Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:6][N:7]([CH3:14])[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:5][CH2:4]1.[F:15][C:16]([F:46])([F:45])[C:17]1[CH:18]=[C:19]([CH2:27][CH2:28][N:29]([CH3:44])[C:30](=[O:43])[CH:31](OS(C)(=O)=O)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(N(CC)CC)C>CC(C)=O.C(=O)([O-])O.[Na+]>[F:15][C:16]([F:45])([F:46])[C:17]1[CH:18]=[C:19]([CH2:27][CH2:28][N:29]([CH3:44])[C:30](=[O:43])[CH:31]([N:11]2[CH2:12][CH2:13][CH:8]([N:7]([CH2:6][CH:3]3[CH2:4][CH2:5]3)[CH3:14])[CH2:9][CH2:10]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(OS(C)(=O)=O)c1ccccc1
Reactant: CN(CC1CC1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(c1ccccc1)N1CCC(N(C)CC2CC2)CC1
Yield: 37.3 %

Procedure:
11.9 g of 4-(Cyclopropylmethyl-methyl-amino)-piperidine-dihydrochloride are taken up in 400 ml of acetone and combined with 21.7 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide and 21 ml of triethylamine. The mixture is refluxed for 16 hours, then the solvent is eliminated in vacuo and the residue is taken up in 10% sodium hydrogen carbonate solution. It is extracted with ether, the combined organic phases are dried over sodium sulphate and freed from solvent in vacuo. The residue is filtered with ethyl acetate/methanol/conc. ammonia solution 70:30:1 over silica gel, freed from the solvents in vacuo and brought to crystallisation in methanol with fumaric acid. The precipitate is suction filtered, washed with methanol and dried in vacuo. 9.3 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide are obtained as the sesquifumarate.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[CH:7][CH:6]=[N:5]1.[N:10](OCCC(C)C)=[O:11].C(OC(C)C)(C)C.CCCCCC>C(O)C.Cl>[F:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[C:7]([N:10]=[O:11])[CH:6]=[N:5]1
Reactant: Nc1ccnn1CCF
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: CCCCCC
Product: Nc1c(N=O)cnn1CCF
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a solution of 1-(2-fluoroethyl)-1H-pyrazol-5-amine (12 g) in ethanol (30 ml) were added concentrated hydrochloric acid (70 mg) and isoamyl nitrite (10.9 g). The reaction mixture was stirred at 25–38° C. for 2 hours. Diisopropyl ether and hexane were added to the reaction mixture, and the resulting oil was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2→1:1→2:1→1:0) to give-1-(2-fluoroethyl)-4-nitroso-1H-pyrazol-5-amine (4.8 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([NH:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])=[O:25]
Reactant: O=C(Cl)CCl
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)CCl)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a solution of (R)-2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (340 mg, 1.03 mmol) in DCM (10 mL) cooled to 0° C. was added TEA (144 μL, 1.03 mmol) followed by chloroacetylchloride (82 μL, 1.03 mmol). Upon completion of addition, the reaction mixture was held at 0° C. for 4 h. After this time, an additional aliquot of chloroacetyl chloride (60 μL) was added followed by additional TEA (150 μL). The resulting solution was diluted with dichloromethane (40 mL) and quenched by the addition of aqueous NaHCO3 (25 mL). The layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified via SiO2 chromatography (20% to 50% EtOac/heptane) to give (R)-2-chloro-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)acetamide as a clear glassy solid (349 mg, 92% yield). MS found: 371.3 (M+), 373.3 (M+2).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:28][CH3:29])[N:21]=1.C>O1CCOCC1>[F:18][C:2]([F:1])([F:17])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:28][CH3:29])[N:21]=1)=[O:16])(=[O:13])=[O:12]
Reactant: O=C=NS(=O)(=O)c1ccccc1CCC(F)(F)F
Reactant: COc1nc(N)nc(OC)n1
Solvent: C1COCCO1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2CCC(F)(F)F)nc(OC)n1

Procedure:
5.6 g of 2-(3,3,3-trifluoropropyl)-phenylsulfonylisocyanate and 3.12 g of 2-amino-4,6-dimethoxy-1,3,5-triazine are stirred up in 60 ml of absolute dioxane at 70°-80° C. for 2 hours. The mixture is subsequently treated with active charcoal, filtered, and concentrated by evaporation to about 1/5 of the volume. There crystallise from the residue, after the addition of ether, 6.8 g of N-[2-(3,3,3-trifluoropropyl)-phenylsulfonyl]-N'-(4,6-dimethoxy-1,3,5-triazin-2-yl)-urea, m.p. 177°-178° C.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][NH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:16]([CH3:15])[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[O:5]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cccc(C(F)(F)F)c1F
Reaction time: 8 h
Yield: 83 %

Procedure:
2-Fluoro-3-trifluoromethylbenzoyl chloride (92 mg, 0.41 mmol, CAS RN 208173-19-7) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (40 mg, 0.20 mmol, example 1, intermediate a) and DIPEA (70 μL, 0.40 mmol) in THF (1 mL). The reaction mixture was stirred overnight, filtered and all volatiles removed. The resulting oil was purified by flash chromatography on silica gel eluting with 33-50% EtOAc in n-hexane to yield the product as a waxy solid (65 mg, 83%). MS (ESI): m/z=470.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Cc1nnc(-c2cc3c(O)cccc3o2)o1
Product: Cc1nnc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)o1
Yield: 28.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(4-hydroxybenzo(b)furan-2-yl)-5-methyl-1,3,4-oxadiazole (3.3 g) and (S)-glycidyl nosylate (3.7 g), the title compound (1.1 g) was obtained as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl.CCN(CC)CC>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15](=[O:17])[CH3:16])[CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3,3-dimethyl-6-nitroindoline (450 mg) in CH2Cl2 (15 mL) and Et3N (0.6 mL) at −10° C. was added acetyl chloride (180 μL, 2.5 mmol). The mixture was stirred at rt overnight and quenched by addition of sat. aq. NaHCO3, and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by column to give a light yellow solid (390 mg, 71% for two steps).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH:6]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:7][C:8]1[O:12][N:11]=[C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)[CH:9]=1)[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1>O>[CH2:2]([O:4][C:5](=[O:25])[CH:6]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:7][C:8]1[O:12][N:11]=[C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:40]([C:35]2[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=2)(=[O:42])=[O:41])[CH:9]=1)[CH3:3]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)OCC
Reaction time: 8 h
Yield: 36.7 %

Procedure:
2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride(110 mg, 0.294 mmol) and sodium carbonate (93.5 mg, 0.882 mmol) were dissolved in water (1.5 mL) and 3,5-dichlorobenzenesulfonylchloride (86.7 mg, 0.353 mmol) was added. This mixture was stirred overnight. The reaction was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound (59 mg, 37%). MS (CI) m/z 545.7 (M+1)
Reaction SMILES: C(OC(=O)[NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:17]=2)=[CH:11][N:10]=1)=S)C.[Cl-].O[NH3+].C([N:38](CC)C(C)C)(C)C.C(O)C>CO>[NH2:38][C:6]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:17]=3)=[CH:11][N:10]2[N:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(Cl)c(NC(=O)OC(C)(C)C)c2)cn1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)nn3c2)ccc1Cl
Yield: 94.2 %

Procedure:
In the same manner as in Example 23-1 and using ethyl{[(5-{3-[(tert-butoxycarbonyl)amino]-4-chlorophenoxy}pyridin-2-yl)amino]carbonothioyl}carbamate (7.23 g, 15.5 mmol), hydroxylammonium chloride (7.64 g, 0.110 mol), N,N-diisopropylethylamine (13.5 mL, 77.4 mmol), ethanol (50 mL) and methanol (50 mL) as starting materials, the title compound (5.49 g, 92%) was obtained as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.[C:9](=[O:12])([O-])[O-].[K+].[K+].CO>CN(C=O)C.C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:12][C:9]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Ic1ccc(Oc2ccc(I)cc2)cc1
Reaction time: 16 h

Procedure:
The bis-mesylate of PEG-400 (15.3 g, 27.5 mmol) in dry DMF (110 ml) was reacted with 4-iodophenol (12.1 g, 55.0 mmol) and potassium carbonate (7.6 g, 55.0 mmol) at 77° C. under an atmosphere of N2. After stirring for 16 hrs, the reaction was allowed to cool, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up with EtOAc (500 ml), washed with 1 M aqueous sodium hydroxide (200 ml), water (200 ml) and brine (200 ml), dried (Na2SO4), filtered, and evaporated in vacuo to provide a light brown syrup. Flash column chromatography (silica, 1% - 5%; CH3OH in CH2Cl2) provided bis-(4-iodophenyl) ether of polyethylene glycol-400 which was slightly contaminated with unreacted mesylates. The product was further purified by dissolving 10.5 g in DMF (100 ml). Sodium methoxide (400 mg) was added. The reaction flask was immersed in an oil bath and warmed to 93° C. After stirring for 16 hrs, the reaction was allowed to cool, diluted with EtOAc (500 ml), washed with water (200 ml) and brine (200 ml) repeatedly (3 times), dried (Na2SO4), filtered and evaporated in vacuo to provide a light yellow syrup. Flash column chromatography (silica, 5% CH3OH in CH2Cl2) provided bis-(4-iodophenyl) ether of polyethylene glycol-400 as a light yellow syrup (8.3 g). 1H NMR (300 MHz) analysis of the product indicates that the average number of ethylene oxide units is eight (n=8). Title Compound: 1H (300 MHz) and 13C (75 MHz) NMR spectra were consistent with the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1)[C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([N:26]=[C:27]=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH:29](N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:27]([NH:26][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])[CH2:15][CH2:14]1)[C:10]([O:12][CH3:29])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCCCN=C=O
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)[O-])[C@H]1CC[C@H](N)CC1
Solvent: ClCCl
Product: CCCCCCNC(=O)N[C@H]1CC[C@H]([C@H](NC(=O)OC(C)(C)C)C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
317 mg (1 mmol) of trans-(2S)-[(tert-butoxycarbonyl)amino](4-azidocyclohexyl)ethanoate was reduced using an identical procedure to that described in Example 1, Step C to yield 290 mg of trans-(2S)-[(tert-butoxycarbonyl)amino](4-aminocyclohexyl)ethanoate. To a solution of 30 mg (0.1 mmol) of trans-(2S)-[(tert-butoxycarbonyl)amino](4-aminocyclohexyl)ethanoate in 1 mL of methylene chloride at 0° C. was added 0.018 mL (0.125 mmol) of hexyl isocyanate and 0.044 mL (0.25 mmol) of diisopropylethylamine (DIEA). The mixture was stirred at ambient temperature for 16 h, concentrated in vacuo, and diluted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution, brine, dried over magnesium sulfate and the solvent removed in vacuo to yield methyl trans-(2S)-[(tert-butoxycarbonyl)amino](4-{[(hexylamino)carbonyl]amino}cyclohexyl)-ethanoate which was used without further purification. To this material, dissolved in 1 mL of THF, was added 21 mg (0.5 mmol) of lithium hydroxide in 1 mL of water and the reaction was stirred for 16 h and concentrated in vacuo. The aqueous solution was acidified with 2N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the carboxylic acid which was dissolved in 1 mL of dimethylformamide (DMF). To this was added 0.008 mL (0.1 mmol) of thiazolidine, 23 mg (0.12 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), 21 mg (0.15 mmol) of 1-hydroxybenzotriazole hydrate (HOBT), and 0.042 mL (0.25 mmol) of diisopropylethylamine (DIEA). The mixture was stirred for 16 h and diluted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium bicarbonate solution, water, brine, dried over magnesium sulfate and the solvent removed in vacuo to yield 53 mg The product was deprotected as described in Example 1, Step D, to give 22 mg of the title compound. 1H NMR (400 MHz, CD3OD) δ 4.70–4.66 (m, 0.45H), 4.61–4.57 (m, 1H), 4.5–4.46 (m, 0.55H), 3.93–3.86 (m, 0.55H), 3.83–3.71 (m, 1.45H), 3.46 (d, 0.45H, J=7 Hz), 3.42–3.35 (m, 1.55H), 3.16–3.02 (m, 4H), 1.98–1.90 (m, 3H), 1.64–1.58 (m, 1H), 1.56–1.39 (m, 3H), 1.39–1.23 (m, 7H), 1.23–1.06 (m, 3H), 0.95–0.87 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>>[ClH:1].[CH:13]1([NH:19][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:23]3[CH:24]=[CH:25][C:21]([CH3:20])=[N:22]3)[N:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc[nH]n1
Reactant: NC1CCCCC1
Product: Cc1ccn(-c2nc(NC3CCCCC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, cyclohexylamine and 3-methylpyrazole. Mp. 269-274.3° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=O)=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26]>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=[CH:27]/[C:25]#[N:26])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1sc(COc2ccc(/C=C/C=O)cc2)nc1-c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Product: Cc1sc(COc2ccc(/C=C/C=C/C#N)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 35, (E)-3-[4-(5-methyl-4-phenyl-2-thiazolylmethoxy)phenyl]-2-propen-1-al was allowed to react with diethyl cyanomethylphosphonate to give (E,E)-5-[4-(5-methyl-4-phenyl-2-thiazolylmethoxy)phenyl]-2,4-pentadienenitrile. Recrystallization from ethyl acetate--ether gave colorless prisms, m.p.108°-109° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[N:8][CH:9]=[C:10]([CH:12]([Cl:14])[Cl:13])[N:11]=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC)(=O)C>CO>[Cl:14][CH:12]([Cl:13])[C:10]1[N:11]=[C:6]([CH2:5][OH:4])[C:7]([N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[N:8][CH:9]=1
Reactant: CC(=O)OCc1nc(C(Cl)Cl)cnc1N1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: COC(C)=O
Product: O=C1c2ccccc2C(=O)N1c1ncc(C(Cl)Cl)nc1CO
Yield: 53.1 %

Procedure:
A mixture of 15 g (0.04 mole) of 3-acetoxymethyl-5-dichloromethyl-2-phthalimidopyrazine, 150 ml of methanol and 0.15 g of p-toluenesulfonic acid was heated to the boil, and a mixture of methanol and methyl acetate was slowly distilled off in the course of 5 hours. The mixture was then evaporated down to one-third of its total volume, and the precipitated crystals were isolated, and recrystallized from ethyl acetate. 7.18 g (54%) of 5-dichloromethyl-3-hydroxymethyl-2-phthalimidopyrazine of melting point 188°-189° C. were obtained. 1H-NMR (CDCl3 270 MHz): δ4.7 (s, 2H), 6.9 (s, 1H), 8.1 (m, 4H), 9.1 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[BrH:10].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Br-:10].[C:24]1([P+:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[NH2:1])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1ccccc1CO
Solvent: CC#N
Product: Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 1 h
Yield: 88.4 %

Procedure:
2-Aminobenzyl alcohol (60.0 g, 0.487 mol) was dissolved in acetonitrile (2.5 L) and brought to reflux. Triphenylphosphine hydrobromide (167 g, 0.487 mol) was added and the mixture was heated at reflux for 3 h. The reaction mixture was concentrated to approximately 500 mL and left at room temperature for 1 h. The precipitate was filtered and washed with cold acetonitrile followed by hexane. The solid was dried overnight at 40° C. under vacuum to give triphenyl(2-aminobenzyl)phosphonium bromide (193 g, 88%).
Reaction SMILES: O[CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].P(Br)(Br)[Br:18].C(=O)([O-])[O-].[Na+].[Na+]>C(OC(C)C)(C)C>[CH2:2]([Br:18])[CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]
Reactant: BrP(Br)Br
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: CC(C)=CCCC(C)=CCCC(C)=CCBr
Temperature: -20 °C
Yield: 224.9 %

Procedure:
Into an argon-replaced 1 liter reaction vessel, 66.6 g (0.3 mol) of farnesol (all trans-form) was charged, and 300 ml of isopropyl ether was further added to dissolve farnesol. The resulting solution was cooled to -20° C., and thereafter 32.5 g (0.12 mol) of phosphorus tribromide was added to carry out reaction at -20° C. to -10° C. for 2 hours. The reaction mixture thus obtained was poured into 400 ml of an aqueous 5% sodium carbonate solution, and the liquid was separated. The organic layer was washed with saturated brine, followed by distillation of the solvent to obtain 77.0 g of farnesyl bromide (yield: 90%). Data of physical properties of this compound are shown below.
Reaction SMILES: Cl.C([N:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])C.ClC(Cl)Cl.Cl[C:22]([O:24][CH3:25])=[O:23].[CH2:26](N(CC)CC)[CH3:27]>>[CH2:26]([CH:5]([CH2:6][C:7]([OH:9])=[O:8])[N:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:22]([O:24][CH3:25])=[O:23])[CH3:27]
Reactant: CCOC(=O)CCN(CC)CCC(=O)O
Reactant: CCN(CC)CC
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCN(C(=O)OC)C(CC)CC(=O)O
Reaction time: 8 h

Procedure:
To a stirred solution of 150 parts of ethyl N-[2-(ethoxycarbonyl)ethyl]-β-alanine hydrochloride in 1800 parts of trichloromethane are added 150 parts of N,N-diethylethanamine, while cooling. Then there are added dropwise 68 parts of methyl chloroformate. Upon completion, stirring is continued overnight at room temperature. The formed precipitate is filtered off and the filter-cake is washed with methylbenzene. The filtrate is evaporated and water is added to the residue. The product is extracted with methylbenzene. The extract is washed three times with water, dried, filtered and evaporated. The residue is distilled, yielding ethyl N-[2-(ethoxycarbonyl)ethyl]-N-(methoxycarbonyl)-β-alanine; bp. 137°-140° C at 0.2 mm. pressure.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=CC=3)=[N:8][C:7]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:6][C:5]=2[S:4][C:3]=1[CH3:30].[CH2:31]([N:33](CC)CC)C.Cl.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45](Cl)=[O:46]>>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[CH:31]=[N:33][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:8][C:7]([N:24]3[CH2:25][CH2:26][N:27]([C:45]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=4)=[O:46])[CH2:28][CH2:29]3)=[N:6][C:5]=2[S:4][C:3]=1[CH3:30]
Reactant: Cc1sc2nc(N3CCNCC3)nc(Nc3ccc(N4CCOCC4)cc3)c2c1C
Reactant: O=C(Cl)c1ccccn1
Reactant: CCN(CC)CC
Agent: Cl
Product: Cc1sc2nc(N3CCN(C(=O)c4ccccn4)CC3)nc(Nc3ccc(N4CCOCC4)nc3)c2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To 240 mg (1.02 mmol) of 2,4-dichloro-5,6-dimethyl-thieno[2,3-d]-pyrimidine in 50 ml of ethyl alcohol were added 226.40 mg (1.26 mmol) of 6-morpholinopyridin-3-amine and 130.90 mg (1.23 mmol) of calcium carbonate, and then the mixture was stirred under reflux. After completion of the reaction, the reaction solvent, ethyl alcohol, was evaporated under reduced pressure, and the residue was crystallized from ethyl alcohol and filtered, yielding 440 mg (quantitative) of 2-chloro-5,6-dimethyl-N-(6-morpholinopyridin-3-yl)-thenio[2,3-d]pyrimidine-4-amine. 200 mg (0.50 mmol) of the obtained product was dissolved in 20 ml of 1-butanol in a sealed tube, and 220 μl (1.50 mmol) of triethylamine and 45.9 mg of piperazine were added thereto, and the mixture was stirred at 120° C. After completion of the reaction, the resulting solid was filtered and the filtrate was concentrated under reduced pressure and then crystallized from ethyl acetate, yielding 25 mg (12% yield) of 5,6-dimethyl-N-(6-morpholinopyridin-3-yl)-2-(piperazin-1-yl)thieno[2,3-d]pyrimidine-4-amine. To 9 mg (0.02 mmol) of the obtained compound, 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine in 5 ml of dimethyl chloride were added 3.5 μl (0.02 mmol) of triethylamine and 4.1 mg (0.02 mmol) of picolinoyl chloride hydrochloride, and then the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solvent, dimethyl chloride, was evaporated under reduced pressure and crystallized from ethyl acetate, thus obtaining 7 mg (35% yield) of the title product.