amine (0.57 mL of 0.2 M in acetonitrile, 0.11 mmol) was added. The resulting mixture was shaken at room temperature overnight. It was then concentrated in vacuo and the residue was taken up in 1:1 MeOH/DMSO and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method). 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.75 (3 H) 2.24 (3 H) 4.05 (2 H) 4.55 (2 H) 7.01-7.10 (1 H) 7.17-7.29 (4 H) 7.29-7.35 (1 H) 7.40-7.54 (1 H) 7.58-7.63 (1 H) 7.66-7.94 (1 H); MS (ESI+) m/z 506 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].O>CN(C)C=O>[N:1]1([CH:7]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(c1ccccc1)C(Br)OCc1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)C(OCc1ccc(Cl)cc1Cl)n1ccnc1
Reaction time: 2.5 h

Procedure:
1H-Imidazole (10.21 g, 150 mmole) was dissolved in dimethylformamide (20 ml) and ω-bromo-2-(2,4-dichlorobenzyloxy)acetophenone (11.2 g, 29.9 mmole) was added slowly. After stirring for 2.5 hours with ice-cooling, water (120 ml) was added and the mixture was extracted with ethyl acetate (120 ml×2). The extract was washed with water (120 ml×2) and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to chromatography on a silica gel columne and eluted with methanol/chloroform to obtain the title compound (8.37 g, 77.2%), m.p. 109°-111° C. (recrystallized from n-hexane/benzene).
Reaction SMILES: S(O)(O[CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH3:16][O:17][CH2:18][C:19]1([CH2:22][O:23][CH3:24])[CH2:21][O:20]1>O.[OH-].[Na+]>[CH2:8]([N:7]1[CH2:6][CH2:5][O:20][C:19]([CH2:18][O:17][CH3:16])([CH2:22][O:23][CH3:24])[CH2:21]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(O)OCCNCc1ccccc1
Reactant: COCC1(COC)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC1(COC)CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 87 h
Yield: 99 %

Procedure:
To a solution of 2-(N-benzylamino)ethyl hydrogen sulfate (28 g) in a mixture of water (36.3 ml) and 40% sodium hydroxide aqueous solution (12.1 ml) was added 2,2-bis(methoxymethyl)oxirane (16.0 g) at room temperature over 30 minutes. After stirring at room temperature for 87 hours, 40% sodium hydroxide aqueous solution (73 ml) was added dropwise to the mixture over 20 minutes. The mixture was stirred at room temperature for 1 hour and at 40° C. for 20 hours, and extracted with ethyl acetate (100 ml×3). The organic layer was extracted with 1N hydrochloric acid (×6). The combined extracts were neutralized with sodium hydroxide, and then added sodium chloride, and extracted with ethyl acetate (100 ml×3). The combined extracts were washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give 4-benzyl-2,2-dimethoxymethylmorpholine (31.79 g) as an orange oil.