Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]([CH3:11])([C:8]([OH:10])=O)[C:5]([OH:7])=O)[CH:2]=[CH2:3].C[N:13](C=O)C.C(Cl)(=O)C(Cl)=O.[CH:23]([N:26]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[C:27](=[O:36])[CH2:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:25])[CH3:24]>C(Cl)Cl.C1COCC1>[CH2:1]([C:4]1([CH3:11])[C:5](=[O:7])[N:29]([CH2:28][C:27]([N:26]([CH:23]([CH3:25])[CH3:24])[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:13][C:8]1=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCC(C)(C(=O)O)C(=O)O
Reactant: CN(C)C=O
Reactant: COc1ccc(N(C(=O)CNc2ccccc2)C(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCC1(C)C(=O)Nc2ccccc2N(CC(=O)N(c2ccc(OC)cc2)C(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.04 g (19.2 mmol) of 2-allyl-2-methyl malonic acid, prepared as in Part A, in 50 mL of DCM at 0° C. is added 7 mL of DMF, followed by 6.7 mL (76.8 mmol) of oxalyl chloride. The resulting solution is stirred 1 h at RT, then the solvent and excess oxalyl chloride is removed in vacuo. The residue is dissolved in 100 mL of THF and added dropwise to a stirring solution of 5.0 g (16.0 mmol) of N-Isopropyl-N-(4-methoxy-phenyl)-2-phenylamino acetamide, prepared as in Intermediate 44, in 300 mL of THF maintained at 0° C. The resulting mixture is stirred at RT for 30 min then refluxed for 16 h. The solvents were removed in vacuo and the residue poured into 200 mL of 1H HCl and extracted with EtOAc (2×100 mL). The organics were washed with NaHCO3 (1×100 mL), brine (1×100 mL), dried over MgSO4, and the solvent removed in vacuo. Purification of the brown oil by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 4.0 g of 2-(3-Allyl-3-methyl-2,4-dioxo-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxyphenyl) acetamide: 1H NMR (CDCl3, 300 MHz) δ9.53 (s, 1H), 7.27-6.85 (m, 8H), 5.67-5.60 (m, 1H), 5.05-4.93 (m, 2H), 4.73 (d, 1H, J=17), 4.50-4,45 (d, 1H, J=16), 3.77 (s, 3H), 3.60 (d, 1H, J=17), 2.1 (s, 1H), 1.46 (s, 2H), 1.09-1.03 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]([NH2:12])[CH2:5]2.[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]([CH3:26])[N:23]([CH2:27][CH2:28][CH2:29]Cl)[CH2:22][C@@H:21]1[CH3:31])=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]([CH3:26])[N:23]([CH2:27][CH2:28][CH2:29][NH:12][CH:6]2[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[O:8][CH2:7]2)[CH2:22][C@@H:21]1[CH3:31])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1CCCCl
Reactant: NC1COc2ccc(Br)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1CCCNC1COc2ccc(Br)cc2C1
Temperature: 150 °C
Yield: 99.1 %

Procedure:
A mixture of 6-bromo-chroman-3-ylamine (0.105 g, 0.46 mmol, 1 eq), (2S,5R)-4-(3-chloro-propyl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.133 g, 0.46 mmol, 1 eq), K2CO3 (0.127 g, 0.92 mmol, 2 eq), and Kl (0.017 g, 0.10 mmol, 0.2 eq) in DMF (0.5 mL) was heated in a microwave reactor at 150° C. for 25 min. The reaction mixture was partitioned between EtOAc (3 mL) and 10% aqueous NaHCO3 (3 mL). The organic layer was separated and aqueous layer was extracted with EtOAc (2 mL×3). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give 0.22 g (100%) of (2S,5R)-4-[3-(6-bromo-chroman-3-ylamino)-propyl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil. The material was carried on to next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1>C(C(C)=O)C(C)C>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Solvent: CC(=O)CC(C)C
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reaction time: 72 h

Procedure:
A suspension of omeprazole (250 mg, 0.72 mmol) and (S)-1,1,2-triphenyl-1,2-ethanediol (315 mg, 1.09 mmol) in methyl isobutyl ketone (8.8 ml) at ambient temperature was stirred for 72 h. The solid was filtered, was washed with methyl isobutyl ketone (2×2 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] (286 mg, 69.1% e.e.) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2S[C:15]([C:17]([O-:19])=O)=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].Cl.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[CH:30]=[C:29]([S:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)(=[O:33])=[O:32])[S:28][C:27]=2[CH:40]=1.O.[OH:42]N1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[O:42][C:15]([C:17]([N:37]3[CH2:38][CH2:39][N:34]([S:31]([C:29]4[S:28][C:27]5[CH:40]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=5[CH:30]=4)(=[O:33])=[O:32])[CH2:35][CH2:36]3)=[O:19])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(c1cc2ccc(Cl)cc2s1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)C1Cc2nc(C(=O)[O-])sc2CN1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3)oc2CN1
Reaction time: 48 h

Procedure:
To a solution of lithium 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (70.0 mg) in N,N-dimethylformamide (4.0 ml) were added 1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine hydrochloride (90.0 mg), 1-hydroxybenzotriazole monohydrate (7.0 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (64.0 mg) at room temperature. After stirring for 2 days, ethyl acetate (30 ml) and water (500 ml) were added to the reaction mixture to separate it into layers. The water layer was extracted with ethyl acetate (30 ml). The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate (100 ml), dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (hexane:ethyl acetate=1:1) using silica gel, whereby the title compound (37.9 mg) was obtained as a colorless transparent glassy substance.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]1[C:17](=[O:18])[C:16]2[NH:15][CH:14]=[N:13][C:12]=2[N:11]=[C:9]1[NH2:10].P(=O)(O)(O)O.[CH3:24][C:25](OC(C)=O)=[O:26].CC(O)=O.N1C(=O)C2NC=NC=2N=C1N.OP(O)(O)=O>C(O)(=O)C>[C:25]([N:10]([C:5](=[O:7])[CH3:6])[C:9]1[NH:8][C:17](=[O:18])[C:16]2[NH:15][CH:14]=[N:13][C:12]=2[N:11]=1)(=[O:26])[CH3:24]
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Yield: 94 %

Procedure:
The effect of the ratio of acetic anhydride and acetic acid on the reaction time and yield was also studied. In general, any range of acetic anhydride, acetic acid, guanine and phosphoric acid can be used that provides the desired results. In the present work, it was found that a ratio of 15/10/1/0.05 (ml) of Ac2O/AcOH/guanine/H3PO4 is preferred. It was discovered that guanine could be acetylated using this ratio of reactants at reflux for 15 hours to give diacetylguanine with minimal discoloration in approximately 94% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH2:7]([I:10])[CH2:8][CH3:9]>C1(C)C=CC=CC=1>[I-:10].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH3:9])[CH:3]=1
Reactant: CCCI
Reactant: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCCn1cc[n+](C)c1
Product: [I-]

Procedure:
1-Methylimidazole (8.2 g, made by Aldrich) and propyl iodide (16.9 g, made by Kanto Chemical) were stirred in toluene at 75° C. for 15 hours. After the end of the reaction, the reaction solution separated into the two layers of a toluene layer and an ionic liquid layer. By removing the toluene layer from the reaction solution, the ionic liquid was obtained. The ionic liquid obtained was washed with toluene 3 times for purification. The toluene was distilled off in vacuo, whereby an ionic liquid 1-methyl-3-propylimidazolium iodide (23.8 g) was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[CH2:6][CH3:7].[Br:15]Br.Br>C(Cl)(Cl)Cl>[Br:15][CH:6]([CH3:7])[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: BrBr
Reactant: CCC(=O)c1ccccc1
Agent: Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)c1ccccc1

Procedure:
A pinch of aluminium chloride ground beforehand in a mortar is added to 13.4 g (0.1 mol) of propiophenone in 100 ml of anhydrous chloroform, and a solution of 5 ml (0.1 mol) of bromine in 20 ml of chloroform is then added dropwise, with stirring. The mixture decolourises instantaneously. It is cooled in an ice bath and then stirred overnight to drive off the hydrobromic acid formed. The catalyst is filtered off and the solvent is driven off from the filtrate. 22 g of an oil remain, which is used as such in a subsequent step.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([CH:10]=O)=[C:4]2[N:3]=[CH:2]1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH2:17])[CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][NH:17][CH2:16][CH:15]([O:18][CH2:19][CH3:20])[O:14][CH2:12][CH3:13])[C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(CN)OCC
Reactant: O=Cc1cccc2scnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(CNCc1cccc2scnc12)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzothiazole-4-carbaldehyde (1.96 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.74 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C=O)C.[CH3:12][O:13][C:14]([CH2:16][CH2:17][C:18]12[CH2:25][CH2:24]C(C(O)=O)([CH2:22][CH2:23]1)[CH2:20][CH2:19]2)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:15])[CH2:16][CH2:17][C:18]12[CH2:23][CH2:22][C:1]([C:2]([Cl:4])=[O:3])([CH2:24][CH2:25]1)[CH2:20][CH2:19]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)CCC12CCC(C(=O)O)(CC1)CC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CCC12CCC(C(=O)Cl)(CC1)CC2
Reaction time: 2 h

Procedure:
Oxalyl chloride (794 mg, 6.25 mmol) in methylene chloride (5 ml) plus a drop of DMF is slowly added to a mixture of 4-(2-methoxycarbonyethyl)-bicyclo[2.2.2]octane-1-carboxylic acid (XXI, Example 96,1.2 g, 5 mmol) in methylene chloride (20 ml). The reaction mixture is stirred for 2 hr and concentrated to give the title compound, NMR (400 MHz, CDCl3) δ 3.66, 2.29, 1.95, 1.54 and 1.46.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[H-].[Na+].Cl[CH2:16][CH2:17][O:18]C1CCCCO1.[I-].[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:16][CH2:17][OH:18])[C:3]1=[O:11]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: ClCCOC1CCCCO1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCO)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,3-Dimethyl oxindole (1.1 equivalent) was dissolved in dry dimethyl formamide. Sodium hydride (60% dispersion in mineral oil) (1.1 equivalent) was added portionwise and the mixture was stirred under nitrogen for one hour at 25° C. 2-(2-Chloroethoxy)tetrahydro-2H-pyran (1 equivalent) was added with a catalytic amount of sodium iodide. The reaction mixture was stirred under nitrogen at 70° C. for 12 hours, then the solvent was removed under reduced pressure. The resulting oil was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered and evaporated to dry under reduced pressure. The resulting oil was taken up in methanol and stirred at room temperature with paratoluenesulfonic acid. After eight hours the solvent was removed and replaced with ethyl acetate. The solution was washed (×2) with saturated sodium hydrogen carbonate solution, dried (MgSO4), filtered and evaporated to dryness. Column chromatography of the resulting oil on silica gel (eluent ethyl acetate/hexane 1:1) gave 2((3,3-dimethyl)oxindolyl)ethanol.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].[F:26][C:27]1[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=1[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C>O1CCCC1.O>[F:26][C:27]1[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=1[CH2:29][N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]([N:5]2[CH2:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:7]3[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]23)=[O:4])[CH2:34][CH2:35]1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Reactant: Fc1ccccc1CN1CCNCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cnn2c1N(C(=O)CN1CCN(Cc3ccccc3F)CC1)CC=C2c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 6.3 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 3.7 of 2-fluorobenzyl piperazine and 4.1 g of triethylamine in 250 ml of tetrahydrofuran was stirred under reflux for 18 hours, then cooled and diluted with 500 ml of water. The resulting solid was collected, washed with water, dried, then heated to solution in 200 ml of ethyl acetate, filtered and refrigerated. The resulting solid was collected, washed with hexane and dried, giving 7.1 g of the desired product, mp 188°-190° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:14][CH3:15])=[N:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([NH:10][OH:11])=[NH:9])[CH3:2].[CH2:16](OC(OCC)OCC)C.B(F)(F)F.CCOCC>>[CH2:1]([C:3]1[C:4]([O:14][CH3:15])=[N:5][C:6]([CH3:13])=[C:7]([C:8]2[N:9]=[CH:16][O:11][N:10]=2)[CH:12]=1)[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCc1cc(C(=N)NO)c(C)nc1OC
Agent: FB(F)F
Solvent: CCOCC
Product: CCc1cc(-c2ncon2)c(C)nc1OC
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a crude mixture of 5-ethyl-N-hydroxy-6-methoxy-2-methylnicotinamidine (formed on 1.705 mmol scale following the procedures of Step 3, Example 22), under a nitrogen atmosphere, is added triethylorthoformate (2 mL), followed by boron trifluoride etherate (42.6 μL, 0.336 mmol). The resulting solution mixture is heated at 100° C. for 3.25 hr. The mixture is allowed to cool, concentrated under vacuum, then treated with aqueous hydrochloric acid (1M, 2 mL). The resulting mixture is allowed to stand for 30 min before making basic with excess solid sodium bicarbonate. The mixture is extracted with five portions of ethyl acetate, dried over magnesium sulfate, filtered and evaporated to leave an oily, brown residue that is purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:dichloromethane (1:1, increasing to 4:1). Fractions containing the product are combined, the solvent evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:dichloromethane (9:1, increasing to 17:3 then 1:1). Fractions containing the product are combined, the solvent evaporated and further purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:dichloromethane (87:13, then 1:1). Clean fractions containing the product are combined, evaporated and triturated with heptane to give 3-ethyl-2-methoxy-6-methyl-5-(1,2,4-oxadiazol-3-yl)-pyridine (57 mg, 15% yield, 2 steps). MS: m/e=220 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 8.72 (1H, s), 7.99 (1H, s), 4.00 (3H, s), 2.76 (3H, s), 2.61 (2H, q), 1.11 (3H, t)
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][CH2:14][C:15]([F:18])([F:17])[F:16].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)[C:25](O)=[O:26]>>[C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N:13]([CH2:14][C:15]([F:16])([F:17])[F:18])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[N:30]=[C:22]([C:21]([F:36])([F:20])[F:35])[CH:23]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1NCC(F)(F)F
Product: Cc1ccccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (4-o-tolyl-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 23 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (26%). MS (ESI): m/z=508.11 [M+H]+.
Reaction SMILES: [C:1]([N:20]1[CH2:22][CH:21]1[CH2:23][OH:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:27]([O:24][CH2:23][CH:21]1[CH2:22][N:20]1[C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCC1CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: c1ccc(COCC2CN2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of lithium aluminum hydride in diethyl ether (1 M, 15 mL, 15 mmol) under an atmosphere of nitrogen, a solution of methyl 1-trityl-2-aziridinecarboxylate (5.04 g, 14.7 mmol) in anhydrous ether (60 mL) was added over a period of 0.5 h. The resultant mixture was allowed to slowly warm up and stirred at room temperature for 1 hour. The resultant mixture was cooled back to 0° C. and treated successively with water (0.57 mL) over a period of 10 minutes, followed by addition of 15% aq NaOH (0.57 mL), and water (1.7 mL). The resultant suspension was filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated with a mixture of ether (40 mL) and hexane (200 mL) with cooling. The precipitate was collected by filtration to provide (1-tritylaziridin-2-yl)methanol as white solid. Without further purification, the alcohol (1.0 g, 3.17 mmol) was added portionwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.24 g, 6.0 mmol). To the resultant mixture, terta-n-butylammonium iodide (50 mg, 0.14 mmol) and benzyl bromide (0.65 g, 3.8 mmol) were added. The reaction mixture was stirred at room temperature overnight and treated with water (20 mL). The organic extract was diluted with ether, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 5% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[O:11][C:10](=[O:12])[CH:9]=[C:8]([CH3:13])[C:7]=2[CH:14]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:29](O)(C)[CH3:30]>>[CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[O:11][C:10](=[O:12])[C:9]([CH2:29][CH2:30][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)=[C:8]([CH3:13])[C:7]=2[CH:14]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)cc(C)c2cc1OC
Reactant: CC(C)O
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4)CC3)c(C)c2cc1OC
Yield: 43 %

Procedure:
Process B; starting materials: 3-[2-methanesulphonyloxy)ethyl]-6,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 28) and 1-phenylpiperazine; yield 43%; m.p. 169°-172° C. (from isopropanol).
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]([CH3:19])([CH3:18])[C:10](=[O:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C.C(O)(=[O:38])C>O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:38][CH:11]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:10](=[O:17])[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:21][CH:20]=2)([CH3:18])[CH3:19])[N:24]=1
Reactant: Clc1ccccn1
Reactant: CC(=O)O
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cn1cncn1
Agent: BrBr
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)C(Oc1cccc(Cl)n1)n1cncn1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
12.8 g (approx. 4.2 ml, that is 0.08 mol) of bromine are added dropwise to 22.4 g (0.08 mol) of 3-(4-chlorophenoxy)-3-methyl-1-(1,2,4-triazol-1-yl)-butan-2-one in 100 ml of glacial acetic acid at 50° C., while stirring. Thereafter, stirring is continued until the mixture has become completely decolourised (approx. 20 minutes), the mixture is poured into water and extracted with methylene chloride, and the organic phase is washed with sodium bicarbonate until it gives a neutral reaction. Thereafter, the solvent is removed in vacuo, and the residue is dissolved in 100 ml of acetonitrile. A homogeneous solution of 11.6 g (0.1 mol) of chloropyridine and 16 ml (0.1 mol) of triethylamine is added, all at once, to the stirred solution. When the exothermic reaction has died down, the mixture is kept at the boil for a further 30 minutes and then poured into water and extracted with methylene chloride. The organic phase is washed twice with dilute sodium hydroxide solution, and freed from the solvent, and the oil which remains is recrystallised from a small amount of methanol. 12.4 g (that is 31% of theory) of 1-(2-chloropyrid-6-yloxy)-3-(4-chlorophenoxy)-3-methyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 101° C. are obtained.
Reaction SMILES: N1C=CC(N)=NC=1N.Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][CH2:25][O:26][C:19]=3[CH:18]=2)[C:13]([F:27])=[CH:12][N:11]=1.[F:28][C:29]([F:39])([F:38])[S:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>>[CH2:25]1[CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14]3[C:13]([F:27])=[CH:12][N:11]=[C:10]([NH:35][C:34]4[CH:36]=[CH:37][C:31]([S:30][C:29]([F:39])([F:28])[F:38])=[CH:32][CH:33]=4)[N:15]=3)=[CH:18][C:19]=2[O:26]1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Agent: Nc1ccnc(N)n1
Product: Fc1cnc(Nc2ccc(SC(F)(F)F)cc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-(trifluoromethylthio)aniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.73 (s, 1H), 9.47 (s, 1H), 8.13 (d, 1H, J=3.6 Hz), 7.79 (d, 2H, J=9.0 Hz), 7.51 (d, 2H, J=9.0 Hz), 7.28 (d, 1H, J=2.1 Hz), 7.12 (dd, 1H, J=2.4 and 9.0 Hz), 6.83 (d, 1H, J=8.7 Hz), 4.23 (s, 4H); 19F NMR (282 MHz DMSO-d6): −12306; LCMS: purity: 97%; MS (m/e): 439(MH+).