Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[N:6]=[CH:5]2.[CH3:19][O:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[CH:26]2)=[O:22]>>[CH3:19][O:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:11][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]3[C:8]=1[N:7]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[N:6]=[CH:5]3)[N:27]=[CH:26]2)=[O:22]
Reactant: CCC(CC)Cn1ncc2cc(Br)cc(CO)c21
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Product: CCC(CC)Cn1ncc2cc(Br)cc(Cn3ncc4cc(C(=O)OC)ccc43)c21
Yield: 47 %

Procedure:
Compound 31 was prepared following general method 3A, using compound 23 as a starting material and 1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 47%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(NC(C)C)(C)C.[CH3:17][O:18][CH2:19]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][O:18][CH3:19])=[CH:4][C:3]=1[CH3:9]
Reactant: COCCl
Reactant: Cc1cc(O)ccc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COCOc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 4-bromo-3-methylphenol (14 g) and N,N-diisopropylamine (39.1 mL) in dichloromethane (150 mL) was added chloromethyl methyl ether (11.4 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 days. The reaction mixture was poured into a saturated aqueous citric acid solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-bromo-3-methyl-1-(methoxymethoxy)benzene (16.7 g). This material was dissolved in tetrahydrofuran (250 mL). To the solution was added n-butyl lithium (2.64 mol/L n-hexane solution, 32.7 mL) at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added N,N-dimethylformamide (16.6 mL), and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-methyl-4-(methoxymethoxy)benzaldehyde (12.9 g). This material was dissolved in tetrahydrofuran (70 mL)—methanol (10 mL). To the solution was added concentrated hydrochloric acid (6 mL), and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) with heating at 60° C. n-Hexane (100 mL) was added to the solution gently, and the mixture was stirred at the same temperature for 10 minutes. The mixture was cooled to room temperature. n-Hexane (170 mL) was added to the mixture, and the resulting mixture was stirred overnight. The precipitated crystals were collected by filtration, and washed with n-hexane and dried under reduced pressure to give the title compound (5.6 g).
Reaction SMILES: Cl.[CH:2]1([N:8]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:39][N:40]1[CH:44]=[C:43]([S:45](Cl)(=[O:47])=[O:46])[N:42]=[CH:41]1>>[CH:24]1([N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([S:45]([C:43]4[N:42]=[CH:41][N:40]([CH3:39])[CH:44]=4)(=[O:47])=[O:46])[CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: O=C(Nc1ncc(CN2CCNCC2)s1)N(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(S(=O)(=O)N2CCN(Cc3cnc(NC(=O)N(C4CCCCC4)C4CCCCC4)s3)CC2)c1
Yield: 66.1 %

Procedure:
Prepared as described in general procedure (Q) using 1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-urea hydrochloride (27 mg, 0.055 mmol), DIEA (29 μL, 0.17 mmol) and N-methylimidazole-4-sulfonyl chloride (20 mg, 0.11 mmol) to afford 20 mg (66%) of the desired product after purification.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:25]=[CH:24][C:17]([CH2:18][N:19]([OH:23])[C:20]([NH2:22])=[O:21])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[OH-].[Na+].Cl[C:29](OCC)=[O:30]>O>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]3[C:20](=[O:21])[NH:22][C:29](=[O:30])[O:23]3)=[CH:24][CH:25]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(CN(O)C(N)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(Cn2oc(=O)[nH]c2=O)cc1
Yield: 76 %

Procedure:
To a stirred solution of N-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl]-N-hydroxyurea (346 mg, 1.0 mmol) (obtained from preparation 19) in water (2 ml) was added 1N NaOH (3 ml) followed by ethyl chloroformate (191 μl, 217 mg, 2.0 mmol) and stirred for 1h at 30° C. The reaction mixture was diluted with water, acidified to pH 3.0 and extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the title compound (283 mg, 76%).
Reaction SMILES: [CH:1]1([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([O:17][CH2:18]C)=[N:11][C:12]=3[NH2:16])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C1(N2C=NC3C2=NC(OC)=NC=3N)CCCC=C1>>[CH3:18][O:17][C:10]1[N:9]=[C:8]2[C:13]([N:14]=[CH:15][N:7]2[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:12]([NH2:16])[N:11]=1
Reactant: CCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Agent: COc1nc(N)c2ncn(C3C=CCCC3)c2n1
Product: COc1nc(N)c2ncn(C3CCCCC3)c2n1

Procedure:
If the procedure of Example 8 is repeated with the 9-(2-cyclohexenyl)-2-ethoxy-9H-adenine used therein replaced by an equivalent weight of 9-(2-cyclohexenyl)-2-methoxy-9H-adenine, there is produced the title product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=O)=[CH:10][CH:9]=2)[CH:2]=1.I.CS[C:21](=[NH:34])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=1>N1C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:21]2[NH:34][C:12]([C:11]3[CH:16]=[CH:17][C:8]([O:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:9][CH:10]=3)=[N:14][N:15]=2)=[CH:24][C:25]=1[C:30]([F:31])([F:32])[F:33]
Reactant: NNC(=O)c1ccc(Oc2cccnc2)cc1
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: I
Solvent: c1ccncc1
Product: FC(F)(F)c1cc(Nc2nnc(-c3ccc(Oc4cccnc4)cc3)[nH]2)ccc1Cl
Yield: 12.7 %

Procedure:
4-(pyridine-3-yloxy)benzohydrazide (2.33 g, 10.2 mmol) was dissolved in ca. 70 mL of anhydrous pyridine and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (4.04 g, 10.2 mmol) was added. The reaction mixture was refluxed for 18 hrs under Ar. The pyridine was removed in vacuo and the resulting residue was purified by silica gel chromatography using EtOAc as eluent to give the title product (0.56 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=O)=[C:8]([OH:18])[N:7]=[C:6]([CH3:19])[N:5]=1)[CH3:2].CN(C)C1C=CC=CC=1>P(Cl)(Cl)(Cl)=O>[CH2:1]([O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[O:18][C:8]=2[N:7]=[C:6]([CH3:19])[N:5]=1)[CH3:2]
Reactant: CCOc1nc(C)nc(O)c1NC(=O)c1ccco1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOc1nc(C)nc2oc(-c3ccco3)nc12
Yield: 77.3 %

Procedure:
A mixture of 4-ethoxy-5-(2-furanylcarbonyl)amino-6-hydroxy-2-methylpyrimidine (2.07 g, 7.87 mM), phosphorus oxychloride (30 ml) and dimethylaniline (1.5 ml, 11.7 mM) was heated at reflux for one hour. After cooling, the excess phosphorus oxychloride was removed by distillation under reduced pressure. Ethanol was then added, and the mixture partitioned between methylene chloride and water. The organic layer was separated, washed with sodium bicarbonate, water, dilute hydrochloric acid, water, and dried. The solvent was then removed by distillation under reduced pressure. Ethanol (10 ml) was added and the solid filtered off. This solid was further purified by flash column chromatography eluting with ethyl acetate/hexane (1:3). There was thus produced 7-ethoxy-5-methyl-2-(2-furyl)-oxazolo[5,4-d]pyrimidine (1.49 g, 77% yield); m.p. 104°-105.5° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[C:6]([CH3:27])[C:7]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:8][C:9]=2[C:10]([CH3:14])([CH3:13])[CH2:11][CH:12]=1)C.[CH:28](=O)[CH3:29]>>[CH2:28]([N:15]([C:7]1[C:6]([CH3:27])=[CH:5][C:4]2[C:3]([CH3:1])=[CH:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=2[CH:8]=1)[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(CC)=CCC3(C)C)cc1
Reactant: CC=O
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Yield: 66.2 %

Procedure:
Following General Procedure D, ethyl 4-(5-ethyl-3,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 55, 0.37 g, 1.0 mmol) was reacted with acetaldehyde (0.56 mL, 10.0 mmol) to give 0.25 g (63%) of the title compound as a clear oil.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:14](=O)[CH2:15][CH2:16][CH3:17]>CS(C)=O.Cl>[OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[C:11]=1[CH:14]=[CH:15][CH2:16][CH3:17])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCCC=O
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: Cl
Solvent: CS(C)=O
Product: CCC=CC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 75 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
To a solution of 20 gram (0.11 moles) of 2-hydroxy-1,4-naphthoquinone in 150 ml of DMSO and 20 ml of concentrated hydrochloride (37%) solution at 75° C., 20 ml of n-butyraldehyde (0.23 mol) was added. The mixture was vigorously stirred at the temperature of 72-78° C. for 4 hours, and then cooled by addition of 300 ml of ice water, and the resulting mixture was extracted with 300 ml of dichloromethane twice. The combined organic phases was washed successively with 500 ml of water, and 500 ml of 5% sodium bisulfite, and 500 ml of 4% sodium bicarbonate, and finally extracted with 400 ml of 5% sodium carbonate twice. The combined sodium carbonate extract was neutralized by addition of concentrated hydrochloric acid to pH 7.2-7.6. After chilling to 0° C., the mixture was filtered, and the resulting brick red solid was washed with cold water and dried under vacuum. 9.6 gram of product was obtained: 38.6% yield. 1H NMR (in CDCl3) δ 1.12 (t, J=8, 3H), 2.31 (m, 2H), 6.60-6.65 (m, 1H), 7.07-7.15 (m, 1H), 7.66-7.77 (m, 3H), 8.06-8.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=O)[CH:3]=1.CN(C)C=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:10])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5.0 ml (0.16 equivalent) of N,N-dimethylformamide are added dropwise at 40° C., with stirring, to 150 ml (2.06 mol) of thionyl chloride. Then, in the course of half an hour, 50 g (0.406 mol) of picolinic acid are added. The mixture is cautiously heated to 70° C. and stirred at that temperature for 24 hours, the gases formed being conveyed away through a wash bottle charged with sodium hydroxide solution. Concentration, and coevaporation a further three times with 50 ml of toluene each time, are carried out. 300 ml of diethyl ether are added to the acid chloride-hydrochloride so obtained. The mixture is cooled to 0° C. using an ice/water bath, and 250 ml of 25% ammonium hydroxide solution are cautiously added. The mixture is warmed to room temperature and stirred for 16 hours to complete the reaction. Filtration is carried out, and the filter residue is boiled in 400 ml of chloroform to remove secondary products and recrystallised from 350 ml of methanol. 4-Chloro-2-picolinic acid amide is obtained in the form of a yellowish solid, which is reacted without further purification. 31.3 g (0.2 mol) of the amide obtained in that manner are suspended in 490 ml of dichloromethane and cooled to 0° C. using an ice/water bath. After the addition of 46.5 ml of N,N-dimethylformamide, 36.7 ml of phosphorus oxychloride are added dropwise in the course of 20 minutes while maintaining the temperature, and stirring is carried out for a further 6 hours with cooling. 100 ml of water are then added and the mixture is rendered neutral with 4N sodium hydroxide solution and stirred overnight at room temperature. The organic solvent is removed using a rotary evaporator, and the aqueous phase is extracted three times using 250 ml of chloroform each time. After concentrating and drying the crude product under a high vacuum, sublimation is carried out at from 70 to 90° C. and 0.2 mbar, yielding 4-chloro-2-cyanopyridine in the form of a yellowish soild.
Reaction SMILES: Cl[C:2]([C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4].C(=O)(O)[O-:27].[K+]>O>[CH3:25][O:24][C:18]1[CH:19]=[C:20]([O:22][CH3:23])[N:21]=[C:16]([C:2]([OH:27])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4])[N:17]=1
Reactant: COc1cc(OC)nc(C(Cl)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: O
Product: COc1cc(OC)nc(C(O)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Reaction time: 72 h
Yield: 94.5 %

Procedure:
2-Chloro-2-(4,6-dimethoxypyrimidin-2-yl)-N-methanesulfonyl-2-phenylacetamide (0.5 g) was stirred at room temperature with potassium bicarbonate (0.2 g) in water (10 ml) for 2 hours, by which time all was in solution. After standing for 3 days, the solution was washed with ether (twice) and acidified with hydrochloric acid. Ether extraction (3 times), washing with water (twice), drying over magnesium sulfate and evaporation under vacuum gave 0.45 g of the desired product as a yellow glass. This glass slowly crystallised to a solid, mp 94°-6° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:12]=[C:13]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:25])[CH:3]=1.[H-].[Na+].S(OC)(O[CH3:32])(=O)=O.C(O)C>CN(C)C=O.O>[CH3:1][C:2]1[C:11]2[CH:12]=[C:13]([C:15]([O:24][CH3:32])([C:16]([F:17])([F:18])[F:19])[C:20]([F:23])([F:22])[F:21])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:25])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)OCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1cc2c3c(c1)c(C)cc(=O)n3CCO2)(C(F)(F)F)C(F)(F)F
Reaction time: 24 h

Procedure:
to a solution of 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-5H-pyrido[1,2,3-de]-1,4-benzoxazin-5-one in dimethylformamide is added sodium hydride and dimethyl sulfate. The solution is stirred for 24 hours, treated with ethanol and added to water. The resultant recipitate is filtered, triterated with 10% sodium hydroxide solution and filtered. The residual solid is recrystallized to give 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl) ethyl]-5H-pyrido[1,2,3-de]-1,4-benzoxazin-5-one. If desired sodium hydride may be replaced by a base such as potassium carbonate or potassium t-butoxide and dimethyl sulfate may be replaced by methyl iodide.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:11]1=[O:17].O.ON1C2C=CC=CC=2N=N1.[C:29]([O:33][C:34]([N:36]([CH3:53])[C@H:37]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=1)[C@H:38]([OH:43])[CH2:39][C:40](O)=[O:41])=[O:35])([CH3:32])([CH3:31])[CH3:30].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])O.[K+].C(=O)=O>CN(C)C=O.O>[C:29]([O:33][C:34](=[O:35])[N:36]([C@H:37]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=1)[C@H:38]([OH:43])[CH2:39][C:40](=[O:41])[NH:9][C@@H:10]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:11]1=[O:17])[CH3:53])([CH3:32])([CH3:30])[CH3:31]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(Cl)c(Cl)c1)[C@H](O)CC(=O)O
Reactant: N[C@@H]1CCCCNC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(Cl)c(Cl)c1)[C@H](O)CC(=O)N[C@@H]1CCCCNC1=O
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Triethylamine (1.396 g=1.91 ml, 13.8 mmol) is added to a stirred mixture of (R)-3-amino-azepan-2-one hydrochloride (7) in N,N-dimethylformamide (12 ml) at 18-22° C., then stirring is continued for approx. 1 hour. 1-Hydroxybenzotriazole hydrate (2.113 g, 13.8 mmol) is added at 18-22° C. to the stirred mixture, followed by the solution of (3R,4R)-4-tert-butoxycarbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-3-hydroxy-pentanoic acid (6) in N,N-dimethyl-formamide. N,N-dimethylformamide (2 ml) is used for rinsing. The mixture is cooled to 0-5° C., then 1,3-dicyclohexylcarbodiimide (2.847 g, 13.8 mmol) is added, followed by N,N-dimethylformamide (1.5 ml), used for rinsing. Stirring at approx. 0-5° C. is continued for approx. 1 hour, then the mixture is warmed to approx. 18-22° C. and stirred at that temperature for approx. 20 hours. The precipitated solids are removed by filtration and the filter cake is rinsed with N,N-dimethylformamide (12 ml). The filtrate is concentrated at a mantle temperature of approx. 60° C. under reduced pressure, until a concentrate of approx. 19.5 g is obtained. The resulting suspension is cooled to approx. 20-25° C., then an aqueous solution of potassium hydrogencarbonate (1.92 g, 19.17 mmol) in water (32 ml) is added over a period of approx. 20 minutes under evolution of carbon dioxide to give a suspension. The precipitated solids are isolated by filtration, rinsed with water (24 ml) and dried in vacuo at approx. 60° C. to constant weight to yield crude [(1R,2R)-1-(3,4-dichloro-benzyl)-2-hydroxy-3-((R)-2-oxo-azepan-3-ylcarbamoyl)-propyl]-methyl-carbamic acid tert-butyl ester (8) (6.019 g, 99.8% of theory based on (R)-2-(tert-butoxycarbonyl-methyl-amino)-3-(3,4-dichloro-phenyl-propionic acid (1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:13][OH:14])[C:5]([NH:9][CH2:10][CH2:11][OH:12])=[N:6][C:7]=1[Cl:8]>CC(C)=O.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:3]=[C:4]([CH:13]=[O:14])[C:5]([NH:9][CH2:10][CH2:11][OH:12])=[N:6][C:7]=1[Cl:8]
Reactant: OCCNc1nc(Cl)c(Cl)nc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1nc(Cl)c(Cl)nc1NCCO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.5 %

Procedure:
A mixture of 5,6-dichloro-3-hydroxymethyl-2-(2-hydroxyethyl)aminopyrazine (38 mg; 0.00016 Mol), prepared as in Step C above, and manganese dioxide (12 mg) was stirred at room temperature for 2.5 hours. Another 24 mg of manganese dioxide was added and stirring was continued for another 5 hours. The manganese dioxide was filtered off, and the precipitate was washed well with acetone. The crude reaction mixture dissolved in 1.5 l of acetone and 36 mg of manganese dioxide was added, followed by stirring at room temperature for 3.5 hours. The manganese dioxide was filtered off, and the precipitate was washed twice with acetone. The filtrate was concentrated under vacuum and passed through a silica gel column, eluting with dichloromethane, then 1:1 ethyl acetate/dichloromethane, to give the title compound (27 mg). Elemental Analysis for C7H7O2N3Cl2 :
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+]=[N-].[H][H]>[Pd].C1(C)C=CC=CC=1>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCOCCN
Yield: 95 %

Procedure:
Under a nitrogen purge, 10% palladium on carbon (9.2 g) was added to a solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (92.0 g, 399 mmol) in toluene (900 mL) in a pressure vessel. The vessel was placed under hydrogen pressure (30 psi, 2.0×105 Pa), and for the first 20 minutes, the hydrogen was replaced every five minutes and brought to a pressure of (20 psi, 1.4×105 Pa). The reaction was maintained under hydrogen pressure (20 psi, 1.4×105 Pa) overnight. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure to yield 77.4 g of tert-butyl 2-(2-aminoethoxy)ethylcarbamate as a light green oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:13])=[C:4]([C:8]([I:12])=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].[Cl:14][CH2:15][C:16](Cl)=[O:17]>CC(N(C)C)=O>[Cl:14][CH2:15][C:16]([NH:1][C:2]1[C:3]([I:13])=[C:4]([C:8]([I:12])=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: Nc1c(I)cc(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: O=C(CCl)Nc1c(I)cc(I)c(C(=O)O)c1I
Yield: 78.9 %

Procedure:
According to the procedure described in Example 1, a suspension of 103 g of 3-amino-2,4,6-triiodobenzoic acid (Beil. XIV, 414) (0.2 mol) in 200 ml of DMA is added to 24.8 g of chloroacetyl chloride (0.22 mol). 93.27 g of 3-[(2-chloroacetyl)amino]-2,4,6-triiodobenzoic acid are obtained (0.158 mol).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[CH3:3]>[Pd].CO>[ClH:1].[ClH:1].[CH2:2]([N:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[CH3:3]
Reactant: CCCCCCCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCCCN(CC)CCCOc1ccc(N)cc1

Procedure:
In a manner similar to Preparation 42 hydrogenate N-ethyl-N-heptyl-3-(4-nitrophenoxy)propanamine hydrochloride over 10% palladium on carbon in methanol to obtain the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cccc(C(F)(F)F)c2)CCN1c1cnccc1C1CC1
Yield: 80 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 150 mg, 0.738 mmol) was reacted with 1-bromo-3-(trifluoromethyl)benzene (831 mg, 3.69 mmol), 1,4-dioxane (10 mL), copper iodide (14.0 mg, 0.073 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (8.4 mg, 0.073 mmol) and potassium phosphate (469.9 mg, 2.21 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in CHCl3) afforded 205 mg of the product (80% yield).