Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([O:16][CH3:17])=[O:15])[NH:2]1.C(N(CC)CC)C.[C:25](=[S:27])=[S:26].[CH3:28]I>CO>[CH3:28][S:26][C:25]([N:2]1[CH:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:27]
Reactant: S=C=S
Reactant: CI
Reactant: COC(=O)C1Cc2c([nH]c3ccccc23)CN1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=S)SC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.6 %

Procedure:
Methyl (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2.30 g) is dissolved in methanol (50 ml) and thereto are added triethylamine (1.21 g) and carbon disulfide (920 mg). The mixture is stirred at room temperature for 20 minutes and thereto is added dropwise methyl iodide (1.70 g). The mixture is stirred for 4 hours and distilled under reduced pressure to remove the solvent. The residue is dissolved in ethyl acetate, and the mixture is washed with water, dried and distilled to remove the solvent. The residue is recrystallized from ether-n-hexane to give the title compound (2.10 g, 65.6%) as colorless needles, m.p. 132°-134° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([S:17]([CH:20]=[CH2:21])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CCN(C(C)C)C(C)C>C(#N)C.ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]1([S:17](/[CH:20]=[CH:21]/[C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(/C=C/c1ccc2[nH]ccc2c1)c1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 5-bromoindole (5.0 g, 25.5 mmol), phenylvinylsulfone (7.50 g, 44.64 mmol), Pd(OAc)2 (0.46 g, 2.05 mmol), tri-O-tolylphosphine (1.55 g, 5.10 mmol) and DIPEA (3.6 g) was heated to reflux for 18 h in acetonitrile. The reaction mixture was cooled to RT, diluted with dichloromethane and filtered over a bed of filter aid. The solvent is completely distilled off and to the crude fresh dichloromethane was charged. The filtrate was sequentially washed with water and brine, and dried over sodium sulphate. The organic layer was concentrated under vacuum and the product precipitated from ethylacetate and hexane as a solid in about 65-70% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].ClCCl>O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)(C)c1ccc(CCO)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)c1ccc(CCOS(C)(=O)=O)cc1
Yield: 109.3 %

Procedure:
In a reaction vessel, 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid ethylester (2.2 g) prepared in the Example 4, triethylamine (1.2 g), methanesulfonylchloride (1.25 g) and dichloromethane (20 mL) were introduced, and the mixture was reacted at room temperature for 2 hours. Distilled water (50 mL) was added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated with Na2SO4, and then condensed by filtration to obtain 2-[4-(2-methanesulfonyloxy-ethyl)-phenyl]-2-methyl-propionic acid ethylester (3.2 g, yield 100%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH2:9]O)[N:5]=[CH:4]1)[CH3:2].S(Cl)([Cl:13])=O>ClCCl>[ClH:13].[Cl:13][CH2:9][C:6]1[N:5]=[CH:4][N:3]([CH2:1][CH3:2])[C:7]=1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCn1cnc(CO)c1C
Solvent: ClCCl
Product: CCn1cnc(CCl)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of (1-ethyl-5-methyl-1H-imidazol-4-yl)methanol (340 mg, 2.4 mmol) in anhydrous dichloromethane (20 mL) was added thionyl chloride (900 μL). The mixture was stirred at room temperature for 4 hours. Dichloromethane was evaporated, and the mixture was then co-evaporated with toluene (20 mL). The residue was dried in vacuo, affording 4-(chloromethyl)-1-ethyl-5-methyl-1H-imidazole hydrochloride (450 mg, 96% yield). The product was used without further purification.
Reaction SMILES: [Na].ClC1N=NN=C(Cl)C=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1.[CH2:21]([OH:23])[CH3:22]>>[Cl:10][C:11]1[N:16]=[C:15]([O:23][CH2:21][CH3:22])[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: CN(C)c1nc(Cl)nc(Cl)n1
Reactant: CCO
Agent: Clc1cc(Cl)nnn1
Agent: [Na]
Product: CCOc1nc(Cl)nc(N(C)C)n1
Temperature: 0 °C

Procedure:
A solution of sodium (0.46 g.) in ethanol (50 ml.) was added with stirring and waterbath cooling (25° C) to a solution of the dichlorotriazine (3.86 g.) from (a) in ethanol (50 ml.). Following the addition the solution was poured into ice water (250 ml.) and the product collected, dried and crystallised from petroleum as needles (2.5 g.) having a melting point of 124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH2:27][CH3:28])=[CH:25][CH3:26])[C:5]2=[CH:4][CH:3]=1.[CH3:30][O:31][CH:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])[CH3:33].[C:38]([O:42][C:43](=[O:46])[CH2:44]Br)([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:38]([O:42][C:43]([CH2:44][N:12]1[C:13](=[O:23])[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:29])[CH:11]1[C:24]([CH2:27][CH3:28])=[CH:25][CH3:26])=[O:46])([CH3:41])([CH3:40])[CH3:39].[CH3:30][O:31][CH:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])[CH3:33]
Reactant: CC=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC=C(CC)C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 37 %

Procedure:
In a manner similar to the method described in example 55c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.6 g, 2.8 mmol) prepared in example 81a was reacted with bromo-acetic acid tert-butyl ester and cesium carbonate in N,N-dimethylformamide to give racemic (2′R,3R,4′S)-1′-[(tert-butoxycarbonyl)methyl]-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield 0.7 g, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:19]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1)(=[O:21])[CH3:20]
Reactant: O=C(NCCc1ccccc1)c1ccc(Br)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(CCNC(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
To a solution of 4-bromo-N-(2-phenylethyl)benzamide (10.0 g, 32.9 mmol) and acetyl chloride (3.04 ml, 42.7 mmol) in dichloromethane (80 ml) was added aluminum chloride (11.0 g, 82.2 mmol), and the mixture was stirred at room temperature for one day. The reaction mixture was poured into ice, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was powderized with isopropyl ether to give the title compound (9.79 g).
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH:14]=[CH2:15])[CH3:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:28]1[CH:37]=[N:36][C:31]2=[N:32][CH:33]=[CH:34][N:35]=[C:30]2[CH:29]=1>O1CCCC1.C1C=CC=CC=1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][CH2:15][C:28]1[CH:37]=[N:36][C:31]2=[N:32][CH:33]=[CH:34][N:35]=[C:30]2[CH:29]=1)[CH3:11]
Reactant: Brc1cnc2nccnc2c1
Reactant: C=CC(OCC)OCC
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCOC(CCc1cnc2nccnc2c1)OCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 9-BBN (10.2 mL of a 0.5M solution in tetrahydrofuran) at 0° C. was added dropwise 0.77 mL of acrolein diethyl acetal and the mixture allowed to warm slowly to room temperature. After 15 hours, the mixture was diluted with 12 mL dry tetrahydrofuran followed by the sequential addition of potassium phosphate (1.6 g), palladium(1,1'-bis(diphenylphosphino)ferrocenyl) dichloride (160 mg) and 7-bromo-pyrido[2,3-b]pyrazine (924 mg) and then heated to reflux on an oil bath. After 5 hours, the mixture was cooled to 0° C., diluted with 15 mL benzene and the excess reagents quenched by the addition of 2N sodium hydroxide (3.5 mL) and 30% hydrogen peroxide (2.5 mL). The mixture then extracted with ethyl acetate, washed with brine and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:4; then 1:1; then 4:1) to give the title compound (1.2 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]4[O:41][C:40]5=[N:42][C:43]([N+:45]([O-:47])=[O:46])=[CH:44][N:39]5[CH2:38][CH2:37]4)=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[CH2:17][CH2:16]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[N+:45]([C:43]1[N:42]=[C:40]2[N:39]([CH:44]=1)[CH2:38][CH2:37][CH:36]([CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH2:21][CH:18]4[CH2:19][CH2:20][N:15]([CH2:13][C:18]5[CH:19]=[CH:20][C:3]([C:2]([F:7])([F:6])[F:1])=[CH:16][CH:17]=5)[CH2:16][CH2:17]4)[CH2:27][CH2:26]3)=[CH:29][CH:30]=1)[O:41]2)([O-:47])=[O:46]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(c3ccc(OCC4CCn5cc([N+](=O)[O-])nc5O4)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(N3CCN(CC4CCN(Cc5ccc(C(F)(F)F)cc5)CC4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a methylene chloride solution (1.5 ml) of 4-{4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}piperidine-1-carboxylic acid tert-butyl ester (300 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, methylene chloride (1.5 ml) and triethylamine (1.5 ml) were added to the residue, and the result was stirred at room temperature for 5 minutes. After concentrating the reaction mixture under reduced pressure, methanol (3 ml), 4-(trifluoromethyl)benzaldehyde (130 mg), sodium cyanoborohydride (160 mg) and acetic acid (1 ml) were added to the residue in this order, and the mixture was stirred at room temperature overnight. The resulting reaction mixture was added to a potassium carbonate aqueous solution, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride:methanol=1:0→methylene chloride:methanol=9:1) and recrystallized from methanol to afford the title compound as a pale yellow powder (50 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[H][H]>CO.C(Cl)Cl.[Ni]>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)cc1
Reaction time: 4 h
Yield: 88.1 %

Procedure:
4-[1-(3-Nitro-2-pyridyl)piperazin-4-yl-carbonyl]benzoic acid methyl ester (5 g) was dissolved in a co-solvent of methanol (80 ml) and methylene chloride (60 ml) in a pressurized reactor. With the addition of about 1 g of Raney-nickel (50% slurry in water), the reaction mixture was filled with hydrogen gas and stirred at 50~60 psi for 4 hours. After completion of the reaction, reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure. The concentrated residue was treated with hexane and ether for crystallization, filtered, washed and dried to give 4.05 g (yield: 88%) of the desired compound.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>C(Cl)Cl.C1(C)C=CC=CC=1>[ClH:18].[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(OCC(F)(F)F)ccnc1CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1c(OCC(F)(F)F)ccnc1CCl
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
160 ml of toluene were added to 14.9 g (0.067 mole) of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine in methylene chloride followed by distillation of methylene chloride. The solution was purified with 2.7 g of activated charcoal, filtered and washed with 36 ml of toluene. To this solution 5.4 ml (0.075 mole) of thionyl chloride in 27 ml of toluene were added dropwise and maintained for 3 hours. The gas was removed under vacuum at room temperature, then the resulting mixture was cooled to a temperature of from 0 to 5° C. and stirred for one hour. The product was filtered, washed with 3 ml of toluene and dried in a vacuum dryer at 35-40° C. The yield was 15.65 g (84%).
Reaction SMILES: [CH3:1][C:2]([NH:9][S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11])([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OC)=[C:18](I)[CH:17]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:2]([NH:9][S:10](/[CH:13]=[CH:14]/[C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)(=[O:12])=[O:11])([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: COc1ccc(Cl)cc1I
Reactant: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1ccc(Cl)cc1
Temperature: 140 °C
Yield: 45.9 %

Procedure:
Ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (8.5 g, 38.8 mmol) and 4-chloroiodoanisole (7.87 g, 33.0 mmol) was dissolved in N,N-dimethylformamide (65 ml). Palladium acetate (139 mg, 0.62 mmol) and triphenylphosphine (357 mg, 1.36 mmol) was added to the reaction followed by triethylamine (12.5 ml, 89.3 mmol). The reaction was flushed with nitrogen and heated at 140° C. for 16 hours. The reaction was cooled to room temperature and quenched with 1N HCl (250 ml). The aqueous solution was extracted with ethyl acetate (3×200 ml). The organic solution was dried over MgSO4, filtered and concentrated in vacuo to afford a solid. The solid was dissolved in dichloromethane and purified by dry flash chromatography (SiO2, heptane to 1:1 heptane: ethyl acetate). The fractions were combined to afford (E)-2-(4-chloro-phenyl)-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (5.0 g, 46% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li]CCCC.[CH:19]([N:22]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:23](=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[C:26]([O:32][CH3:33])[CH:25]=1)([CH3:21])[CH3:20].OS([O-])(=O)=O.[K+]>C(OCC)C.C1COCC1>[CH:35]1([N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([OH:31])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[C:26]([O:32][CH3:33])[CH:25]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1C=O
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1C(O)c1cc(OC)c(OC)c(OC)c1
Temperature: -8 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cold (-15°) solution of 3,4,5-trimethoxybromobenzene (965 mg, 3.9 mmol) in ethyl ether (15 ml) is added n-BuLi (3 ml of 1.6 M solution in hexane). The reaction mixture is stirred at -8° C. for 10 min., diluted with THF (5 ml) and warmed to 0° C. After stirring for 5 min., the reaction is cooled to -30° C. and a solution of 4-formyl-3-methoxybenzoic acid N-isopropyl-N-cyclohexyl amide (1.18 g, 3.9 mmol) in THF (5 ml) is added. After stirring at -30° C. for 10 min. and warming to room temperature, the reaction is poured onto 0.5 N KHSO4 and extracted with ethyl acetate. The organic layer is washed with saturated NaCl solution and dried (MgSO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([OH:17])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:39]=[C:40]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)[CH2:41][NH:42][C:43](=[O:57])[C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:46][CH:45]=1>CN(C=O)C.O>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([N:61]1[CH2:62][CH2:63][N:58]([C:40](=[O:39])[CH2:41][NH:42][C:43](=[O:57])[C:44]2[CH:45]=[CH:46][C:47]([O:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)=[CH:48][CH:49]=2)[CH2:59][CH2:60]1)=[O:17]
Reactant: O=C(O)c1ccco1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccco2)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
DIPEA (0.091 mL, 0.53 mmol) was added drop wise to furan-2-carboxylic acid (23 mg, 0.21 mmol) in DMF (5 mL). EDCI (84 mg, 0.44 mmol) and HOBT (28 mg, 0.21 mmol) were added consecutively and, after 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide (60 mg, 0.18 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the resulting solid was filtered under reduced pressure to afford N-{2-[4-(furan-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide in 65% yield. LC-MS purity: 92%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 8 (t, 3H), 7.4 (t, 2H), 7.2 (t, 1H), 7 (m, 4H), 6.6 (s, 1H), 4.2 (d, 2H), 3.6 (m, 8H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9])(=[O:20])[CH:18]=[CH2:19]
Reactant: Cc1ncsc1CCO
Reactant: C=CC(=O)Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(=O)OCCc1scnc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 100 g of 5-(2-hydroxyethyl)-4-methylthiazole (0.70 mol.), 71 g of triethylamine (0.70 mol.), 500 g of chloroform and 3 g of phenothiazine. Next, 63 g of acryloyl chloride (0.70 mol.) was slowly added to the reaction over 1.5 hour via the addition funnel. The reaction was stirred for 2 hours at room temperature. The reaction mixture was extracted with NaCl(aq.), NH4OH(10%), NaCl(aq.) and dried over MgSO4. The chloroform was evaporated with a rotoevaporator to yield 113 g (82%) of a dark brown liquid. The product was confirmed by IR and 13C NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1.[CH2:20]=O.Cl>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH3:20])=[CH:18][CH:19]=1
Reactant: Clc1ccc(OCCNCCCn2ccnc2)cc1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CN(CCCn1ccnc1)CCOc1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
N-[2-(4-Chlorophenoxy)ethyl]-3-(imidazol-1-yl) propylamine (1.50 g) was added dropwise to 98% formic acid (1.0 ml) at 0° C. Formaldehyde (0.96 ml of a 37% aqueous solution) was added and the mixture heated at 95° C. for 6 hours. On cooling, concentrated hydrochloric acid (0.6 ml) was added. The mixture was evaporated to dryness and the residue dissolved in water, basified with 5M sodium hydroxide solution and extracted with ethyl acetate to give N-[2-(4-chlorophenoxy)ethyl]-3-(imidazol-1-yl)-N-methylpropylamine as an oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]=[C:25]=[S:26].CCOCC>C1COCC1>[CH3:23][NH:24][C:25]([NH:19][NH:18][C:16](=[S:17])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:26]
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN=C=S
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNC(=S)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 8 h

Procedure:
1.62 g (5 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydrazine carbothioamide are dissolved in 30 ml of THF, 0.44 g (6 mmol) of methyl isothiocyanate are added, and the reaction mixture is left to stand overnight at room temperature. Ether is added to complete precipitation and the precipitate formed is suction filtered, washed with ether and recrystallised from ethanol. The analytical values are summarized in Table I.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=2)[CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)#[CH:18]>>[Cl:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[N:10]=3)[CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: Brc1cnc2nc(N3CCOCC3)nn2c1
Product: Clc1cccc(C#Cc2cnc3nc(N4CCOCC4)nn3c2)c1

Procedure:
The title compound, a light brown solid, MS: m/e=340.0/342.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, step 1) and ethynyl-3-chlorobenzene.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])C1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:13]([O:12][CH2:11][C@H:10]([CH2:9][OH:8])[O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCOC[C@H](COCc1ccccc1)OCCCCCCCCCCCCCCCCCCCCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCCCOC[C@H](CO)OCCCCCCCCCCCCCCCCCCCCCCCC
Yield: 60.8 %

Procedure:
3-O-Benzyl-1,2-di-O-tetracosyl-Sn-glycerol (1.47 g) was reacted in a mixture (30 ml) of toluene-ethyl acetate (1:1) by the general procedure according to 15-B to obtain the title compound (0.80 g, 66%) as white solid.