Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:21]([O:23]CC)=[O:22])[CH2:10][CH2:9][N:8]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])[CH3:2].O.C(OCC)(=O)C.Cl>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1([C:21]([OH:23])=[O:22])[CH2:10][CH2:9][N:8]([C:11](=[O:20])[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCN(C(=O)c2ccc(OC)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)O)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 30 °C
Reaction time: 144 h
Yield: 53.4 %

Procedure:
1-(4-Methoxy-benzoyl)-pyrrolidine-3,3-dicarboxylic acid diethyl ester (679.9 g, 1.95 mol) (see Preparation 7) in acetonitrile (1000 mL) was added to pH 7 buffer solution (10 L, 0.1M potassium phosphate) then Savinase 16T Type W enzyme (3200 g) was added and the resulting slurry was heated to 30° C. The pH of the reaction mixture was kept at 8.5 using a pH stat (TIM856 Titration Manager) and stirred for 6 days. Water (6 L) and ethyl acetate (12 L) was added to the reaction mixture then acidified to pH1 using 2M HCl aqueous solution (6 L). This was filtered through Arbocel™ and the organic layer was separated, washed with water (5 L) then extracted with 0.5M NaOH aqueous solution (7 L). The aqueous phase was acidified using 2M HCl aqueous solution (5 L) and extracted with ethyl acetate (6.5 L). The organic phase was concentrated under reduced pressure to afford the title compound as an orange oil (334.3 g, 53%). (92.9:7.1 ratio of isomers)
Reaction SMILES: [Cl:1]Cl.[C:3]([NH:7][N:8]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C>CCCCC>[C:3]([N:7]=[N:8][C:9]([Cl:1])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])([CH3:4])([CH3:5])[CH3:6]
Reactant: ClCl
Reactant: CC(=NNC(C)(C)C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C)(C)N=NC(C)(Cl)c1ccccc1

Procedure:
1-t-Butylazo-1-chloro-1-phenylethane was prepared in 99% crude yield by adding 34.8 grams (0.49 moles) of chlorine to a pentane solution of 92.8 grams (0.49 moles) of acetophenone t-butylhydrazone and 50.5 grams (0.50 moles) of triethylamine at 0° C., filtering off the insoluble triethylamine hydrochloride that forms and evaporating the pentane under reduced pressure. The yield was 109 grams of a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:14])[O:13]CCO2)=[CH:5][C:3]=1[NH2:4].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N([CH2:29][CH3:30])C(C)C)(C)C>C(OCC)(=O)C.CCCCCC>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:4]([CH2:16][C:17]([O:19][CH2:29][CH3:30])=[O:18])[C:3]1[CH:5]=[C:6]([C:9](=[O:13])[CH3:14])[CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(C2(C)OCCO2)cc1N
Reactant: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(C(C)=O)ccc1C
Temperature: 140 °C
Yield: 99.3 %

Procedure:
The compound (9.87 g, 51.08 mmol) obtained in step A, ethyl bromoacetate (23 ml, 207 mmol) and N,N-diisopropylethylamine (45 ml, 265 mmol) were mixed, and the mixture was stirred with heating at 140° C. for 200 min. The reaction mixture was cooled, diluted with an ethyl acetate-hexane=1:1 mixed solvent, and the organic layer was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (160 ml), 6N aqueous hydrochloric acid solution (25 ml) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture were added water and an ethyl acetate-hexane=1:1 mixed solvent, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (16.30 g, yield 99%) as a yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:9])=[CH:7][CH3:8].[FH:10]>>[CH3:8][CH:7]([N+:1]([O-:4])=[O:2])[C:6]([F:10])([F:9])[F:5]
Reactant: CC=C(F)F
Reactant: O=[N+]([O-])O
Reactant: F
Product: CC([N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
1400 ml of hydrogen fluoride (anhydrous) and 320 g of nitric acid (concentrated) were initially introduced into a stirred steel autoclave and cooled to -30° to -40° C. 390 g (5 mol) of 1,1-difluoropropene were passed in at this temperature. The reaction mixture was allowed to warm up to room temperature, was further stirred for 6 hours, and was then poured onto 2 kg of ice. The aqueous phase was extracted three times with 250 ml of dichloromethane and the combined organic phases were washed neutral with NaHCO3 solution and water, dried with MgSO4 and distilled. After the solvent and first runnings (25 g; boiling range: 43°-98° C.) had been separated off, 615 g (=86% of theory) of 1-methyl-2,2,2-trifluoronitroethane [=1-(trifluoromethyl)nitroethane] were obtained; boiling point 98° to 100° C.; nD20 : 1.3380. ##STR17##
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[C:7](SC)[N:6]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.ClCCl.C(=O)([O-])O.[Na+].[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1.C(Cl)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl.ClCCl>[C:11]([C:10]1[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][C:7]([NH:42][CH2:41][CH2:40][C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[N:8][CH:9]=1)#[N:12]
Reactant: CCCNc1nc(SC)ncc1C#N
Reactant: NCCc1ccncc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Product: CCCNc1nc(NCCc2ccncc2)ncc1C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 40 mL of dichloromethane, 4-n-propylamino-5-cyano-2-methylthiopyrimidine obtained in Step 1 was dissolved, then mCPBA-dichloromethane solution (0.50 mol/L, 25 mL, 12.5 mmol) was added thereto over 5 minutes, followed by stirring at room temperature for 2 hours. The reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then the solvent evaporated under reduced pressure. The residue was dissolved in THF (40 mL), then 2-(4-pyridyl)ethylamine (1.47 g, 12.0 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction was confirmed by thin-layer chromatography, chloroform (80 mL), benzoylchloride polymer bound [about 2.5 mmol/g, 4.6 g, Canadian Journal of Chemistry, Vol. 55, p. 3351 (1977)] and poly(4-vinylpyridine) (4.6 g) were added thereto, followed by further stirring at room temperature for 12 hours. After resins in the reaction mixture were filtered out, the filtrate was concentrated to give 5-cyano-4-n-propylamino-2-[2-(4-pyridyl)ethylamino]pyrimidine [Compound (Y) in which R1 is n-propylamino and R1 is 2-(4-pyridyl)ethylamino].
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](O)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:24])=O>O>[Cl:24][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CCOc1cccnc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)c1ccccc1
Product: CCOc1cccnc1Cl
Temperature: 150 °C
Yield: 70.5 %

Procedure:
A mixture of 3-ethoxy-pyridin-2-ol (4.0 g, 28.8 mmol, 1.0 equiv), N,N-diethylaniline (4.61 mL, 4.29 g, 28.8 mmol, 1.0 equiv) and phosphorus oxychloride (2.62 mL, 4.41 g, 28.8 mmol, 1.0 equiv) was heated to 150° C. under microwave irradiation for 20 min. The crude reaction mixture was poured into water (100 mL), the solution adjusted to pH 7 and extracted with dichloromethane (3×100 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (4:1) providing 3.2 g (71%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J=7.0 Hz, 3H), 4.12 (q, J=7.0 Hz, 2H), 7.18 (d, J=3.2 Hz, 2H), 7.98 (t, J=3.2 Hz, 1H). MS (ISP): 157.7 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:15]N>>[CH3:15][NH:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C:2](=[O:1])[CH3:14])=[CH:9][CH:8]=1)(=[O:11])=[O:12]
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Reactant: CN
Product: CNS(=O)(=O)c1ccc(CC(C)=O)cc1

Procedure:
4-(2-Oxo-propyl)-benzenesulfonyl chloride (prepared as described in European patent specification EP 91749 A2) (0.087 g, 4.1 mmol) was treated with methylamine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:17]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:18])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(Cl)cc1)C1CCCCC1
Reaction time: 1.5 h

Procedure:
[2-(4-chlorophenyl)ethyl]amine (3.5 g) was dissolved in a 1:2 mixed solution (45 mL) of EtOAc-saturated aqueous sodium bicarbonate. A solution of cyclohexanecarbonyl chloride (3.35 mL) in EtOAc (18 mL) was added dropwise to the reaction liquid over 5 minutes. After stirring for 1.5 hours, the reaction liquid was extracted with EtOAc, washed with an aqueous 1 M sodium hydroxide solution and water, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dried to obtain N-[2-(4-chlorophenyl)ethyl]cyclohexanecarboxamide (5.69 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)=[CH:4][CH:3]=1.[C:22]([N:29]1[CH:33]=[CH:32]N=[CH:30]1)(N1C=CN=C1)=[O:23].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2CCNC[CH2:42]2)=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:42][CH2:30][N:29]([C:22]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]4)=[CH:4][CH:3]=3)=[O:23])[CH2:33][CH2:32]2)=[CH:37][CH:36]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(N)cc2)C1
Product: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1

Procedure:
tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate was reacted with carbonyldiimidazole and then with 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 513.09 (C28H37CIN4O3); MS (ESI): 513 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9](C(=O)C)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][CH:17](OC)[O:18][CH3:19].O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:15][O:16][C:17]([C:11]1[S:10][CH:9]=[CH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O:18][CH3:19])[CH3:23]
Reactant: COC(OC)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)c1cc(-c2ccccc2)cs1
Solvent: CO
Solvent: O
Product: COC(C)(OC)c1sccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(4-Phenylthiophen-2-yl)ethanone (1.33 g, 6.57 mmol) was dissolved in MeOH and treated with trimethylorthoformate (1.44 mL, 13.2 mmol) and p-toluenesulfonic acid monohydrate (0.050 g). The resulting solution was stirred at ambient temperature for 16 h at which time the solution was partitioned between Et2O and saturated aqueous NaHCO3 solution. The organic phase was separated and washed with two portions of water and three portions of brine, then dried over Na2SO4 and concentrated in vacuo. The resulting white semi-solid was used without further purification. MS (M+H)+ 249.
Reaction SMILES: C.N[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:11]([O-])=O.[Na+]>O>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[CH2:3])=[CH:6][CH:7]=1
Reactant: NC=Cc1ccccc1
Reactant: O=N[O-]
Agent: C
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc(N)cc1

Procedure:
11.4 g of sodium nitrite, 28.0 g of sulfanilic acid and 1200 g of 0° C. water were fed into a reactor to form diazonium sulfanilate, to which was added 200 g of a carbon black pigment, Raven C. When the generation of nitrogen ceased, the reaction mixture was concentrated, and further reacted at an elevated temperature. The resulting mixture was extracted with ethanol for 12 hours in a Soxhlet's extractor to remove unreacted compounds and side products, and this was again dissolved in water and filtered to obtain a dispersion of about 20 wt. % sulfanilate-processed carbon black pigment. On the other hand, 3.6 g of aminostyrene, 2.1 g of sodium nitrite and 150 g of water were fed into a separate reactor to form a diazonium salt of 4-aminostyrene, and this was dissolved in 10 g of ethanol. The sulfanilate-processed carbon black pigment dispersion was added to the diazonium salt solution and reacted for 18 hours with stirring. Then, this was filtered and purified through Soxhlet extraction to obtain a dispersion of a carbon black pigment having 4-aminostyrene added to its surface. Next, 30 g of deionized water was degassed in a nitrogen atmosphere at 90° C. in a reactor, and a mixture of 28.13 g of the 4-aminostyrene-added carbon black pigment dispersion, 2.0 g of methyl methacrylate, 2.0 g of butyl acrylate, and 1.0 g of polyethylene glycol 2000 monomethyl ether acrylate dissolved in 3.0 g of deionized water was dropwise added thereto over a period of 20 minutes. 0.22 g of potassium persulfate was added thereto and reacted at 80° C. for 18 hours. The resulting product was concentrated under reduced pressure, and extracted with acetone in an Soxhlet's extractor to remove the non-added polymer. The process gave an intended dispersion of a pigment having a polymer group bonded to its surface.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
To a solution of N-(3-nitrophenyl)-3-(trifluoromethyl)benzamide (30.0 g, 96.7 mmol) in tetrahydrofuran (300 mL) was slowly added with heating under reflux, a solution (500 mL) of sodium hydrosulfite (97.8 g, 562 mmol) in water, and the obtained two-layer solution was vigorously stirred with heating under reflux for 2 days. After cooling the reaction solution to room temperature, the aqueous layer was separated, and extracted with ethyl acetate (150 mL×2). The organic layer separated earlier was diluted with ethyl acetate (350 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated brine (100 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated brine (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (17.8 g, 66%) as a pale-brown solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][OH:19]>>[Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][C:13]([C:14](=[N:18][OH:19])[NH2:15])=[CH:16][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)cn1
Reactant: NO
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)cn1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1d) using 6-({[t-butyl(dimethyl)silyl]oxy}methyl)nicotinonitrile (2.0 g, 8.1 mmol) that was obtained in Example 23 (23b) and a 40% aqueous solution of hydroxylamine (1 ml). Subsequently, the crude product of the title compound thus obtained was purified by recrystallization from a mixed solvent of ethyl acetate and hexane (1:9) to afford the title compound (2.1 g) in a yield of 94% as a white crystalline solid.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[C:18]([F:19])=[C:17]([F:20])[C:8]([CH2:9][O:10]C2CCCCO2)=[C:7]([F:21])[C:6]=1[F:22].Cl>CO.O>[Cl:1]/[CH:2]=[CH:3]\[CH2:4][C:5]1[C:6]([F:22])=[C:7]([F:21])[C:8]([CH2:9][OH:10])=[C:17]([F:20])[C:18]=1[F:19]
Reactant: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1CC=CCl
Agent: Cl
Solvent: O
Solvent: CO
Product: OCc1c(F)c(F)c(C/C=C\Cl)c(F)c1F
Reaction time: 2 h

Procedure:
The tetrahydropyranyl ether prepared in stage (ii) was dissolved in methanol (30 cm3), and to the stirred solution was added a catalytic amount of concentrated hydrochloric acid. After stirring for two hours, the reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed and dried, and the solvent evaporated under reduced pressure to give Z-4-(3-chloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyl alcohol (0.6 g) as a colourless oil, which solidified on standing.
Reaction SMILES: [C:1]([NH:9][N:10]([CH2:36][CH2:37][C:38]([O:40]CC1C=CC=CC=1)=[O:39])[C:11]([N:13]1[C@H:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][CH2:15][N:14]1C(OCC1C=CC=CC=1)=O)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[C:1]([NH:9][N:10]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:11]([N:13]1[C@H:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:17][CH2:16][CH2:15][NH:14]1)=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)N1C(=O)N(CCC(=O)OCc1ccccc1)NC(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CCCNN1C(=O)N(CCC(=O)O)NC(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
A solution of 260 (1.59 g, 2.47 mmol) in MeOH (142 ml) was treated with 10% Palladium on carbon (230.0 mg) and stirred under an atmosphere of H2 for 1.5 h. The mixture was filtered and the solvent evaporated to afford 1.04 g (100%) of a white foam. This was used in the next step without further purification: mp<40° C.; [α]D26 +1.6° (c 0.26, CH2Cl2); IR (KBr) 3422, 2977, 2986, 1728, 1677, 1486, 1445, 1396, 1369, 1309, 1228, 1155, 916, 716; 1H NMR (CDCl3) δ 10.0-9.7 (1H, brm), 7.86 (2H, d, J=7.5), 7.62-7.38 (3H, m), 7.3-5.6 (2H, brm), 4.57 (1H, brd, J=4.0), 4.05-3.77 (2H, m) 3.00-2.82 (1H, m), 2.80-2.43 (3H, m), 2.20-2.03 (1H, m), 2.00-1.47 (1H, m), 1.62-1.14 (11H, m); 13C NMR (CDCl3) δ 175.00, 171.17, 167.62, 160.68, 132.39, 131.77, 128.67, 127.38, 82.27, 54.38, 48.04, 46.35, 33.62, 28.02, 25.68, 21.61. MS (ES+) 443 (M+Na, 68%), 421 (M+ +1), 100), 365 (50), 131 (61).
Reaction SMILES: N1C2C(=C(C3N=[C:12]([N:22]4[CH2:27][CH2:26]OCC4)[C:13]4SC(COC)=[CH:16][C:14]=4N=3)C=CC=2)C=N1.[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[C:32]2[S:37][C:36]([CH2:38][OH:39])=[CH:35][C:33]=2[N:34]=1.N1C=CC=CC=1CCl>CN(C=O)C.[H-].[Na+]>[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:32]2[S:37][C:36]([CH2:38][O:39][CH2:26][C:27]3[CH:16]=[CH:14][CH:13]=[CH:12][N:22]=3)=[CH:35][C:33]=2[N:34]=1
Reactant: COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(COCc3ccccn3)cc2n1

Procedure:
Following the procedures for compound 314, (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMF and sodium hydride was alkylated with 2-picolyl chloride to give 4-(2-chloro-6-((pyridin-2-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine. Suzuki coupling of 4-(2-chloro-6-((pyridin-2-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine and 7 was carried out via General Procedure A. Purification using column chromatography gave 317. NMR: CDCl3: 3.80-3.90 (4 H, m, CH2), 4.01-4.08 (4 H, m, CH2), 4.72 (2 H, s, CH2), 4.88 (2 H, s, —CH2), 7.10-7.14 (1H, m, Ar), 7.38 (1 H, s, Ar), 7.40-7.48 (2 H, m, Ar), 7.51 (1 H, d, J 8.23, Ar), 7.65 (1 H, t, J 8.22, Ar), 8.18 (1 H, d, J 7.20, Ar), 8.52 (1 H, d, J 4.60, Ar), 8.96 (1 H, s, Ar) and 10.06 (1 H, s, NH). MS: (ESI+): MH+ 459.17
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH2:12][OH:13])[CH:5]=[CH:4][C:3]1=2.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>C(Cl)Cl>[C:18]([O:17][C:15](=[O:14])[NH:1][CH:2]1[C:3]2[C:8](=[CH:7][C:6]([CH2:12][OH:13])=[CH:5][CH:4]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: NC1CCCc2cc(CO)ccc21
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanol (2.0 g, 11.28 mmol) in CH2Cl2 (20 mL) was added (BOC)2O (2.7 g, 12.41 mmol). The resulting mixture was stirred at RT under N2 gas for 2 h. Reaction mixture was quenched with sat. NH4Cl, the organic layer was isolated and washed with water, brine, dried over MgSO4 and evaporated in vacuo to give the final product. MS m/z: 278.12 (M+H). Calc'd. for C16H23NO3-277.36.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>ClCCl>[CH3:15][CH:14]([CH3:16])[C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[CH3:12])=[O:17]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)C(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (28.0 g, 0.21 mole) was suspended in 200 ml of anhydrous dichloromethane and cooled to 0° C. A solution of m-xylene (21.2 g, 0.2 mole) and isobutyryl chloride (21.3 g, 0.20 mole) in 50 ml of anhydrous dichloromethane was slowly added to this suspension. After the addition was completed, the reaction mixture was stirred at 0° C. for 1 h.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:15]([CH2:20][CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC=CC=1>[CH3:1][N:2]([CH3:14])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:20]([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)=Cc1ccc(N(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Into 250 ml of benzene, 20.0 g (0.10 mol) of 4-dimethylamino-2-nitrobenzaldehyde and 36.2 g (0.10 mol) of carbethoxyethylidene triphenylphosphorane (manufactured by Aldrich Chemical Co., Inc.) were dissolved, and the mixture was stirred at room temperature for one night. The solvent was evaporated under a reduced pressure, whereby 58 g of a crude product were obtained. This product was refined by a column chromatography (aminopropylated silica gel: Fuji Silysia Chem. Co., NH-DM1020), whereby 20.8 g of the aimed compound were obtained as a crystal (yield: 74.7%).