Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:40]=[CH:39][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][C@@H:14]2[N:19]([C:20](=[O:33])[CH2:21][NH:22][C:23](OCC3C=CC=CC=3)=[O:24])[CH2:18][CH2:17][N:16]([CH2:34][C:35]([OH:37])=[O:36])[C:15]2=[O:38])=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].ON1C(=O)CCC1=O.C(OC([NH:56][CH2:57][CH2:58][C:59]1[CH:67]=[CH:66][C:62](C(O)=O)=[CH:61][CH:60]=1)=O)(C)(C)C.Cl.C(N=C=NCCCN(C)C)C.[F:80][C:81]([F:86])([F:85])[C:82]([OH:84])=[O:83]>CO.[H][H].CN(C)C=O>[F:80][C:81]([F:86])([F:85])[C:82]([OH:84])=[O:83].[NH2:56][CH2:57][CH2:58][C:59]1[CH:67]=[CH:66][C:62]([C:23]([NH:22][CH2:21][C:20]([N:19]2[CH2:18][CH2:17][N:16]([CH2:34][C:35]([OH:37])=[O:36])[C:15](=[O:38])[C@@H:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:8](=[O:9])[C:7]2[CH:39]=[CH:40][C:4]([C:1](=[NH:3])[NH2:2])=[CH:5][CH:6]=2)=[O:33])=[O:24])=[CH:61][CH:60]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Reactant: N=C(N)c1ccc(C(=O)NCCC[C@H]2C(=O)N(CC(=O)O)CCN2C(=O)CNC(=O)OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: N=C(N)c1ccc(C(=O)NCCC[C@H]2C(=O)N(CC(=O)O)CCN2C(=O)CNC(=O)c2ccc(CCN)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 20 ml of methanol was dissolved 300 mg of (S)-3-[3-(4-amidinobenzoylamino)propyl]-4-benzyloxycarbonylaminoacetyl-2-oxopiperazine-1-acetic acid produced in Reference Example 21. To the solution was added 120 mg of 10% Pd--C, and the mixture was stirred for one hour at room temperature in hydrogen streams. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give an oily product, which was dissolved in 5 ml of dimethylformamide. To the solution was added 5 ml of activated-ester solution in dimethylformamide which was prepared from 94 mg of N-hydroxysuccinimide and 173 mg of 4-(2-t-butoxycarbonylaminoethyl)benzoic acid in the presence of 167 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred for two hours at room temperature. The reaction mixture was concentrated to give an oily product, which was dissolved in 7 ml of trifluoroacetic acid. The solution was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by means of a CHP-20 column (eluted with 10% acetonitrile/water) to afford 110 mg of the titled compound as a colorless amorphous powdery product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:25][CH2:24][C:19]3(OCC[O:20]3)[CH2:18][CH2:17]2)[CH3:15])=[CH:4][CH:3]=1.Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:17][CH2:18][C:19](=[O:20])[CH2:24][CH2:25]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCC(=O)CC1
Temperature: 85 °C

Procedure:
To a solution of 8-[1-(4′-Chloro-biphenyl-2-yl)-ethyl]-1,4-dioxa-8-aza-spiro[4.5]decane (3.1 g, 8.66 mmol) in dioxane-water (1:1 60 mL) is added HCl 37% (10.5 mL, 346 mmol). The reaction is then heated up to 85° C. for 26 hours. The solvent is then removed under vacuum and the aqueous phase is basified to pH=9 using sodium hydroxide 4N and then extracted with DCM. The organic layer is then washed with brine. The combined organic phase is then dried on MgSO4 and concentrated to afford 1-[1-(4′-Chloro-biphenyl-2-yl)-ethyl]-piperidin-4-one. The crude material is used without further purification. Found m/z ES+=314.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 7.57 (1H, d, J=7.1 Hz), 7.32 (1H, t), 7.30 (2H, d, J=8.6 Hz), 7.22 (1H, t), 7.15 (2H, d, J=8.6 Hz), 7.09 (1H, d, J=6.1 Hz), 3.58 (1H, m), 2.63 (2H, m), 2.52 (2H, m), 2.25 (4H, t, J=6.1 Hz), 1.24 (3H, d, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].CC(C[AlH]CC(C)C)C.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](OC)=[O:27])=[CH:21][CH:20]=1)#[N:18]>C1COCC1.CCOC(C)=O>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH:5][C:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=1)=[O:27]
Reactant: COC(=O)Cc1ccc(C#N)cc1
Reactant: CC(C)(C)CCN
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)CCNC(=O)Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
Dissolve 3,3-dimethylbutylamine (0.8 mL, 6.4 mmol) in anhydrous THF (2 mL) under nitrogen. Cool the solution at 0° C. and add DIBAL-H (6.2 mL, 6.2 mmol, 1M solution in toluene). Allow the mixture to warm up to room temperature and stir for 2 h. Add this complex to a solution of methyl (4-cyanophenyl)acetate (192 mg, 1.1 mmol) in THF (4 mL) and stir at room temperature overnight. Dilute with EtOAc and quench with 5% KHSO4. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:3) to obtain the desired intermediate (160 mg, 60%). MS (ES+) m/z: 245 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=O.C([BH3-])#N.[Na+]>C(O)C.CO>[CH:7]1([NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)CN
Reactant: O=C1Cc2ccccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COC(=O)CNC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Glycine methyl ester (0.053 moles, 6.64 g) is dissolved in absolute ethanol (420 ml) and methanol (42 ml), added with 2-indanone (0.053 moles, 7 g), and with sodium cyanoborohydride (0.058 moles, 3.7 g) under stirring, in 40 minutes. The mixture is left under stirring at r.t. overnight, evaporated to dryness under vacuum and the residue is taken up with water (500 ml) and ethyl acetate (500 ml). The phases are separated and the organic phase is extracted with a 0.1N HCl solution (3×200 ml). The acidic solution is adjusted to pH 8.5-9 with a sodium bicarbonate saturated solution and 20 extracted with ethyl acetate (3×250 ml). The organic solution is separated, dried over sodium sulfate and evaporated under vacuum. The resulting product is dried under vacuum at r.t. Yield: 5.8 g (53.4%)
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(OCC)C.[Br:18][C:19]([F:24])([F:23])[C:20](Cl)=[O:21].C(N(CC)CC)C>O>[Br:18][C:19]([F:24])([F:23])[C:20]([O:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:21]
Reactant: O=C(Cl)C(F)(F)Br
Reactant: OCC12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OCC12CC3CC(CC(C3)C1)C2)C(F)(F)Br
Temperature: 0 °C
Yield: 95 %

Procedure:
A 200 mL, three-necked flask was charged with 4.76 g (31.8 mmol, 1.11 equivalents) of 1-adamantane methanol and 55 g of diethyl ether, followed by stirring to obtain a suspension. Then, 6.15 g (28.6 mmol, 1.0 equivalent) of bromodifluoroacetic chloride were added thereto. The resulting suspension was cooled down to 0° C. by using an iced bath, followed by adding 5.78 g (57.2 mmol, 2.0 equivalents) of triethylamine in a slow dropwise manner. This reaction liquid was allowed to stand with stirring to reach room temperature, followed by stirring at room temperature for 1 hour. Then, 50 g of water were added to wash the reaction liquid. The resulting organic layer was washed with 50 g of saturated sodium hydrogencarbonate, 50 g of saturated brine, and 50 g of water in sequence. Then, it was dried with magnesium sulfate, followed by distilling the solvent off, thereby obtaining 8.78 g of the target adamantane-1-ylmethyl bromodifluoroacetate (yield: 95%, purity: 100%).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]([NH:17][NH2:18])=[O:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[K+]>CO.O>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:15]3[O:16][C:2]([NH2:1])=[N:18][N:17]=3)[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: COc1ccc(C2(C(=O)NN)CC2)cc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2(c3nnc(N)o3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Cyanogen bromide (0.424 g, 4.0 mmol) was added to an ice-cooled slurry of 1-(4-methoxyphenyl)cyclopropanecarbohydrazide (0.750 g, 3.64 mmol) and potassium bicarbonate (0.50 g, 5.0 mmol) in methanol (8 mL). The mixture was stirred at 0° C. for 1 h. the ice bath was allowed to warm slowly and stirred at RT for overnight. The reaction mixture was diluted with water (10 mL), stirred for 1 h. The precipitate was collected by filtration and washed with water, and dried on high vacuum to afford the desired product (600 mg, 71.3%). Analytical LCMS: (M+H)+=232.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:19]([NH2:39])[CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[CH2:19]([NH2:39])[CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4]
Reactant: O=C(O)C(F)(F)F
Agent: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C([O-])C(F)(F)F
Reaction time: 0.33 h

Procedure:
To a magnetically stirred solution of 69 mg (0.6 mmol) of trifluoroacetic acid, in 2 ml of dry methylene chloride, at 0° C., 0.046 ml (0.6 mmol) of dry DMF was added and then 0.3 ml (0.6 mmol) of 2.0 M solution of oxalyl chloride in methylene chloride, dropwise. The reaction mixture was stirred for 20 min and then a solution of 172 mg (0.6 mmol) of arachidonyl amine in 2 ml of methylene chloride was added and the reaction was stirred for 2 hrs at ambient temperature. The product was purified with silica gel column chromatography (eluents: petroleum ether/ethyl acetate, up to 50% ethyl acetate). Evaporation of the solvent, followed by Millipore filtration of a CH2Cl2 solution of the product gave 153 mg (0.4 mmol, 67% yield) of arachidonyl-amine-trifluoroacetate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([F:27])[CH:13]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:14]([F:27])[CH:13]=1)[C:34](=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Br)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of (2-bromo-5-methoxyphenyl) [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (690 mg), pyridine (2 ml) and acetic anhydride (2 ml) was stirred for 4 hours at 80° C. The reaction mixture was diluted with an aqueous solution of 1N sodium hydroxide, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (530 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[C:11](=[O:16])[O:12][C:13](=O)[NH:14][C:9]=2[CH:8]=[CH:7][CH:6]=1.O>CO>[NH2:14][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH3:3])[C:10]=1[C:11]([O:12][CH3:13])=[O:16]
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(N)cccc1OC
Temperature: 65 °C
Reaction time: 14.5 h
Yield: 93.7 %

Procedure:
To a stirred solution of sodium hydroxide (0.06 g, 1.5 mM) in methanol (7 mL) under a nitrogen atmosphere was added 5-methoxy-2H-3,1-benzoxazine-2,4(1H)-dione (2.90 g, 15.0 mM). The reaction mixture was stirred at 65° C. for 14.5 hr, cooled to room temperature and poured into water. The resulting solution was extracted with ethyl acetate and the combined extracts were dried (Na2 SO4), filtered and concentrated to provide the title compound (2.55 g, 94%) as a tan oil; MS(CI): 182 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6]/[C:7](/[CH3:22])=[CH:8]/[CH2:9][CH2:10]/[C:11](/[CH3:21])=[CH:12]/[CH2:13][CH:14](C(O)=O)[C:15]([OH:17])=[O:16])[CH3:3]>CCCCCCCCCC>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6]/[C:7](/[CH3:22])=[CH:8]/[CH2:9][CH2:10]/[C:11](/[CH3:21])=[CH:12]/[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH3:3]
Reactant: C/C(=C\CC(C(=O)O)C(=O)O)CC/C=C(\C)CCCN(C)C
Solvent: CCCCCCCCCC
Product: C/C(=C\CCC(=O)O)CC/C=C(\C)CCCN(C)C
Yield: 105.5 %

Procedure:
To a boiling mixture of 6.2 g of sodium and 80 ml of xylene, with stirring are added gradually 80.2 g of geranylmalonic ester; the mixture is heated for one hour until all of the sodium is dissolved and then 29-32 g of dimethylaminoethyl chloride (in a solvent or without it) are added at a rate that ensures slight boiling of the reaction mixture. The reaction mixture is then heated with stirring so that the solvent boils until the reaction of a sample to phenolphthalein is neutral. After the mixture is cooled, the formed salt precipitate is dissolved by adding sufficient water, the reaction products are extracted with an organic solvent immiscible with water, for example with xylene. The solvent is then distilled and the residue (dimethylaminoethylgeranylmalonic ester) is fractionated in vacuum. As a result, 42 g of the dimethylaminoethylgeranylmalonic ester are produced. The boiling point of the ester is 178°-179° C/4 mm, n20 1.4720. To the boiling concentrated alcoholic solution of potassium hydroxide taken in excess, are added with stirring 42 g of dimethylaminoethylgeranylmalonic ester, the mixture is heated for one hour, then the alcohol is removed, the residue is dissolved in water and neutralized for example with hydrochloric acid. The isolated dimethylaminoethylgeranylmalonic acid is filtered with suction, washed with water and dried in a vacuum desiccator. As a result, 32 g of dimethylaminoethylgeranylmalonic acid are produced. The melting point of the acid is 145.5° - 146.0° C (with decomposition). The 32 g of dimethylaminoethylgeranylmalonic acid are decarboxylated in a hydrocarbon solvent having a boiling point of 150° C and above, for example in n-decane, after which the formed monocarboxylic acid is purified by fractionation in vacuum. 29 g of dimethylaminoethylgeranylacetic acid are obtained. The melting point of the acid is 183° - 185° C/2 mm, n20 1.4945.
Reaction SMILES: [NH2:1][CH:2]1[C:5]([CH3:7])([CH3:6])[S:4][C:3]1([CH3:9])[CH3:8].[O-:10]I(=O)(=O)=O.[Na+].[OH-:16].[Na+]>O>[NH2:1][CH:2]1[C:5]([CH3:7])([CH3:6])[S:4](=[O:10])(=[O:16])[C:3]1([CH3:9])[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: [OH-]
Reactant: CC1(C)SC(C)(C)C1N
Agent: [Na+]
Solvent: O
Product: CC1(C)C(N)C(C)(C)S1(=O)=O

Procedure:
A solution of 14.53 g. (0.1 mole) 3-amino-2,2,4,4-tetramethylthietane and 64.17 g. (0.3 mole) sodium m-periodate in 500 ml. water was stirred overnight at room temperature. The reaction mixture was adjusted to pH 13 with sodium hydroxide solution and the precipitated sodium iodate removed by filtration. The filtrate was washed with 100 ml. ethyl ether, the aqueous phase extracted continuously with methylene chloride over 18 hours, the extract dried (MgSO4) and solvent evaporated in vacuo. The residual solid was recrystallized from ethyl acetate to provide 8.5 g. of product, M.P. 104°-106.5° C. A second crop of crystals was obtained, 2.7 g., M.P. 103°-106° C. Total yield, 63%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[N:14]#[C:15][NH2:16].[N+:17]([O-:20])([OH:19])=[O:18]>C(O)C>[N+:17]([O-:20])([O-:19])=[O:18].[CH3:13][O:12][C:8]1[CH:7]=[C:5]([NH:6][C:15]([NH2:16])=[NH2+:14])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: N#CN
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=[N+]([O-])O
Solvent: CCO
Product: COc1cc(NC(N)=[NH2+])cc(OC)c1OC
Product: O=[N+]([O-])[O-]
Temperature: 25 °C

Procedure:
3,4,5-Trimethoxyphenylguanidinium nitrate was prepared by heating a solution of 3,4,5-trimethoxyaniline (5.49 g, 30.0 mmol), cyanamide [Aldrich, 50% solution in water w/v] (3.50 ml, 34.5 mmol) and concentrated HNO3 (2.1 ml, 30.0 mmol) in ethanol (30 ml). The solid which formed on cooling to room temperature was collected by filtration, washed with ethanol and dried to give the desired material (4.60 g) as a grey solid m.p. 187°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>O1CCOCC1>[C:42]([NH:46][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
5-Bromopicolinic acid (200 mg, 0.99 mmol) was dissolved in dioxane (2 ml) and Hunig's Base (520 μl, 2.97 mmol, 3 equiv.), TBTU (350 mg, 1.09 mmol, 1.1 equiv.) and tert-butyl amine (124 μl, 1.19 mmol, 1.2 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 50:50. The desired 5-bromo-pyridine-2-carboxylic acid tert-butylamide (235 mg, 92% yield) was obtained as a colorless oil, MS: m/e=257.0/259.0 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.[CH2:28]([CH2:31][NH2:32])[CH:29]=C.[CH3:33]C(N(C)C)=O>>[CH2:31]([N:32]([CH3:33])[CH2:2][CH2:3][CH2:4][O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1)[CH:28]=[CH2:29]
Reactant: CN([C@H]1CC[C@H](COCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)N(C)C
Reactant: C=CCCN
Product: C=CCN(C)CCCOC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 69 mg (0.146 mmol) of trans-N-[4-(3-Bromo-propoxymethyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 0.8 ml DMA was treated at 0° C. with 0.028 ml (0.29 mmol) of N-allylmethylamine and stirred at RT for 22 h. The solution was cooled (0° C.) and treated again with 0.028 ml (0.29 mmol) of N-allylmethylamine. After 6 h at RT, the solution was concentrated and dissolved in aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried over Na2SO4 and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (95:5) yielded 43 mg (64%) of trans-N-{4-[3-(Allyl-methyl-amino)-propoxymethyl]-cyclohexyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 463 (MH+).
Reaction SMILES: [H-].[Na+].C(O)C.[CH2:6]([O:8][C:9](=[O:15])[C:10](OCC)=[O:11])[CH3:7].[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[CH3:17].Cl>C(OCC)C>[CH2:16]([O:18][C:19](=[O:29])[CH:20]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:10](=[O:11])[C:9]([O:8][CH2:6][CH3:7])=[O:15])[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)COc1cccc(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)C(Oc1cccc(F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 105.7 %

Procedure:
60% NaH in mineral oil (19.5 g, 488.4 mmol) is covered with 600 ml of dry diethyl ether. Ethanol (28.1 ml, 444 mmol) is added dropwise within 25 min. Then oxalic acid diethyl ester (66 ml, 488 mmol) is added dropwise within 20 min. After 10 min stirring at room temperature, the mixture is heated to reflux. A solution of 107 (88 g, 444 mmol) in 80 ml of dry diethyl ether is added dropwise within 30 min and the mixture is allowed to reflux for 1 hour. After cooling down to room temperature, the reaction mixture is poured on 2M HCl (400 ml)/ice (400 g) and extracted with diethyl ether. The organic layers are dried over sodium sulfate, filtrated and evaporated. The crude product is purified by filtration over silica gel (ethyl acetate/hexane 1:1). Evaporation gave 140 g of an red oil. The mineral oil could be removed using a separatory funnel. Yield: 132 g (100%).
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)[C:4](=[O:17])[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[F:25]C1C=CC(NN)=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:25][C:21]1[CH:22]=[CH:23][C:18]([N:3]2[C:4](=[O:17])[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=3)=[CH:6][NH:2]2)=[CH:19][CH:20]=1
Reactant: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1ccccc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1ccc(F)cc1

Procedure:
A 5.5 gram portion of the atropic ester of Example 1 was combined with 3.5 grams of 4-fluorophenylhydrazine hydrochloride and 2 grams triethylamine in 50 ml. benzene. The mixture was stirred at reflux temperature for 5 hours, after which about half of the benzene was allowed to evaporate and an equivalent amount of meta-xylene was added. The mixture was then stirred at reflux overnight, and the reaction mixture was evaporated to dryness under vacuum. The residue was partitioned between ethyl acetate and water, and the organic layer was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel with ethyl acetate as the eluant. The product containing fractions were combined and evaporated to dryness to produce about 3.5 grams of crude intermediate, which was recrystallized from methanol to produce 2.7 grams of purified 1-(4-fluorophenyl)-4-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 171°-173° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]([CH3:15])=[C:5]([N+:16]([O-])=O)[C:4]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:19])[CH2:3]1>C(O)(=O)C.CO.[Fe]>[NH2:16][C:5]1[C:4]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:19])[CH2:3][C:2]([CH3:1])([CH3:28])[CH:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]=1[CH3:15]
Reactant: CC1=C([N+](=O)[O-])C(C)(NCc2ccccc2)CC(C)(C)C1Nc1ccccn1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC1=C(N)C(C)(NCc2ccccc2)CC(C)(C)C1Nc1ccccn1
Temperature: 70 °C

Procedure:
Add iron powder (7.0 g) to a solution of 6-methyl-3-nitro-4-[benzylamino](2-pyridyl)(2,4,6-trimethylphenyl)amine (8.75 g, 23.2 mmol) in acetic acid (14 mL) and MeOH (70 mL). Heat the resulting mixture at 70° C. for 1 h, cool to ambient temperature, and filter through a pad of celite. Evaporate the filtrate to dryness under reduced pressure. Treat he residue with 1N aq NaOH and extract with EtOAc. Wash the EtOAc extract with water and saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate to obtain the title compound as a brown solid which is used without further purification.