Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[O-].[K+].[Br:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[C:10]([F:15])[CH:9]=1.C[O:17]CCOCCOC.Cl>COC(C)(C)C>[Br:7][C:8]1[CH:13]=[C:12]([OH:17])[CH:11]=[C:10]([F:15])[CH:9]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COCCOCCOC
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COC(C)(C)C
Product: Oc1cc(F)cc(Br)c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a N2 flushed, 2 L four necked flask equipped with a mechanical stirrer, a condenser, a temperature controller and a N2 inlet, was added potassium trimethylsilanolate (225.0 g, 1.75 mol, tech. purify 90%), 1-bromo-3,5-difluorobenzene (96.5 g, 0.5 mol) and diglyme (300 mL). The reaction mixture was heated to 120° C. under N2 for 5 h. After cooling to rt, the heating mantle was replaced with an ice bath. The reaction mixture was acidified with a 3 N HCl solution (600 mL) while keeping the reaction temperature below 30° C. Tertiary butyl methyl ether (1 L) was added and the resulting mixture was stirred below 20° C. for 30 min then transferred to a 5 L separatory funnel. The organic layer was separated and washed with water (3×500 mL), sat. NaCl (500 mL), dried over MgSO4, filtered and concentrated in vacuo to give the crude red solid (145.0 g). The crude material was then distillated at 52-55° C./0.1 mm Hg to yield 3-bromo-5-fluorophenol as a slightly yellow oil (88.0 g, 92% yield). 1H NMR (300 MHz, CDCl3) δ 5.34 (s, H), 6.47-6.52 (m, 1H), 6.77-6.83 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:26]2[CH2:27][CH2:28][N:23]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:24][CH2:25]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)nn1
Yield: 75.2 %

Procedure:
A stirred mixture of 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide (0.113 g, 0.5 mmol), 1-benzylpiperazine (90 mg, 0.5 mmol), tetrabutylammonium bromide (27 mg, 0.084 mmol) and 1,8-diazabicylco[5.4.0]undec-7-ene (152 mg, 1.0 mmol) was heated under reflux in dioxane (10 mL) overnight. The solvent was evaporated. Residue was treated with 2% methanol in water (25 mL). The solid, which precipitated, was filtered off and dried in vacuo to give 138 mg (0.376 mmol) of the title compound in 75% yield. 1H NMR (300 MHz, CDCl3) δ 7.98, 7.87, 7.36-7.32, 6.94, 3.76-3.74, 3.57, 3.50-3.46, 2.60-2.58, 1.74-1.68, 1.52-1.48, 0.94. MS (ES+) m/z 368.2 (M+1).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(NC(C(O)=O)C(C)C)(=O)C1C=CC=CC=1.Cl.ClC1C=CC(C2CCNCC2)=CC=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([C:15](=[O:17])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CC(C)CC(NC(=O)c1ccccc1)C(=O)O
Agent: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: Clc1ccc(C2CCNCC2)cc1
Product: CC(C)CC(NC(=O)c1ccccc1)C(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
Example 215 was prepared in a similar manner as described for the preparation of Example 208 with the exceptions that benzoyl-DL-leucine and 4-(4-chlorophenyl)-4-hydroxypiperidine were substituted for benzoyl-DL-valine and 4-(4-chlorophenyl)piperidine hydrochloride, respectively. MS found: (M+H)+=430.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1.[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])([CH3:15])[CH3:14]>C(Cl)(Cl)Cl>[OH:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:26]([NH:25][C:17]2[C:16]([CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=[CH:19][C:18]=2[CH:22]([CH3:24])[CH3:23])=[O:27])[CH2:5][CH2:6]1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NCCN1CCN(CCO)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCCN1CCN(CCO)CC1
Reaction time: 0.08 h
Yield: 54 %

Procedure:
Into a solution of 4-(aminoethyl)piperazine-1-ethanol in chloroform (20 ml) was dropped a solution of 2,6-diisopropylphenyl isocyanate (2.03 g, 10 mmol) in chloroform (20 ml) followed by stirring for 5 minutes. The reaction solution was concentrated in vacuo and the residue was purified by a silica gel column chromatography (100 g of silica gel; developing solvents, chloroform→chloroform:ammonia-saturated methanol =20:1) to provide 2.03 g (yield 54%) of N-[2-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl]-N′-(2,6-di-isopropylphenyl)urea.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:21])([F:20])[CH2:17][CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC(Cl)=CC=1)=O)=NC(OCC1C=CC(Cl)=CC=1)=O>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([O:11][CH2:18][CH2:17][C:16]([F:21])([F:20])[F:15])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCC(F)(F)F
Reactant: CC(=O)c1cc(O)cc(C(C)(C)C)c1
Agent: O=C(N=NC(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)c1cc(OCCC(F)(F)F)cc(C(C)(C)C)c1
Reaction time: 120 h

Procedure:
To a solution of 1-(3-tert-butyl-5-hydroxyphenyl)ethanone (O3.106; 300 mg, 1.56 mmol), 3,3,3-trifluoropropanol (178 mg, 1.56 mmol) and triphenylphosphine (409 mg, 1.56 mmol) in dichloromethane (5 ml) at RT was added a solution of di(4-chlorobenzyl) azodicarboxylate (573 mg, 1.56 mmol) in dichloromethane (1 ml). The mixture was stirred for 5 days and then filtered. The solvent was removed and the residue was purified by flash chromatography (n-heptane:ethyl acetate). Yield: 170 mg, 38%.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#N.[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Mg]Br.CC[O:22]CC.Cl>C1COCC1.O>[Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:19])=[O:22]
Reactant: CCOCC
Reactant: Cc1ccccc1[Mg]Br
Reactant: Cc1cccc(C#N)c1Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1cccc(C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-3-methylbenzonitrile (0.40 g, 2.04 mmol) in THF (2.04 mL) under inert atmosphere was cooled to 0° C. in an ice-water bath. A solution of o-tolylmagnesium bromide, ˜2M in Et2O (1.22 mL, 2.45 mmol) was added dropwise via syringe. On completion of addition reaction mixture was allowed to warm to ambient temperature and then heated to 50° C. for 3 h. 2 mL of 2N aq. HCl was added carefully, the heating element was turned off and the reaction mixture allowed to be cooled to ambient temperature and stirred overnight. Then the reaction mixture was diluted with water (75 mL) and extracted with EtOAc (1×75 mL). The organic extract was washed with water (75 mL), saturated aqueous sodium bicarbonate (75 mL), and brine (75 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude material was purified by column chromatography eluting with a gradient of 5-50% Et2O in hexane, to provide (2-bromo-3-methylphenyl)(o-tolyl)methanone as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[Cl-].[Na+]>C(O)CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:4]=2[C:3]=1[NH:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(Br)cnc21
Reactant: NC1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(Br)cnc21
Temperature: 25 °C
Yield: 80 %

Procedure:
5-Bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.415 mmol) and cyclohexylamine (1 mL, 9 mmol) in ethylene glycol (1 mL) were stirred at 200° C. for 2 hour under microwave irradiation. The reaction mixture was allowed to cool to room temperature and, after addition of saturated aqueous sodium chloride, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 (v/v)) to give the title compound as an orange oil (141 mg, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:44][C:45]1[S:46][C:47]([CH3:51])=[C:48]([CH3:50])[N:49]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:35]([NH:44][C:45]2[S:46][C:47]([CH3:51])=[C:48]([CH3:50])[N:49]=2)=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(N)sc1C
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nc(C)c(C)s4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.8 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added thereto, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-4,5-dimethylthiazole hydrochloride (55 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 29 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][CH2:13][OH:14].CCN(CC)CC.[Cl:22][C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][CH2:13][O:14][C:23]([Cl:22])=[O:24]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1CCO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 94.3 %

Procedure:
For 5 min, a solution of 2-(2,4-dichloro-6-nitrophenyl)ethanol (500 mg, 2.12 mmol) and Et3N (214 mg, 2.12 mmol, dist. over KOH) in THF (5 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (503 mg, 2.5 mmol) in THF (5 ml, see above). It was stirred for 1 h while being cooled in an ice bath and stirred for 2 h at room temperature. The mixture was then filtered over Celite. Rewashing the filter cake with THF and removing the solvent and excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2,4-dichloro-6-nitrophenyl)ethoxycarbonyl chloride (597 mg, 94%) as a bright yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24]Cl.O>CN(C)C=O>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][C:12]([F:13])([F:14])[F:15]
Reactant: COCCl
Reactant: CC(=O)c1ccc(O)c(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C(C)=O)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-hydroxy-3-trifluoromethoxyphenyl)ethanone (1.55 g) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.46 g) and chloromethyl methyl ether (0.64 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.54 g) as a colorless oily substance.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]([O:12]C)=[O:11])=[CH:8][N:7]=[C:6]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:24][C:25]([NH:28][CH:29]([CH3:31])[CH3:30])=[N:26][N:27]=5)[CH:21]=4)[N:16]([S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[CH:15]=3)[N:5]=2)[CH2:3][CH2:2]1.C1COCC1.O.[OH-].[Li+].Cl>O>[CH:1]1([C:4]2[C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=[C:6]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:24][C:25]([NH:28][CH:29]([CH3:31])[CH3:30])=[N:26][N:27]=5)[CH:21]=4)[N:16]([S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:33])=[O:34])[CH:15]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)nc1C1CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(C(=O)O)c(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 4-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-5-carboxylate (110 mg, 0.192 mmol) was treated with THF (2 mL), water (1.0 mL) and lithium hydroxide monohydrate (20 mg, 0.48 mmol) and stirred at RT for 1.5 h. The reaction mixture was treated with a 5 N HCl (0.5 mL) and concentrated on the rotovap. It was then dried further by azeotroping with toluene and drying under high vacuum at 50° C. for 3 h. MS (ESI, pos. ion) m/z: 559.0 (M+H)+. It was then used in the subsequent step with further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl.[NH2:21][OH:22].CCN(CC)CC>CCO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:21][OH:22])=[NH:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: NO
Reactant: N#Cc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 80 °C

Procedure:
To a 25 ml rbf was added 0.100 g (0.347 mmol) of 2-(2,6-Dichloro-phenyl)-3H-benzoimidazole-5-carbonitrile, 2 mL of EtOH, 0.0482 g (0.694 mmol) of hydroxylamine HCl, and 0.048 mL (0.694 mmol) of Et3N. It was allowed stir at 80° C., under reflux, for 4 h. It was reduced in vacuo and the crude was used directly in the next reaction. MS (m/z) 321.1 M (+1), tR=0.93, Meth 10
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][Br:7])(=[O:3])[CH3:2].[CH2:8]([N:22]([CH3:24])[CH3:23])[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]>CC(CC)=O>[Br-:7].[CH2:8]([N+:22]([CH3:24])([CH3:23])[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[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: CCCCCCCCCCCCCCN(C)C
Reactant: CC(=O)OCCBr
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCC[N+](C)(C)CCOC(C)=O
Product: [Br-]
Temperature: 90 °C
Reaction time: 7 h

Procedure:
In a reaction vessel was placed 42.8 grams of 2-bromoethyl acetate, 58.9 grams of tetradecyldimethylamine and 107.6 grams of methylethyl ketone (MEK) solvent. The mixtures was refluxed (ca. 90° C.) under nitrogen with stirring for 7 hours. The reaction mixture was cooled and the solvent decanted leaving as the product tetradecyldimethyl 2-acetyloxyethylammonium bromide.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]=[CH2:8])=[CH:3]1.[CH:9]([C:12]([CH3:22])([N:15]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]1=[O:21])[C:13]#[N:14])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[CH:9]([C:12]([CH3:22])([N:15]1[C:19](=[O:20])[CH:18]2[CH2:8][CH2:7][CH:4]3[CH2:5][CH2:6][N:2]([CH3:1])[C:3]3=[C:17]2[C:16]1=[O:21])[C:13]#[N:14])([CH3:11])[CH3:10]
Reactant: C=Cc1ccn(C)c1
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Solvent: ClC(Cl)Cl
Product: CC(C)C(C)(C#N)N1C(=O)C2=C3C(CCC2C1=O)CCN3C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A mixture of 1-methyl-3-vinylpyrrole (9.50 g, 0.089 mol), α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (17.0 g, 0.089 mol) and chloroform is stirred overnight at room temperature and concentrated in vacuo to an amber oil residue. The residue is flash chromatographed (silica gel, gradient elution: 50% hexanes: methylene chloride to ether) to afford the title product as an orange glass (13.0 g, 48.8%), identified by 1HNMR spectroscopy.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[ClH:1].[ClH:1].[N:16]1([CH2:2][CH:3]2[O:8][CH2:7][CH2:6][NH:5][CH2:4]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: C1CCNCC1
Product: C1CCN(CC2CNCCO2)CC1
Product: Cl

Procedure:
By the use of 2-chloromethyl-4-benzylmorpholine and piperidine, the reaction is similarly carried out as Reference example 2 to give 2-(piperidinomethyl)morpholine dihydrochloride as white crystals, melting at 172°-174° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:3]=12.[CH3:20][Si:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][O:24][CH:25](Cl)Cl.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:29])([CH3:28])[CH3:20])[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:3]=12
Reactant: C[Si](C)(C)CCOC(Cl)Cl
Reactant: CSc1nc(Cl)c2c(-c3ccccc3Cl)n[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2c(-c3ccccc3Cl)nn(COCC[Si](C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of 4-chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (2.30 g, 7.39 mmol) and 2-(trimethylsilyl)-ethoxymethylene chloride (1.96 mL, 11.086 mmol) in dry DMF (40 mL) at 0° C. under nitrogen was added sodium hydride (0.354 g of 60% solids in mineral oil, 14.78 mmol). The reaction mixture was stirred for two hours and allowed to warm to room temperature during this time. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separate, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (01% to 20% EtOAc in hexanes) to give 2.30 g of 4-chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl>CCO>[ClH:19].[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: Clc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c(Cl)c1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,4-dichlorobenzyl chloride (0.218 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 287 mg of the product 199. 1H NMR (DMSO-d6) δ 11.38 (s, 2H), 7.95-7.75 (m, 2H), 7.65-7.50 (m, 1H), 7.20-7.00 (m, 6H), 7.00-6.80 (m, 4H), 5.83 (s, 2H), 4.90 (s, 2H); MS: m/z 413 (M++1).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1)#[CH:9].[C:17]([N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=[O:31])[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C1(C)C=CC=CC=1.O.FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O>[OH:31][CH:30]([CH:27]1[CH2:28][CH2:29][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:25][CH2:26]1)[C:9]#[C:8][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C#Cc1cccc(C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(C#CC(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of zinc trifluoromethanesulfonate (0.07 g, 0.19 mmol) and triethylamine (0.065 mL, 0.47 mmol) in anhydrous toluene (5 mL) was stirred at room temperature under nitrogen atmosphere. After 1 h, 2-ethynyl-6-methyl-pyridine (0.13 g, 1.13 mmol) prepared as described in WO200544267 was added and after 15 min was dropped a solution of 1-Boc-4-piperidinecarboxaldehyde (0.2 g, 0.938 mmol) in toluene (1 mL): the resulting mixture was heated at 100° C. for 6 h. Afterwards, it was cooled to r.t., diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to give a crude, which was purified twice by automated flash liquid chromatography (Horizon™-Biotage) eluting with CHCl3-MeOH 98-2 affording the title product (0.13 g) as a brown oil.
Reaction SMILES: C(OC(N([CH2:13][C:14]([NH:16][C:17]1([C:31](OCC)=[O:32])[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[CH2:18]1)=[O:15])C)=O)C1C=CC=CC=1.[CH2:36](O)[CH3:37]>[Pd].[C]>[CH3:28][O:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:29][CH3:30])[CH2:18][C:17]1([C:31](=[O:32])[CH:36]([CH3:37])[CH2:13][C:14](=[O:15])[NH:16]1)[CH2:26][CH2:25]2
Reactant: CCO
Reactant: CCOC(=O)C1(NC(=O)CN(C)C(=O)OCc2ccccc2)CCc2cc(OC)c(OC)cc2C1
Agent: [Pd]
Product: COc1cc2c(cc1OC)CC1(CC2)NC(=O)CC(C)C1=O
Temperature: 80 °C

Procedure:
A solution of ethyl 2-[(N-benzyloxycarbonyl-N-methylamino)acetylamino]-1,2,3,4-tetrahydro-6,7-dimethoxynaphthalene-2-carboxylate (550 mg, 1.1 mmol) in ethanol (20 ml) was hydrogenated in the presence of 10% Pd-carbon (250 mg) for 6 hr. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in 1N sodium hydroxide (2 ml) and THF (10 ml) and heated at 80° C. for 17 hr. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with water, and sat. sodium chloride, dried, and concentrated in vacuo. The residue was recrystallized from chloroform-isopropylether to give the titled compound (150 mg).