Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[C:26]([Cl:34])[C:25]=1[N:35]=[C:36]=[O:37].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[C:26]([Cl:34])[C:25]=1[NH:35][C:36](=[O:37])[N:2]([CH3:1])[C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[N:6]=[CH:5][N:4]=1
Reactant: CNc1ncnc(Nc2ccc(N3CCN(C)CC3)cc2)n1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2ncnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)c1Cl
Reaction time: 3 h

Procedure:
To a solution of 2,6-dichloro-3,5-dimethoxy-aniline (124 mg, 0.56 mmol; Preparation 2) in 2 ml of dioxane under a nitrogene atmosphere, phosgene (0.52 ml 20% in toluene, 0.98 mmol) is added. The mixture is stirred for 70 min at 100° C., cooled to RT and concentrated in vacuo, yielding 2,6-dichloro-3,5-dimethoxyphenylisocyanate. The resulting solid is added portion-wise to a boiling solution of N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine (140 mg, 0.47 mmol) in 8 ml of toluene during 20 min. After 3 h, another 2 eq of 2,6-dichloro-3,5-dimethoxyphenylisocyanate are added and stirring is continued for totally 5 h. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; DCM/MeOH/NH3aq, 97:3:0.2) gives the title compound: ESI-MS: 547/549 [MH]+; tR=3.5 min (purity: 100%, gradient J); TLC: Rf=0.40 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.CCCCCC.C([Li])CCC.[O:25]1CCC[CH2:26]1>>[CH:26]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1)=[O:25]
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=Cc1cccc(-c2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A tetrahydrofuran (20 ml) solution of 2-bromo-6-phenylpyridine (1.3 g, 5.5 mmol) was cooled to −78° C., then a hexane solution of n-butyllithium (3.5 ml, 1.58 M, 5.6 mmol) was dropwise added thereto while 20 minutes. The reaction mixture was additionally stirred at −78° C. for 1 hour, then a tetrahydrofuran (5 ml) solution of 2-formyl-6-phenylpyridine (1.0 g, 5.5 mmol) obtained by Reference Example 11 was dropwise added thereto while 10 minutes, the reaction temperature was allowed to warm to 0° C. while 30 minutes. Then the reaction mixture was poured into an aqueous ammonium chloride-saturated solution, an organic layer was separated, furthermore an aqueous layer was extracted with toluene. The organic layer was combined, and the solvent was distilled off, and the residue was purified by silica gel column chromatography and recrystallization, thereby obtaining 1.1 g of 1,1-bis(6-phenylpyridine-2-yl)methanol as white powder. Yield: 61.2%.
Reaction SMILES: C([O:8][C:9](=[O:22])[CH:10]=[CH:11][C:12]1[CH:13]=[N:14][C:15]([C:18](=[O:21])[NH:19][CH3:20])=N[CH:17]=1)C1C=CC=CC=1.[CH2:23](O)C>[Pd]>[CH3:20][NH:19][C:18]([C:15]1[CH:23]=[CH:17][C:12]([CH2:11][CH2:10][C:9]([OH:8])=[O:22])=[CH:13][N:14]=1)=[O:21]
Reactant: CNC(=O)c1ncc(C=CC(=O)OCc2ccccc2)cn1
Reactant: CCO
Agent: [Pd]
Product: CNC(=O)c1ccc(CCC(=O)O)cn1
Reaction time: 8 h

Procedure:
3-(2-methylcarbamoyl-pyrimidin 5-yl)acrylic acid benzyl ester was dissolved in ethanol (20 mL) in presence of 15 mg of Pd/C, 10% and HClc (2 mL). The mixture was stirred under hydrogen balloon overnight to give 3-(2-methylcarbamoyl-pyridine-5-yl)-propionic acid which was used without further purification.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:11](=O)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:13])C.Cl.[C:15]([NH:19]N)([CH3:18])([CH3:17])[CH3:16]>C(O)CCC.C(O)(=O)C>[C:15]([N:19]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:13])[C:5]=2[CH:4]=[N:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)NN
Reactant: CN(C)C=C1C(=O)CCCCC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCCO
Product: CC(C)(C)n1ncc2c1CCCCC2=O

Procedure:
A solution of 1,3-cycloheptadione (2 g, mmol) was heated to reflux for 1 hour with dimethylforamide dimethylacetal (15 mL). The reaction mixture was concentrated and triturated with ether to yield 1.8 g of 2-dimethylaminomethylene-cycloheptane-1,3-dione. A solution of 2-dimethylaminomethylene-cycloheptane-1,3-dione (0.52 g, 2.9 mmol) and t-butylhydrazine hydrochloride (0.44 g, 3.5 mmol) in n-butanol (25 mL) and 0.3 mL of acetic acid was heated to reflux for 16 hours. The solvents were evaporated and the residue was chromatographed, eluting with 30% ethyl acetate/hexane to yield the title compound: 1H NMR (300 MHz, CDCl3) δ 7.85 (s, 1 H), 3.17 (m, 2 H), 2.68 (m, 2 H), 1.98 (m, 2 H), 1.89 (m, 2H) 1.68 (s, 9 H); MS (DCI/NH3) m/z 207 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([N+:19]([O-:21])=[O:20])=[C:7]([C:13]#[C:14][Si](C)(C)C)[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:13]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[N+:19]([O-:21])=[O:20])[N:3]=[C:2]([OH:1])[C:11]([OH:12])=[N:10]2)#[CH:14]
Reactant: C[Si](C)(C)C#Cc1cc2nc(O)c(O)nc2cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc2nc(O)c(O)nc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of 300 mg (0.99 mmol) 2,3-dihydroxy-6-trimethylsilylethynyl-7-nitroquinoxaline in 10 ml methanol is added 200 mg (1.45 mmol) potassium carbonate and then stirred at room temperature for 1 h. The reaction mixture is evaporated in vacuo and added water and 4N hydrochloric acid to pH 6. The precipitated product is filtered off and washed with water to give 200 mg (88%) of 6-ethynyl-2,3-dihydroxy-7-nitroquinoxaline m.p. >300° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH:22]1([O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)[CH2:26][CH2:25][CH2:24][CH2:23]1.[O-]CC.[Na+]>C(O)C>[CH:22]1([O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2/[CH:30]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:21][CH:20]=[CH:19][N:5]3[C:6](=[O:18])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COc1cccc(C=O)c1OC1CCCC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)c1OC1CCCC1
Yield: 44.8 %

Procedure:
The title compound was prepared by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 2-cyclopentyloxy-3-methoxybenzaldehyde (398 mg, 1.813 mmol) in presence of sodium ethoxide (163 mg, 2.411 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to afford 296 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.50-1.60 (m, 6H), 1.74-1.81 (m, 2H), 3.77 (s, 3H), 4.83 (s, 1H), 6.85-6.99 (m, 4H), 7.51 (d, J=5.1 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.83 (d, J=7.2 Hz, 2H), 8.00 (d, J=4.8 Hz, 1H), 8.12 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 529.30 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:24]([C:23]3[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=3)=[O:25])[CH2:3][CH2:2]2)[N:12]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc(F)cc4)CC3)cccc2n1
Yield: 36 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 4-fluorobenzoyl chloride (65 mg; 0.41 mmol) to obtain 26 mg. (36% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.54 (m, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.30 (m, 2H), 7.16 (br s, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 5.93 (br s, 2H), 4.55 (br s, 1H), 3.67 (br s, 1H), 3.37 (m, 2H), 3.08 (m, 2H), 2.77 (m, 2H). ESIMS+367.5 m/z
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)(=O)C(Cl)=O.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[C:25]([NH:29][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)c1ccc(-c2cccc3cncn23)cc1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(-c2cccc3cncn23)cc1
Reaction time: 1.5 h

Procedure:
To a slurry of 0.4 g of 5-(p-carboxyphenyl)imidazo[1,5-a]-pyridine in 40 ml of methylene chloride under nitrogen at room temperature, is added 30 μl of N,N-dimethylformamide followed by 0.16 ml of oxalyl chloride. The reaction mixture is stirred until gas evolution is complete and 0.46 ml of tert-butylamine is added dropwise. Stirring is discontinued after 90 min and 10 ml of saturated sodium bicarbonate solution is added. The organic layer is separated, dried over sodium sulfate and evaporated to yield the title compound, m.p. 128°-131°.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]1([CH:43]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:44](O)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:47]1([CH:43]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:44]([O:20][CH:5]([C:6]2[C:16](=[O:17])[C:15]3[C:10]([C:8](=[O:9])[CH:7]=2)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=3[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])=[O:45])[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCC(OC(=O)C(c1ccccc1)c1ccccc1)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 56 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 212 mg (1 mmole) of diphenylacetic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 270 mg (Yield: 59%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19]C(Cl)Cl>ClCCl>[CH2:1]([O:8][C:9]1[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[C:12]([CH:18]=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(Cl)Cl
Reactant: c1ccc(COc2cccc3ccsc23)cc1
Solvent: ClCCl
Product: O=Cc1ccc(OCc2ccccc2)c2sccc12

Procedure:
In analogy to the procedure described in example 91 b], 7-benzyloxy-benzo[b]thiophene (prepared from benzo[b]thiophen-7-ol [J. Chem. Soc., Perkin Trans. 1 (1983), (12), 2973-7], benzylchloride, potassium carbonate in N,N-dimethylformamide at room temperature) was reacted with dichloromethyl methyl ether in dichloromethane at 0° C. to give 7-benzyloxy-benzo[b]thiophene-4-carbaldehyde. Treatment of 7-benzyloxy-benzo[b]thiophene-4-carbaldehyde with (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride and potassium carbonate in 2-propanol in analogy to the procedure described in example 93 a] gave 3-(7-benzyloxy-benzo[b]thiophen-4-yl)-2(Z,E)-ethoxy-acrylic acid ethyl ester. Reduction of 3-(7-benzyloxy-benzo[b]thiophen-4-yl)-2(Z,E)-ethoxy-acrylic acid ethyl ester with magnesium in THF/MeOH (1:1) at 50° C. in analogy to the procedure described in example 93 b] yielded [rac]-3-(7-benzyloxy-benzo[b]thiophen-4-yl)-2-ethoxy-propionic acid methyl ester, subsequent removal of the benzyl protective function with dimethyl sulfide and boron trifluoride diethyl etherate in dichlormethane at room temperature in analogy the procedure described in example 93 c] gave [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:19])[CH2:14][O:13][CH2:12]/[C:11](=[CH:15]/[N+:16]([O-])=O)/[NH:10]2)=[CH:5][CH:4]=1>[Ni].O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:19])[NH:10][CH:11]([CH2:15][NH2:16])[CH2:12][O:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C)COC/C(=C/[N+](=O)[O-])N2)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2(C)COCC(CN)N2)cc1
Reaction time: 5 h

Procedure:
A mixture of 50 mmol of 3-(4-methoxyphenyl)-3-methyl-5-[1-nitrometh-(Z)-ylidene]morpholine and 5 teaspoons full of Raney nickel in 500 ml of tetrahydrofuran and 250 ml of methanol is hydrogenated under atmospheric pressure for 5 hours. The reaction mixture is filtered through Hyflo and the filtrate is evaporated. The crude title compound is identified from the residue on the basis of the Rf. The title compound is employed without further purification in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(C)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1cc(CBr)ccc1Cl
Reaction time: 3 h
Yield: 23.5 %

Procedure:
To a solution of 4-chloro-3-methoxytoluene (5.65 g) and N-bromosuccinimide (6.74 g) in anhydrous dichloromethane (60 mL) was added 2,2′-azolbis(4-methoxy-2,4-diaethylvaleronitrile) (674 mg). After stirring for 3 hours under reflux, the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with hexane to give 4-chloro-3-methoxybenzyl bromide as white powders (2.00 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:17]([O-])=O)[CH:3]=1.C1COCC1>[Pt].CO>[Cl:1][C:2]1[C:9]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[NH2:17]
Reactant: CNc1cc(N2CCN(C)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(N2CCN(C)CC2)c(Cl)cc1N

Procedure:
The sub-title compound was prepared from 4-chloro-5-(4-methyl-piperazin-1-yl)-2-nitro-N-methyl-aniline (500 mg, 1.8 mmol), THF (6 mL), MeOH (6 mL) and Pt/C (50 mg) in analogy to example 1 step (f).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[N:9]2[CH:10]=[C:11]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][C:8]2=[N:7][CH:6]=[C:5]1[C:30]([O:32]CC)=[O:31].O.Cl>O.O1CCCC1>[O:3]=[C:4]1[N:9]2[CH:10]=[C:11]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][C:8]2=[N:7][CH:6]=[C:5]1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1cnc2cc(OCc3ccccc3)c(OCc3ccccc3)cn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2cc(OCc3ccccc3)c(OCc3ccccc3)cn2c1=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
20.3 ml of 1N sodium hydroxide solution was added to a solution of 4-oxo-7,8-bis(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid, ethyl ester (6.61 g, 15.36 mmol) in 240 ml of water:tetrahydrofuran 1:1). After stirring overnight at 40° C., 200 ml of water was added, and the pH was adjusted to 2 with 3N hydrochloric acid. The resulting precipitate was filtered off with suction, washed with water and dried in vacuo. Yield: 5.28 g; melting point 207.8° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: Brc1ccccn1
Product: C[C@@H]1CN(c2ccccn2)CCN1
Temperature: 120 °C
Yield: 89.1 %

Procedure:
(R)-(−)-2-Methylpiperazine (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120° C. for 14 hours. The reaction mixture was allowed to cool to 23° C. and partitioned between a large volume of ethyl acetate and water. The layers were separated, and then additional water was added to the ethyl acetate solution. Drops of 1 N HCl solution were added to the water/ethyl acetate mixture with vigorous mixing. The layers were separated, and the combined aqueous phases were basified to pH ˜11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with chloroform containing a few drops of isopropyl alcohol (5×). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.79 g (89% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:30](O)=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:30]([O:14][C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9]1)=[O:31]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: O[C@@H]1CCCN(Cc2ccccn2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CCCN(Cc2ccccn2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1
Yield: 54.7 %

Procedure:
(3R)-1-(2-Pyridinylmethyl)-3-piperidinol (117 mg) [see Preparation 35] was added to a stirred solution of (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid (150 mg) [see Preparation 3], triphenylphosphine (192 mg) and diethyl azodicarboxylate (0.115 ml) in dry tetrahydrofuran (6 ml). The reaction mixture was stirred at reflux for 16 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 0.5M aqueous hydrochloric acid. The aqueous layer was then basified with 15% sodium hydroxide and the product extracted with ethyl acetate. The organic layer was then separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 98:2, by volume, ethyl acetate:methanol to afford (3S)-1-(2-pyridinylmethyl)-3-piperidinyl (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (140 mg) as a yellow oil. The hydrochloride salt was prepared by dissolving the title compound in ethyl acetate and bubbling hydrogen chloride gas through the solution, to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH2:11]=[O:12]>>[OH:12][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: C=O
Reactant: Cn1cnc2ccccc21
Product: Cn1c(CO)nc2ccccc21
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A solution of 1-methylbenzimidazole (2.5 g, 19 mmol), (J. Chem. Soc. 1929, 2820-2828), and paraformaldehyde (2 g) was heated at 165° C. for 30 minutes. Further paraformaldehyde (1 g) was added and heating continued for 2 hours. The mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride, followed by methylene chloride/methanol (95/5) to give 2-hydroxymethyl-1-methylbenzimidazole (1.34 g, 45%). 1H NMR Spectrum: (DMSOd6) 3.84(s, 3H); 4.73(s, 2H); 5.57(br s, 1H); 7.19(t, 1H); 7.25(t, 1H); 7.54(d, 1H); 7.60(d, 1H) MS-ESI: 185 [MNa]+
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](=[O:14])(=[O:13])[NH2:12])C.Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[C:27]3[C:28]=2[C:23](=[CH:24][CH:25]=[CH:26]3)[C:22]1=[O:35]>>[O:35]=[C:22]1[C:23]2[C:28]3[C:27](=[CH:34][CH:33]=[CH:32][C:29]=3[C:30](=[O:31])[N:21]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:12][S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([OH:3])=[O:15])(=[O:13])=[O:14])[CH:26]=[CH:25][CH:24]=2
Reactant: CCOC(=O)c1ccccc1S(N)(=O)=O
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C(O)c1ccccc1S(=O)(=O)NCCCCN1C(=O)c2cccc3cccc(c23)C1=O

Procedure:
The compound was prepared according to GP-2 using 2-sulfamoylbenzoic acid ethyl ester 4 and compound 3b. The crude product was purified by flash column chromatography using MeOH—CHCl3 to obtain 5b. 1H NMR (500 MHz, DMSO-d6) δ 9.27 (bs, 2H), 8.49-8.45 (m, 4H), 7.87 (t, J=8.0 Hz, 2H), 7.69 (d, J=8.0 Hz 1H), 7.63 (d, J=8.0 Hz 1H), 7.44 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 3.99 (t, J=7.0, 2H), 2.71 (q, J=7.0 Hz, 2H), 1.64-1.56 (m, 2H), 1.46-1.38 (m, 2H). MS (ES−) m/z 451 (M−H)−.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6]([O:26]CC)(=O)[C:7]#[C: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][CH2:21][CH2:22][CH2:23][CH3:24].Cl>C(O)C>[OH:26][C:6]1[CH:7]=[C: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][CH2:21][CH2:22][CH2:23][CH3:24])[O:3][N:2]=1
Reactant: NO
Reactant: CCCCCCCCCCCCCCCCC#CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCc1cc(O)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
13.24 g of hydroxylamine hydrochloride were added to a mixture of 130 ml of a 10% w/v aqueous solution of sodium hydroxide and 100 ml of ethanol, whilst ice-cooling. A solution of 5.08 g of ethyl 2-nonadecynoate (prepared as described in Preparation 31) in ethanol (30 ml) was then added dropwise to the resulting mixture, which was then stirred at room temperature for 16 hours. The mixture was then adjusted to a pH value of 3 by adding concentrated hydrochloric acid, and then the mixture was extracted three times with diethyl ether. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 50 g of silica gel. 4.09 g of the title compound were isolated from the fractions eluted with a 1:1 by volume mixture of methylene chloride and hexane, to give crystals melting at 85°-86° C. (from cold diethyl ether).