Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][O:16][CH:15]([CH3:18])[O:14][CH:13]1C.[CH2:20](N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]([NH:11][CH:12]2[CH2:13][O:14][C:15]([CH3:18])([CH3:20])[O:16][CH2:17]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: CCN(CC)CC
Reactant: CC1OCC(N)C(C)O1
Solvent: Cc1ccccc1
Product: CCc1ncnc(NC2COC(C)(C)OC2)c1Cl

Procedure:
2.65 g (15 mmol) of 4,5-dichloro-6-ethyl-pyrimidine, 2.40 g (18.3 mmol) of 5-amino-2,4-dimethyl-1,3-dioxane and 3.03 g (30 mmol) of triethylamine were heated under reflux in 10 ml of toluene for 4 hours. After cooling, the mixture was extracted by stirring with water and the organic phase was dried and concentrated. For purification, the residue was chromatographed over silica gel (ethyl acetate/petroleum ether 4:1). This gave 0.46 g (11% of theory) of product as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:16]([O-])=O)[CH:5]=1)[CH3:2].[Cl-].[NH4+].O>[Fe].CO>[NH2:16][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]([O:14][CH3:15])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOc1cc(N)c(C(=O)OC)cc1OC
Yield: 82.7 %

Procedure:
A mixture of 24.110 g (94.5 mmol) methyl 4-ethoxy-5-methoxy-2-nitrobenzoate, 15.81 g (283 mmol) iron powder, 25.28 g (472 mmol) ammonium chloride, 135 ml water, and 350 ml methanol was heated to reflux under N2. At both 3 and 5.5 hours added the same amount of iron and ammonium chloride. Removed heat at 6.5 hours, added ethyl acetate and saturated sodium bicarbonate, filtered through celite and separated layers. Washed organic layer with saturated sodium bicarbonate, dried with magnesium sulfate, stripped solvent, and dried in vacuo, giving 17.594 g of pink solid: mass spectrum (electrospray m/e): M+H=226.2.
Reaction SMILES: [Cl:1][C:2]1[CH:59]=[CH:58][C:5]([CH2:6][CH:7]2[N:12]3[C:13](=[O:53])[CH:14]([NH:28][C:29]([CH:31]4[CH2:35][CH2:34][CH2:33][N:32]4C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)=[O:30])[CH2:15][N:16]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])(=[O:19])=[O:18])[CH:11]3[CH2:10][N:9]([CH:54]([CH3:56])[CH3:55])[C:8]2=[O:57])=[CH:4][CH:3]=1.C(NCC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[N:12]3[C:13](=[O:53])[CH:14]([NH:28][C:29]([CH:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)=[O:30])[CH2:15][N:16]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])(=[O:19])=[O:18])[CH:11]3[CH2:10][N:9]([CH:54]([CH3:56])[CH3:55])[C:8]2=[O:57])=[CH:58][CH:59]=1
Reactant: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCN3C(=O)OCC3c4ccccc4-c4ccccc43)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCN3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A mixture of 50 mg (0.089 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione, 1 ml of DCM, 23 mg (0.178 mmol) of DIEA and 32 mg (0.090 mmol) of Fmoc-Pro-Cl was stirred at room temperature for 1 hour. The mixture was purified by chromatography on 2 g of SiO2 (elution with EtOAc/DCM, gradient 0-20%). 72 mg of the intermediate 9H-fluoren-9-ylmethyl 2-[6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-ylcarbamoyl]pyrrolidine-1-carboxylate were obtained. LC/MS: (calculated, monoisotopic MW=877, measured value (M+H)=878) A mixture of 60 mg (0.068 mmol) of 9H-fluoren-9-ylmethyl 2-[6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-ylcarbamoyl]pyrrolidine-1-carboxylate and 2 ml of 15% strength diethylamine in DCM was stirred at room temperature overnight. The mixture was concentrated and subjected to a flash chromatography on 2 g of SiO2 (elution with DCM, EtOAc and then with 10% methanol/EtOAc). The amine was converted into the hydrochloride salt. 30 mg of solid were obtained. This was further purified by preparative reverse phase (RP)HPLC. 17 mg of the desired compound were obtained. LC/MS (calculated, monoisotopic MW=655.12; measured value (M+H)=656)
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Li+]>CN(C=O)C.O.C1COCC1>[CH:18]1([N:17]([CH3:16])[C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CNC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(C(=O)O)cc1[N+](=O)[O-])C1CCCCC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.) and N-methylcyclohexylamine (Aldrich 10,332-2; 796.59 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was stirred at 50° C. for 3 hours. The reaction was then allowed to return to room temperature and diluted with water. Extraction with ethyl acetate, drying over sodium sulfate and concentration in vacuo gave a yellow oil. The oil was taken up in THF (15 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) was added followed by water (15 mL). The reaction mixture was stirred at room temperature for 5 hours. After evaporation of the solvent, the solution was diluted with water and washed with Et2O. The aqueous layer was acidified to pH 4 with AcOH, extracted with Et2O, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:27]1[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]=2[CH:29]=[CH:28]1>C(Cl)Cl>[NH:27]1[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]([C:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)=[O:12])[C:30]=2[CH:29]=[CH:28]1
Reactant: c1cc2c([nH]1)CCCCN2
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]ccc32)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
To a mixture of 1-acetyl-piperidine-4-carboxylic acid (822 mg, 4.8 mmol, 1.2 eq.), EDC (920 mg, 1.2 eq.), HOBt (648 mg, 1.2 eq.) in DCM (15 mL) was added TEA (1.3 mL, 2 eq.) and 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (550 mg, 4 mmol). The mixture was stirred at rt for 2 days. The reaction was diluted with DCM, washed with water, sat. NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 1.1 g of 1-[4-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-piperidin-1-yl]-ethanone as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH:15]3C)=[O:13])[N:10]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1.O>CN(C)C=O>[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[N:10]=3)[N:7]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccc(S)cc1
Reactant: CC1CC1C(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide (2.0 g, 6.10 mmol) in N,N-dimethylformamide (20.0 mL) were added potassium carbonate (1.27 g, 9.14 mmol) and 4-aminothiophenol (0.92 g, 7.31 mmol), and the mixture was stirred at 80° C. for 4 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate to give the title compound (1.53 g, 77%) as brown crystals.
Reaction SMILES: CC1(C)[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH2:14][C:15](=O)[CH3:16])[CH:11]=[CH:12][C:4]=2[O:3]1.C(O[C:27]1[CH:36]=[CH:35][C:30]([CH:31]([OH:34])[CH2:32][NH2:33])=[CH:29][CH:28]=1)C1C=CC=CC=1.[H][H]>CO>[C:6]([C:5]1[CH:9]=[C:10]([CH:11]=[CH:12][C:4]=1[OH:3])[O:13][CH2:14][CH:15]([NH:33][CH2:32][CH:31]([OH:34])[C:30]1[CH:35]=[CH:36][CH:27]=[CH:28][CH:29]=1)[CH3:16])(=[O:8])[NH2:7]
Reactant: NCC(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)COc1ccc2c(c1)C(=O)NC(C)(C)O2
Reactant: [H][H]
Solvent: CO
Product: CC(COc1ccc(O)c(C(N)=O)c1)NCC(O)c1ccccc1

Procedure:
A solution of 9.6 g of 2,3-dihydro-2,2-dimethyl-6-(2-oxo-propoxy)-4H-1,3-benzoxazin-4-one and 9.37 g of 4-benzyloxy-α-(aminomethyl)benzyl alcohol in 250 ml of methanol is hydrogenated analogously to Example 1 until one equivalent of hydrogen has been taken up. The catalyst is filtered off and, after adding 40 ml of isopropylamine, the solution is refluxed for 1 hour. Evaporation of the reaction mixture yields 4-benzyloxy-α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl-benzyl alcohol in the form of a crystalline mass which can be hydrogenated without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[O:2].[BH4-].[Na+]>CO.C[O-].[Na+]>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)Oc1cccc(C=O)c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)Oc1cccc(CO)c1
Yield: 97.5 %

Procedure:
By the method of Example 1, Step G, 15.7 g (0.0761 mole) of methyl 2-(3-formylphenoxy)propionate, 0.76 g (0.020 mole) of sodium borohydride, and 0.10 g (0.0018 mole) of sodium methoxide were reacted in 40 mL of methanol, yielding 15.6 g of methyl 2-(3-hydroxymethylphenoxy)propionate as a yellow liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([C:7]1[C:12]([NH2:13])=[C:11]([CH2:14][CH3:15])[N:10]=[C:9]([CH3:16])[N:8]=1)[CH3:6]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:14]([C:11]1[C:12]([N:13]=[C:1]=[S:2])=[C:7]([CH2:5][CH3:6])[N:8]=[C:9]([CH3:16])[N:10]=1)[CH3:15]
Reactant: S=C(Cl)Cl
Reactant: CCc1nc(C)nc(CC)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc(C)nc(CC)c1N=C=S
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Thiophosgene (2.53 mL, 33.2 mmol) was added dropwise to a stirred mixture of 4,6-diethyl-2-methylpyrimidin-5-amine (4.22 g, 25.5 mmol) in tetrahydrofuran (40 mL) and saturated aqueous sodium hydrogen carbonate (40 mL) at 0° C., and the mixture was stirred at 0° C. for 20 minutes. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow solid (5.28 g, 25.5 mmol, 100%).
Reaction SMILES: C(Cl)Cl.[F:4][C:5](F)(F)[C:6]([C:16]([F:19])([F:18])[F:17])=[C:7](F)[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].CCN(CC)CC.[CH3:29][NH:30][NH2:31]>O>[CH3:29][N:30]1[C:5]([F:4])=[C:6]([C:16]([F:19])([F:18])[F:17])[C:7]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:31]1
Reactant: CNN
Reactant: FC(=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a 3-kneck flask equipped with condenser, thermometer, and a dropping funnel 130 ml methylene chloride and perfluoro-2-methyl-2-pentene (19.6 g, 0.065 mol) was placed and then 15 ml water were added. The mixture was cooled to 0° C. and Et3N (16.4 g, 0.16 mol) was added at a temperature ranging from 0° C. to 5° C. The mixture was stirred at this temperature for 15 min and 40% solution of methylhydrazine in water (7.4 g) was slowly added to this mixture at 0° C. The reaction mixture was stirred for 1 h at 5° C. and finally for 1.5 h at 20° C. The mixture was washed with water (3×50 ml), the organic layer was dried over Na2SO4 and the solvent was distilled off under atmospheric pressure. The crude product was purified via vacuum distillation. The yield of N-methyl-3-pentafluoroethyl-4-trifluoromethyl-5-fluoro-1H-pyrazole was 13.9 g. (75%), boiling point 62-65° C. at 17 mbar.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)O)=[CH:31][CH:30]=1>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:11])[CH2:3]2
Reactant: COc1ccc(C(O)c2ccccc2)cc1
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1ccc(C(OC(=O)C2CN3CCC2CC3)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 13.5 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (150 mg, 0.78 mmol), EDC (225 mg, 1.17 mmol), and HOBT (180 mg, 1.17 mmol) were dissolved in dry THF (7.5 ml). (4-Methoxyphenyl)(phenyl)methanol (184 mg, 0.86 mmol) and TEA (382 μl, 2.74 mmol) were added, and the resulting reaction was stirred at room temperature for four days. THF was removed under vacuum, and the crude residue was partitioned between EtOAc and water. The organic phase was washed with a sat. NaHCO3, dried over Na2SO4, filtered, and evaporated. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to EtOAc/MeOH=7:3+1% NH4OH) to give (4-methoxyphenyl)(phenyl)methyl quinuclidine-3-carboxylate (37 mg, mixture of diastereoisomers). The compound was used as such in the next step.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][C:10]=1[NH2:11])=[O:4].CCN(C(C)C)C(C)C.[CH3:33][S:34]([NH:37][NH2:38])(=[O:36])=[O:35].[O:39]1CCOC[CH2:40]1>>[C:22]([C:18]1[CH:17]=[C:16]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][C:8]=2[C:12]([F:15])([F:13])[F:14])[NH:11][C:40](=[O:39])[N:38]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])[C:3]3=[O:4])[CH:21]=[CH:20][CH:19]=1)#[N:23]
Reactant: C1COCCO1
Reactant: COC(=O)c1cc(-c2cccc(C#N)c2)c(C(F)(F)F)cc1N
Reactant: CS(=O)(=O)NN
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-c3cccc(C#N)c3)cc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 4-amino-3′-cyano-6-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.7 g, 2.19 mmol) in dioxane (15 mL) was treated with i-Pr2NEt (0.5 mL, 2.92 mmol) and (CCl3O)2CO (0.655 g, 2.19 mmol) and the mixture was stirred at 60° C. for 1 h under nitrogen. To this solution was added CH3SO2NHNH2 (0.24 g, 2.19 mmol) and stirring was continued for 1 h at 60° C. and for 16 h at r.t. The mixture was concentrated in vacuo, diluted with water and extracted three times with 25 mL each of EtOAc. The combined organic layers were washed twice with water and dried (Na2SO4), filtered and the solvent evaporated. The product was recrystallized from MeOH/DCM 3:1 to give N-[6-(3-cyano-phenyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (0.78 g, 1.84 mmol, 84%), m.p. 291-292° C., ESI-MS: m/z 425 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18]CC4CC4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:29]1(N)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH:29]4[CH2:31][CH2:30]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: NC1CC1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(NCC4CC4)CC3)cc2n1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(NC4CC4)CC3)cc2n1

Procedure:
Prepared according to the method used in the preparation of [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-cyclopropylmethyl-amine using cyclopropylamine in place of cyclopropanemethylamine. The title compound was obtained as a pale yellow solid (38 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([NH:8][C:9]([NH2:11])=[O:10])[CH:7]=1.O.[C:15]1([C:21]([CH:23]=[O:24])=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[K+].[Br-]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([N:8]2[CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:23](=[O:24])[NH:11][C:9]2=[O:10])[CH:7]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: COc1ccc(Cl)cc1NC(N)=O
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cl)cc1N1C(=O)NC(=O)C1c1ccccc1
Reaction time: 18 h

Procedure:
N-(5-Chloro-2-methoxyphenyl)urea (1 g, 5 mmol) and phenylglyoxal monohydrate (760 mg, 5 mmol) were taken up in absolute ethanol (100 ml) and acetic acid (1 ml) and 1 ml of conc. HCl added. The reaction mixture was heated at reflux 3.5 h and allowed to stand at 24° C. for 18 h prior to concentration by rotary evaporation. The residue was dissolved in ethyl acetate, washed with sat'd NaHCO3 solution and brine. Recrystallization from methylene chloride/hexanes gave 1 g (63%) mp 200° C.; IR(KBr, ν=cm-1) 3168, 3064, 1772, 1701, 1504, 1444, 1426, 1408, 1260, 1190, 1150; 1H NMR (300 MHz, CDCl3) δ3.59 (3H, s), 5.60 (1H, s), 6.80 (1H, d, J=8.8 Hz), 7.14-7.37 (7H, m), 8.92 (1H, br.s); MS(DCl)m/z: 317(MH+)
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:28]([O:31]O)(=[O:30])[CH3:29].[C:33]([O:36]CC)(=[O:35])[CH3:34]>C(O)(=O)C>[C:28]([O:31][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][C:2]([OH:35])([CH3:1])[CH3:3])[CH2:17]1)(=[O:30])[CH3:29].[C:33]([O:36][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@:16]([OH:30])([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)(=[O:35])[CH3:34]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OO
Reactant: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]32)C1
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3CC[C@@]2(O)C1

Procedure:
A solution of 15 g of 3β-acetoxy-5 -cholestane (I) in 250 cc of ethyl acetate was treated with 30 cc peracetic acid (40%) in acetic acid and was irradiated with ultra-violet light of at about 300 mμ wavelength for 24 hours. The resulting reaction mixture was washed consecutively with an aqueous solution of sodium bisulfite, sodium bicarbonate and water and the solvents were evaporated in vacuo to dryness. The residue was chromatographed on a column of silica gel to give 3.5 g of the known 3β-acetoxy-25-hydroxy-5α-cholestane (III), m.p. 125°-126°C and 1.8 g of the known 3β-acetoxy-5α-hydroxy-cholestane (II), m.p. 180°-181°C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8].C(N(CC)CC)C>C(Cl)Cl>[OH:8][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][NH:5][C:1](=[O:3])[CH3:2]
Reactant: NCC(O)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC(O)c1ccccc1
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A solution of acetyl chloride (10 ml, 0.146 moles) in 200 ml of methylene chloride was added under nitrogen dropwise over 45 minutes to a solution of 2-amino-1-phenylethanol (20.0 g, 0.146 moles) and triethylamine (20 ml, 0.146 moles) in 300 ml of methylene chloride at ice bath temperature. After the addition the reaction was stirred at ice bath temperature for 3 hours and overnight at room temperature. The reaction was extracted with 1N HCl. The organic layer was separated and the aqueous layer was extracted with methylene chloride and then 10% methanol-methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give a solid material. Recrystallization of this solid from isopropyl alcohol gave N-(2-hydroxy-2-phenyl-ethyl)-acetamide (9.0 g, 34%) as a white solid, mp 120-122° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20](=O)[CH2:21][C:22](OCC)=[O:23])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)(=[O:10])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[NH:7][C:5]4[N:4]([N:3]=[C:2]([CH3:1])[N:6]=4)[C:22](=[O:23])[CH:21]=3)=[CH:17][CH:18]=2)[CH:13]=[N:12]1)(=[O:10])[CH3:9]
Reactant: Cc1n[nH]c(N)n1
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)n1ncc2cc(-c3cc(=O)n4nc(C)nc4[nH]3)ccc21
Temperature: 170 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-1H-1,2,4-triazol-5-amine (150 mg, 1.52 mmol) in diphenyl ether (2 ml) was added ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate (710 mg, 2.59 mmol), TsOH (11 mg, 0.06 mmol), and the mixture was stirred for 1 h at 170° C. The resulting solution was diluted with petroleum ether (8 ml), and solids were collected by filtration and washed with ethyl ether (3 ml) to afford 5-(1-acetyl-1H-indazol-5-yl)-2-methyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a crude brown solid (100 mg, crude).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][S:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:9]1([S:8][S:7][CH2:6][C@H:2]2[C:3](=[O:5])[O:4][C:16](=[O:18])[NH:1]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H](CSSc1ccccc1)C(=O)O
Solvent: C1CCOC1
Product: O=C1N[C@@H](CSSc2ccccc2)C(=O)O1
Temperature: 47.5 °C
Yield: 85 %

Procedure:
To a rapidly stirred (over-head stirrer) suspension of S-thiol-phenyl-L-cysteine (1b) (57.5 g, 0.25 mol) in THF (250 mL) was added solid triphosgene (26 g, 88 mmol) in one portion at 45-50° C. (before addition, remove the heating mantle). When the temperature drops to 45° C., put the heating mantle back on and maintain the inside temperature around 45-50° C. until the solution becomes homogeneous. After the removal of the heating mantle, the solution was purged with argon overnight into a NaOH bubbler to remove any residual phosgene. The solvent was evaporated in vacuo and this provided anhydride 2b (55 g) in 85% yield. 2b: m.p. 217° C. (decomp); 1H NMR (300 MHz, CDCl3) δ 2.90-2.98 (m, 1H), 3.30 (d, 1H, J=12 Hz), 4.68 (d, 1H, J=9 Hz), 6.01 (s, 1H), 7.34-7.58 (m, 5H); 13C NMR (75.5 MHz, CD3Cl3): δ 39.4, 56.5, 128.3, 128.9, 129.5, 135.2, 150.8, 167.7. Due to the unstable nature of this anhydride, it was stored in the refrigerator overnight under an atmosphere of argon and used immediately the next day without further purification.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23]>>[N+:22]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
Anthraquinone is nitrated using a mixed acid comprising sulfuric acid and nitric acid, the concentration of sulfuric acid being 70 to 76% by weight and the amount of nitric acid being 33 to 55% by weight based on the total weight of sulfuric acid and nitric acid, whereby 1-nitroanthraquinone is obtained in a high yield and a high purity.