Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[CH2:20]([C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCI
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 65.5 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.3 g of 1-iodobutane were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 7 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.1 g of 2-butyl-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (80)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][O:22][CH:23]([CH3:27])[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:24](=[O:25])[CH:23]([O:22][CH3:21])[CH3:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: COC(C)C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: COC(C)C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-methoxy-propanoic acid (CAN 4324-37-2) as starting materials; MS (EI) 389.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1.[Zn]>[OH:3][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:1])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(=O)Cc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C)(O)Cc1ccccc1
Reaction time: 3 h
Yield: 68.7 %

Procedure:
A mixture of benzyl methyl ketone (134 g, 1 mole) and ethyl bromoacetate (168 g, 1 mole) was added to a mixture of mossy zinc (100 g) in toluene (500 cm3) in a large flask. When the vigorous exothermic reaction had subsided, the mixture was boiled for 3 hours. The solution was cooled, and washed sequentially with dilute sulfuric acid, 10% aqueous sodium hydroxide and then with water. The organic layer was separated, dried and filtered. The toluene solvent was removed, leaving the hydroxy ester, ethyl 3-hydroxy-3-benzylbutanoate (152.8 g), as an orange oil. The ester's structure and purity were established by NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:24]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(F)cc1)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
4-Fluoro phenylacetic acid (12.3 g, 79.79 mmoles) was dissolved in 30 ml dichloromethane. To this mixture, oxalylchloride (10.17 g, 79.79 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-bromoanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (10.6 g, 79.79 mmoles) was added and the reaction mixture was warmed to RT and stirred overnight. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as white solid (6.1 g, 37% yield. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 12.05 (s, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.58 (dd, J=8.9, 2.4 Hz, 1H), 7.24 (dt, J=5.4, 1.9 Hz, 2H), 7.09 (dt, J=8.6, 2.1 Hz, 2H), 6.79 (d, J=8.7 Hz, 1H), 4.27 (s, 2H).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C.O>[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1cc(=O)c(O)c(CO)o1
Reactant: CCOC(=O)CCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCOc1c(CO)oc(C)cc1=O
Yield: 60 %

Procedure:
To a solution of 2.00 g (0.0304 mole) of potassium hydroxide in 33 ml of ethanol and 5 ml of water was added 4.75 g (0.0304 mole) of 2-hydroxymethyl-3-hydroxy-6-methyl-4-pyrone, and the resulting mixture heated to 50°. A 7.8 g (0.029 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atmosphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 5.4 g (60%) of oily product, 2-hydroxymethyl-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone. NMR (CDCl3): δ1.22 (3H, t, J = 7 Hz), 2.26 (3H, s); 4.61 (2H, m); 6.17 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](Cl)=[O:9].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].O>C(Cl)Cl>[CH2:12]([N:14]([CH2:15][CH3:16])[C:8]([C:7]1[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=1[Cl:1])=[O:9])[CH3:13]
Reactant: CCNCC
Reactant: O=C(Cl)c1cc(Cl)nnc1Cl
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(Cl)nnc1Cl

Procedure:
3,6-Dichloropyridazine-4-carbonyl chloride (2.5 g) was initially charged in DCM (25 ml) at RT. Thereafter, diethylamine (1.5 ml) predissolved in DCM (5 ml) was slowly added dropwise while stirring. After stirring at RT for 3 h, the mixture was admixed with water and extracted three times with DCM. The combined DCM phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of silica gel (70 g cartridge, n-heptane/EA gradient). 1.8 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:14]([Cl:13])(=[O:16])=[O:15])=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)Cc1cccc(Br)c1
Product: COC(=O)Cc1cc(Br)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-(3-bromophenyl)acetate (22 g, 67 mmol) was slowly added into ClSO3H at −10° C. After 1 h, the mixture was warmed up to rt and stirred overnight, diluted slowly with ice water and extracted with EA. The organic layer was washed with water, dried over Na2SO4 and evaporated to give compound P15a (17 g, 54%).
Reaction SMILES: [C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6](O)=[O:7])#[N:2].C(Cl)(=O)C([Cl:24])=O>ClCCl>[C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6]([Cl:24])=[O:7])#[N:2]
Reactant: N#CC(CCC(=O)O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: N#CC(CCC(=O)Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Dimethyltormamide (1 drop) was added to a suspension of 4-cyano-4,4-diphenylbutanoic acid [(7.8 g, 29 mmol), WO97/24325] and oxalyl chloride (5.2 mL, 60 mmol) in dichloromethane (40 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was azeotroped with toluene (3×50 mL) to afford the crude title compound. The material was used in preparation 60 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[C:4]([F:14])[CH:3]=1.[OH-].[Na+].Cl[CH:18]([F:20])[F:19]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:18]([F:20])[F:19])[NH:10][N:9]=2)=[C:4]([F:14])[CH:3]=1
Reactant: FC(F)Cl
Reactant: Oc1cc(-c2ccc(Cl)cc2F)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(Cl)ccc1-c1cc(OC(F)F)[nH]n1
Reaction time: 6 h
Yield: 14.7 %

Procedure:
64 g of the 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole obtained in step 1.1 were initially charged in 600 ml of dioxane. A solution of 24 g of sodium hydroxide in 70 ml of water was added, and the mixture was heated at reflux. With stirring, 238.7 g (2.76 mol, 9.2 eq.) of gaseous chlorodifluoromethane were added, and during the addition the pH was monitored constantly and, when it approached the neutral range (pH<9), increased by addition of additional NaOH solution to about pH 12. After 6 h, the mixture was allowed to cool, 1800 ml of water were added and the mixture was extracted twice with in each case 500 ml of MTBE. The combined organic phases were washed with in each case 500 ml of water and saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated. This gave 58.7 g of crude 3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1H-pyrazole. 32.3 g of this mixture were distilled under reduced pressure, giving 11.6 g of the title compound as an oil of a purity of 86%. Yield: 22.9%
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Cl[CH2:11][CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][CH2:11][CH:12]=[O:13]
Reactant: Cc1ccc(Cl)cc1N
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(Cl)cc1NCC=O
Temperature: 150 °C

Procedure:
2-Methyl-5-chloroaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at about 150° C. for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-chloroanilino)acetaldehyde.
Reaction SMILES: [H-].[Na+].C[CH:4]([CH2:8][CH3:9])[CH2:5][CH:6]=[O:7]>CCCCCC.C(COC)OC>[CH3:4][CH:9]([CH2:5][CH3:6])[CH2:8][CH:4]=[CH:5][C:6]([O:7][CH2:9][CH3:8])=[O:7]
Reactant: CCC(C)CC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CCOC(=O)C=CCC(C)CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 122 %

Procedure:
Sodium hydride (60% dispersion, 2.4 g, 65 mmol) was washed with hexane and suspended in dimethoxyethane 60 mL. While cooling in ice water bath triethyl phosphonoacetate was slowly added, calcd. 5 minutes. The reaction was stirred for 15 minutes at 0° C. and a solution of 3-methyl-1-pentanal 11 (6.5 g, 65 mmol) in imethoxyethane 20 mL was added. After refluxing overnight, it was concentrated, water and hexane were added, the organic phase was separated, and the aqueous portion discarded. The solution was washed twice with brine and dried on magnesium sulfate. The solvent was evaporated to give 12 (6.75 g, 61%). 1H-NMR (CDCl3) δ6.89 (m, 1H, —CH2CH:CHCOOEt), 5.77 (d, 1H, —CH2CH:CHCOOEt), 4.16 (q, 2H, —COOCH2CH3), 2.15 and 1.98 (1H each and a multiplet, —CH2CH:CHCOOEt), 1.48 (m, 1H, C2H5(CH3)CHCH2), 1.30-1.10 (m), and 0.83.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30](OCC)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([NH2:42])[C:37]1[O:41][CH:40]=[CH:39][CH:38]=1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:42][CH2:36][C:37]3[O:41][CH:40]=[CH:39][CH:38]=3)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCc3ccco3)c(O)c3ncc(Cc4ccccc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and furfurylamine employing methods similar to those described in Example 2. The product was obtained as a light beige solid: 1H NMR (CDCl3) δ 10.37 (1H, br t, J=5.5 Hz), 8.62 (1H, s), 7.81 (2H, d, J=8 Hz), 7.39 (1H, s), 7.30 (3H, m), 7.17 (2H, d, J=8 Hz), 7.06 (1H, s), 7.03 (2H, m), 6.33 (2H, m), 5.40 (2H, br), 4.66 (2H, br d, J=5.5 Hz), 4.05 (2H, s), 3.01 (3H, s); HRMS calcd for C29H25N3O6S+H+: 544.1542. Found: 544.1534.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([O-:16])(=[O:15])=[O:14])[CH:8]=2)[N:3]=1.[Na+:17].[CH2:18]1[CH2:24][S:21](=[O:23])(=[O:22])[O:20][CH2:19]1>>[CH3:1][C:2]1[C:10]([CH3:11])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([O-:16])(=[O:15])=[O:14])[CH:8]=2)[N+:3]=1[CH2:19][CH2:18][CH2:24][S:21]([O-:23])(=[O:22])=[O:20].[Na+:17]
Reactant: O=S1(=O)CCCO1
Reactant: CC1=Nc2ccc(S(=O)(=O)[O-])cc2C1(C)C
Agent: [Na+]
Product: CC1=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C
Temperature: 110 °C
Yield: 97.3 %

Procedure:
A mixture of 14 g of sodium 2,3,3-trimethyl-3H-indole-5-sulfonate and 14 g 1,3-propanesultone in 100 mL dicholorobenzene was heated at 110° C. for 2 h. After it cooled down, the solvent is decanted. The resulting solid was then dissolved in 100 mL of acetonitrile, and 300 mL of ethyl acetate was added. The resulting sticky solid was again stirred in 300 mL of ethyl acetate to yield 20 g of the product.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=[O:25])=[CH:18][CH:17]=1.S(Cl)(Cl)=O.[NH2:31][C:32]([NH2:34])=[O:33]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([NH:31][C:32]([NH2:34])=[O:33])=[O:25])=[CH:20][CH:21]=1
Reactant: NC(N)=O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)NC(N)=O)cc1
Temperature: 100 °C
Yield: 49.9 %

Procedure:
To 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (1.00 g, 2.85 mmol) obtained in Example 17 was added thionyl chloride (1.7 ml), and the mixture was stirred under heating for 1 hr at 100° C. Excess thionyl chloride was evaporated under reduced pressure and urea (257 mg, 4.28 mmol) was added to the obtained residue. The mixture was stirred under heating for 1 hr at 120° C. and purified by silica gel column chromatography (developing solvent; dichloromethane: methanol=10:1) to give the title compound (560 mg, yield 50%) as a white solid.
Reaction SMILES: S(O[CH2:6][CH2:7][O:8][S:9](=[O:12])(=[O:11])[NH2:10])(=O)(=O)N.[CH2:13]([OH:17])CCO>>[S:9]([O:17][CH2:13][CH2:6][CH2:7][O:8][S:9](=[O:11])(=[O:12])[NH2:10])(=[O:11])(=[O:8])[NH2:10]
Reactant: NS(=O)(=O)OCCOS(N)(=O)=O
Reactant: OCCCO
Product: NS(=O)(=O)OCCCOS(N)(=O)=O

Procedure:
1,3-Bis-O-sulfamyl-1,3-propanediol is prepared in the same manner as 1,2-bis-O-sulfamyl-1,2-ethanediol in Example 1 except that 1,3-propanediol (29.2 g., 0.385 mol.) is employed as the alkanediol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7]C)=O.[NH2:14][O:15][CH2:16][CH2:17][OH:18].C[O-].[Na+].Cl>CO.O>[Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:7]
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1N
Reactant: NOCCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1c(Cl)cc(Cl)cc1C(=O)NOCCO
Temperature: 50 °C
Reaction time: 8 h

Procedure:
9 g (40.9 mmol) of methyl 3,5-dichloro-2-aminobenzoate and 6.3 g (81.8 mmol) of 2-(aminooxy)ethanol are initially charged in 90 ml of methanol, and 22.1 g (122.7 mmol) of sodium methoxide as a 30% strength solution in methanol are added dropwise at 20° C. The mixture is stirred at 50° C. overnight. The mixture is cooled and poured onto 400 ml of water, and the pH is adjusted to 3 using 1 N hydrochloric acid. The mixture is extracted 3 times with in each case 150 ml of ethyl acetate and the extracts are dried with sodium sulphate and concentrated using a rotary evaporator.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:12](=[O:15])[CH2:13][CH3:14])[CH3:9])=[C:4]([F:11])[CH:3]=1
Reactant: CCC(=O)Cl
Reactant: CC(N)c1ccc(Br)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NC(C)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
61 mg (1 eq, 0.24 mmol) of 1-(4-bromo-2-fluorophenyl)ethanamine from Stage 1 were dissolved in 4 ml of dichloromethane, and 24 mg (1.1 eq, 23 μl, 0.264 mmol) of propanoyl chloride and 70 mg (2.2 eq, 90 μl) of Hünig's base were added. The mixture was stirred at room temperature for 5 h and then concentrated. The crude product was dissolved in ethyl acetate and washed 1× with 1M HCl, 1× with sat. sodium carbonate solution and then with water, and dried over magnesium sulphate. After concentrating under reduced pressure, the resulting crude product was purified by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate). 50 mg (67%) of N-[1-(4-bromo-2-fluorophenyl)ethyl]propanamide were obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].Cl.[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:11](=[O:12])[CH:10]=[CH:9][C:8]2[CH:14]=[CH:15][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([O:16][CH3:17])[CH:7]=2)[CH2:22][CH2:21]1
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Reactant: CC1CCC(N)CC1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)NC2CCC(C)CC2)ccc1OC(C)=O
Yield: 65.3 %

Procedure:
Using 5.09 g of 4-acetoxy-3-methoxycinnamoyl chloride, 2.98 g of 4-methylcyclohexylamine hydrochloride, and 100 ml of pyridine, a reaction similar to that conducted in Example 53 was carried out. As a result, 4.31 g of N-(4-methylcyclohexyl)-4-acetoxy-3-methoxycinnamamide was obtained as yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].C([Li])CCC.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>CCOCC>[CH3:16][Si:17]([CH3:19])([CH3:18])[NH:4][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:5]=1[Cl:10]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)Nc1c(Cl)cc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Et2O (50 mL) was added to a Schlenk flask under argon containing 2,4,6-trichloroaniline that had been recrystallized from hot hexane. The solution was chilled to −78° C. and n-butyllithium (2.0M in cyclohexane, 4.03 mL, 8.06 mmol) was added via syringe under an argon flow and the resulting white slurry was allowed to stir for 2 h; the slurry acquired a reddish tint over time. Trimethylsilylchloride (1.86 mL, 14.6 mmol) was added by syringe and the solution was allowed to warm to room temperature. Solvent was removed and the orange residue was charged with CH2Cl2. The mixture was filtered over Celite, the Celite washed with CH2Cl2 and the filtrate concentrated under reduced pressure to give an analytically pure orange oil in 90% yield (1.776 g, 6.61 mmol): 1H NMR (C6D6, 20° C.) δ 6.95 (s, 2H, Ar), 3.76 (s, 1H, NH), 0.16 (s, 9H, SiMe3); 13C NMR (C6D6, 20° C.) δ s179.50, 141.26, 124.83, 123.64, 1.783. Anal. Calcd for C9H12Cl3NSi: % C, 40.24; % H, 4.50; N, 5.21. Found: C, 40.01; H, 4.39; N, 5.22.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([CH2:22][OH:23])[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([CH2:22][O:23][S:41]([CH3:40])(=[O:43])=[O:42])[N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-9-(hydroxymethyl)-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidine-8-carboxylate in dry CHCl3, triethylamine (2 eq.) was added and mixture was stirred ten minutes at room temperature. Methanesulfonyl chloride (1.5 eq.) was slowly added and the resulting mixture was aged at room temperature for 1.5 hours to afford tert-butyl 2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-9-{[(methylsulfonyl)oxy]methyl}-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidine-8-carboxylate as the main product (monitored by LC-MS). MS (ES) C22H27FN4O8S requires 526. Found: 527 (M+H+). The reaction mixture was concentrated under vacuum at 30° C. and the solvent switched to dry acetonitrile. The insoluble material was filtered off and to the filtrated 5 equivalents of N-benzylmethylamine were added. The mixture was warmed at 110° C. upon microwave irradiation for 30 minutes then stirred at room temperature for further 36 hours. The mixture was concentrated by rotary evaporation and the resulting residue, dissolved in the minimum amount of MeOH, was carefully acidified with some drops of glacial acetic acid applied on cation-exchange resin. The resin was washed with MeOH and the crude product was eluted with 1M ammonia in methanol. The pooled eluants were concentrated to dryness under reduced pressure to get tert-butyl 9-{[benzyl(methyl)amino]methyl}-2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidine-8-carboxylate as a brown oil. MS (ES) C29H34FN5O5 requires 551. Found: 552 (M+H+).