Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[Cl:21][C:22]1[C:23]([NH2:30])=[N:24][C:25]([NH2:29])=[N:26][C:27]=1Cl.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:21][C:22]1[C:27]([NH:20][C@H:18]([C:8]2[N:7]=[C:6]3[CH:5]=[CH:4][N:3]([CH3:2])[C:11]3=[CH:10][C:9]=2[C:12]2[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=2)[CH3:19])=[N:26][C:25]([NH2:29])=[N:24][C:23]=1[NH2:30]
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 14.2 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (95 mg, 0.372 mmol), 5,6-dichloropyrimidine-2,4-diamine (100 mg, 0.559 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.20 mL, 1.1 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then at 160° C. for 1.5 hours. The mixture was concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 30% ACN in water. The fractions containing the desired compound were combined and extracted with EtOAc (200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (21 mg, 14%). 1H NMR (500 MHz, CD3OD) δ ppm 1.38 (d, J=6.35 Hz, 3 H), 3.65 (s, 3 H), 3.83-3.89 (m, 3 H), 5.38 (q, J=6.67 Hz, 1 H), 6.40-6.46 (m, 1 H), 6.65-6.70 (m, 1 H), 7.58-7.64 (m, 2 H), 7.80 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H20ClN9, 398; found 398.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1CCCCC1.[H][H]>[Pd]>[CH2:9]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH3:8])=[O:6])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: [H][H]
Reactant: CCCCCC=O
Reactant: COC(=O)CC(C)=O
Agent: [Pd]
Solvent: C1CCNCC1
Product: CCCCCCC(C(C)=O)C(=O)OC
Temperature: 90 °C

Procedure:
The reaction mixture from the condensation of methyl acetoacetate (193.5 g) and hexanal (151.8 g) with piperidine catalysis was hydrogenated in an autoclave at 50° C. with hydrogen and Pd/C catalysis. After the end of the hydrogenation and filtering off the Pd/C catalyst, the two-phase mixture was concentrated at a pressure of 15 mbar and a temperature of 70° C. The residue (262 g) still contained 1.2 percent of methyl 2-hexenylacetoacetate. Methyl acetoacetate (3.14 g) and sodium methoxide (1.46 g of a 5.4 molar solution) were then added and this mixture was heated at 90° C. for 5 hours. At the end of this treatment, 0.39 percent of methyl 2-hexenylacetoacetate was still measured. The crude product was then distilled in a high vacuum (3 to 4 mbar) in a thin-layer evaporator. The methyl 2-hexylacetoacetate distillate (240.9 g), with a content of 97.8 percent, still contained 0.26 percent of methyl 2-hexenylacetoacetate.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[OH-].[Na+]>CO.O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:8][C:5]2[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1cc(CO)occ1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1cc(CO)occ1OCc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
Kojic acid (70, 5.00 g, 35.2 mmol) and 4-chlorobenzyl bromide (22, 7.95 g, 38.7 mmol) were suspended in methanol (40 mL) in an 80 mL sealed tube. Sodium hydroxide in water (12 M, 2.93 ml) was added, The reaction was heated at 80° C. overnight. The resulting suspension was concentrated. Water was added and the mixture was filtered and washed with water to provide a brown solid. Washing with minimal methanol on the filter removed the brown color. A white solid (71, 7.58 g, 80%) was isolated. 1H-NMR was consistent with the desired compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N+:35]([O-])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].CCN(CC)CC>C(Cl)Cl.[Cl-].[Na+].O>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([Br:20])[CH:33]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(-c2cc[n+]([O-])cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(-c2ccnc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To triphenylphosphine (Aldrich) (2.4 g, 9.1 mmol) dissolved in 10 mL of CH2Cl2 in a 50-mL round-bottomed flask was added bromine (Aldrich) (0.43 mL, 8.5 mmol). After stirring at 0° C. for 10 min, 4-[4-(tert-butyl)phenyl]pyridine 1-oxide (1.5 g, 6.5 mmol) was added dropwise, followed by Et3N (1.2 mL, 8.5 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature overnight. Methylene chloride and brine were added, and the aqueous layer was extracted with CH2Cl2. The organic layer was collected and dried over Na2SO4, filtered and concentrated in vacuo. Following purification by silica gel chromatography (10:1 hexane:EtOAc), the title compound was obtained as a pale yellow oil. MS (ESI, pos. ion) m/z: 293 (M+1).
Reaction SMILES: [CH2:1]([N:17]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:24]([Br:26])[CH3:25]>>[Br-:26].[CH2:24]([N:18]1[C:19]([CH3:23])=[CH:20][C:21]([CH3:22])=[N+:17]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:25]
Reactant: CCCCCCCCCCCCCCCCn1nc(C)cc1C
Reactant: CCBr
Product: CCCCCCCCCCCCCCCC[n+]1c(C)cc(C)n1CC
Product: [Br-]

Procedure:
In the same way as described in Example 4-A, reaction of 1-hexadecyl-3,5-dimethyl-pyrazole with ethyl bromide yields 2-ethyl-1-hexadecyl-3,5-dimethyl-pyrazolium bromide; m.p. 97°-101° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Br-].[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[Zn+]>C1COCC1>[N:25]1([C:23]([C:10]2[C:11]3[CH2:20][S:19](=[O:22])(=[O:21])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]=3[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:33]4[S:32][CH:36]=[CH:35][N:34]=4)[CH:3]=3)[N:9]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: [Zn+]c1nccs1
Reactant: O=C(c1nn(-c2cccc(Br)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(c1nn(-c2cccc(-c3nccs3)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1

Procedure:
1-(3-bromophenyl)-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg, 0.20 mmol, 1 eq.) is taken in THF in and bubbled with nitrogen for 5 minutes. To this are added thiazolyl zinc bromide (2 mL), tetrakis(triphenyl phosphine)palladium(0) (12 mg, 0.010 mmol, 0.05 eq.) and the reaction mixture is heated under sealed condition at 65° C. for 4 h. The reaction mixture is filtered through a celite pad, concentrated under reduced pressure and purified by flash chromatography to afford the title compound as a pink solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.18-8.16 (d, J=7.7 Hz, 1H), 8.07 (s, 1H), 8.04-8.02 (d, J=7.7 Hz, 1H), 7.96-7.95 (d, J=3.2 Hz, 1H), 7.87-7.86 (d, J=3.2 Hz, 1H), 7.76-7.72 (t, J=7.9 Hz, 1H), 7.65-7.56 (m, 3H), 6.98-6.96 (d, J=7.7 Hz, 1H), 4.91 (s, 2H), 3.93 (m, 2H), 3.67 (m, 4H), 3.62-3.61 (m, 2H). MS (ESI+): 493.0. HPLC (max plot) 98.44%; Rt 4.02 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].C([Sn](CCCC)(CCCC)[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)CCC.CCOC(C)=O.CCCCCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][C:3]=1[Cl:9]
Reactant: Clc1cc(I)ccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Clc1cc(-c2cccs2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-bromo-2-chloro-4-iodobenzene (2.0 g, 6.30 mmol) in dioxane 30 mL, 2-tributylstannyl thiophene (2.352 g, 6.30 mmol), and 5% equivalent of Pd(PPh3)4 (0.364 g, 0.3155 mmol) is refluxed under nitrogen for 5 h. After cooling and evaporation of the solvent, the residue is dissolved in EtOAc 50 mL. 10% KF 30 mL is added and the solution is stirred at r.t. for 30 min. The resultant precipitate is removed by filtration. The solution is washed with water 20 mL×3, and dried with Na2SO4 and concentrated. The pure product (1.2 g, 4.39 mmol, white solid) is obtained by column chromatography using EtOAc/Hexane, 1-3% ration solvent system. 1H-NMR (CDCl3/300 MHz): 7.74 (d, J=2.1 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.37 (m, 3H), 7.14 (m, 1H). MS (ES−, m/z): 529.2 (M+−Br, 20.0).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16]([OH:18])=O.[NH2:24][CH:25]1[CH2:32][CH2:31][CH2:30][NH:29][C:27](=[O:28])[CH2:26]1>C1COCC1>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[C:15]=1[C:16]([NH:24][CH:25]1[CH2:32][CH2:31][CH2:30][NH:29][C:27](=[O:28])[CH2:26]1)=[O:18]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: NC1CCCNC(=O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CC(NC(=O)c2c(F)cccc2F)CCCN1
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
1,1'-Carbonyldiimidazole (14.8 g), was added to a solution of 2,6-difluorobenzoic acid (12 g) in THF (200 ml) and followed by stirring for 15 mins. at room temperature. Then to the mixture was added 9.73 g of 3-amino-ε-caprolactam, and the whole was stirred for 5 hrs. at room temperature and the solvent was distilled off under reduced pressure. The residue was washed with methylenechloride to give 3-(2,6-difluorobenzoyl)amino-ε-caprolactam (13.5 g) as crude crystals. The crude crystals and phosphorus pentasulfide (8.96 g) were added to 200 ml of pyridine, and the whole was refluxed under stirring for 24 hrs. After cooling, the mixture was distilled to remove the solvent. To the residue was added a saturated sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with water, dried and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel and then recrystallized from a mixture of methylenechloride and isopropyl ether to give the title compound (3.19 g, 23.8 %).
Reaction SMILES: Cl.[N:2]#[C:3][NH2:4].[NH2:5][C:6]([NH2:8])=N.[H-].[Na+].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:2][C:3]1[N:8]=[C:6]2[C:12]3[C:11]([CH2:17][N:5]2[N:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: Cc1ccccc1
Reactant: N#CN
Reactant: N=C(N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2n(n1)Cc1ccccc1-2
Yield: 78 %

Procedure:
A mixture of 26.2 g of N-aminophthalimidine hydrochloride (0.142 mole) and 6.25 g of cyanamide (0.149 mole) in 270 ml of anhydrous toluene are refluxed for two hours then, after cooling, the resulting solid precipitate is recovered by filtration. Yield, 31 g of the hydrochloride of 1-(2-phthalimidinyl)- guanidine. M.p. 269-70°C. An amount of 7.6 g (0.033 mole) of this latter compound is added to a solution of 1.5 g of 80% sodium hydride (0.05 mole) in 90 ml of ethanol and the mixture is refluxed for five hours. The solvent is distilled off in vacuo and the solid residue is taken up with water and the pH of the mixture is brought to 7 by addition of acetic acid. Extraction with dichloromethane and evaporation of the organic phase yields 4.5 g (78%) of the title product. M.p. 193-4°C (from ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[N:13]1([C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyano-4-fluoronitrobenzene (3.3 g, 19.9 mmol) was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (3.5 mL, 20 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was used without further purification.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]2[N:8]([C:18]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[N:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)[CH:2]([CH3:4])[CH3:3].[S].[CH:30]1([NH2:33])[CH2:32][CH2:31]1.C[S:35](C)=O>>[CH:30]1([NH:33][C:25]([C:24]2[CH:27]=[CH:28][C:21]([C:18]3[N:8]4[N:9]=[C:10]([C:12]5[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=5)[CH:11]=[C:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:7]4=[N:20][CH:19]=3)=[CH:22][CH:23]=2)=[S:35])[CH2:32][CH2:31]1
Reactant: CS(C)=O
Reactant: CC(C)CNc1cc(-c2ccncc2)nn2c(-c3ccc(C=O)cc3)cnc12
Reactant: NC1CC1
Agent: [S]
Product: CC(C)CNc1cc(-c2ccncc2)nn2c(-c3ccc(C(=S)NC4CC4)cc3)cnc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A mixture of 40 mg (108 μmol) 4-[8-(isobutylamino)-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl]benzaldehyde which was prepared according to intermediate example 13a, 3.45 mg sulfur, 37 μL cyclopropanamine and 250 μL dimethyl sulfoxide were heated at 100° C. under microwave irradiation for 4 hours. The mixture was stirred at 90° C. overnight, the solvent was evaporated and the residue purified by chromatography to give 4.8 mg (10%) of the title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)([CH3:7])=[O:6].[C:9]([O:12][CH2:13][C:14]([NH:28][C:29](=[O:31])[CH3:30])([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:10]>ClCCCl>[C:17]([O:16][CH2:15][C:14]([NH:28][C:29](=[O:31])[CH3:30])([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:5](=[O:6])[CH3:7])=[CH:26][CH:27]=1)[CH2:13][O:12][C:9](=[O:11])[CH3:10])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CC(=O)NC(CCc1ccccc1)(COC(C)=O)COC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)NC(CCc1ccc(C(C)=O)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (16 mmol) in DCE (20 mL) is added AcCl (8 mmol) in one portion. After stirring at room temperature for 30 minutes, to the solution is added acetic acid 2-acetoxymethyl-2-acetylamino-4-phenyl-butyl ester (2 mmol) in DCE (5 mL). After an additional 30 minutes, the mixture is poured into ice-cold 1 N NaOH and is extracted with DCM. The organic phase is washed with 1 N HCl, brine and dried over Na2SO4. After concentrating, the crude material is purified by column chromatography using EtOAc/hexane (2/1) to give acetic acid 2-acetoxymethyl-2-acetylamino-4-(4-acetyl-phenyl)-butyl ester as a white solid. MS: (ES+): 364.2 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([Cl:32])=[CH:25][C:26]([NH:30][NH2:31])=[N:27]4)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH:33](OCC)(OCC)OCC>CCO>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([Cl:32])=[CH:25][C:26]5[N:27]4[CH:33]=[N:31][N:30]=5)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc(NN)nc4c3)c2)CCOCC1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc5nncn5c4c3)c2)CCOCC1
Temperature: 65 °C

Procedure:
To 5c (3.7 mmol) in EtOH (60 mL) was added triethyl orthoformate (10 mL), and the reaction was heated to 65° C. overnight. After cooling to room temperature, the mixture was concentrated, and the residue was purified by silica gel chromatography (100% EtOAc) to give the desired product, 5d.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[S:23][C:22](=[O:24])[NH:21][CH:20]2[C:25](O)=[O:26])=[CH:15][CH:14]=1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:25]([CH:20]1[CH:19]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=2)[S:23][C:22](=[O:24])[NH:21]1)=[O:26])([O-:7])=[O:6]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2ccc(Cl)cc2)S1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2ccc(Cl)cc2)S1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 394 mg of N-(2-nitrooxyethyl)-amine nitrate and 500 mg of 5-(4-chlorophenyl)-2-oxothiazolidine-4-carboxylic acid, to obtain 350 mg of the title compound as colorless needles, melting at 125°-127° C. (after recrystallization from methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([C:11](OC)=[O:12])[CH2:10][CH2:9]1)=[O:7].[BH4-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:11][OH:12])[CH2:9][CH2:10]1)=[O:7]
Reactant: COC(=O)C1(C(=O)NCc2ccccc2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1Cl)C1(CO)CC1
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of methyl 1-(2-chlorobenzylcarbamoyl)cyclopropanecarboxylate (330 mg, 1.2 mmol) in THF (5 mL) and CH3OH (5 mL) was added sodium borohydride (93 mg, 2.4 mmol, 2 equiv.). The reaction mixture was stirred for 3 h and quenched with diluted AcOH. The reaction mixture was concentrated and dissolved in EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4, and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give N-(2-chlorobenzyl)-1-(hydroxymethyl)cyclopropanecarboxamide (164 mg, 55%). LRMS (M+H+) m/z 240.0.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:4])=[O:3].[C:15]1([CH2:21]C(O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:25]1([CH:31]([CH2:35][CH3:36])[C:32](O)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[S:2]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:21]([C:32]([CH:31]([C:25]2[CH:30]=[CH:29][C:28]([O:8][CH2:7][CH2:6][O:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:27][CH:26]=2)[C:35]2[CH:36]=[CH:11][CH:10]=[CH:9][CH:14]=2)=[O:33])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)([CH3:1])(=[O:4])=[O:3]
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: O=C(O)Cc1ccccc1
Reactant: CS(=O)(=O)OCCOc1ccccc1
Product: CS(=O)(=O)OCCOc1ccc(C(C(=O)C(c2ccccc2)c2ccc(OCCOS(C)(=O)=O)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
The oil comprising 2-Phenoxyethyl methanesulfonate was prepared as described above in Example 1. The acylation and workup procedure was identical to that of Example 1 with the exception that 30.26 g (220 mmol) 2-phenylacetic acid was reacted instead of the 2-phenylbutyric acid. The organic layer obtained by the workup procedure was cooled to 25° C. and stirred at this temperature for 1 hour. The resulting crystallized product was filtered, washed with toluene and dried under vacuum at 40° C. to yield 53.18 g (159 mmol) of the 4-(2-mesyloxyethoxy)phenyl benzylketone as a tan colored solid. Yield: 80% on 2-phenoxyethanol.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[CH2:14]([N:21]1[C:25]([CH3:26])=[C:24]([CH3:27])[N:23]=[C:22]1[CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O>[Br-:1].[CH2:14]([N+:21]1[C:25]([CH3:26])=[C:24]([CH3:27])[N:23]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:22]=1[CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCn1c(C)nc(C)c1C
Reactant: COc1ccc(CCCCBr)cc1
Solvent: O
Product: CCCCCCC[n+]1c(C)c(C)n(CCCCc2ccc(OC)cc2)c1C
Product: [Br-]
Temperature: 125 °C

Procedure:
Add 3.23 g (0.0133 mole) of 1-(4-bromobutyl)-4-methoxybenzene to 2.77 g (0.0133 mole) of 1-heptyl-2,4,5-trimethyl-1H-imidazole and heat at 125° C. for two hours. Follow the progress of the reaction by thin-layer chromatography on silica gel (methanol: 1M sodium chloride, 95:5). At the completion of the reaction, the cooled reaction mixture in 100 ml water and then wash with 100 ml cyclohexane. Extract aqueous layer with 150 ml methylenechloride and evaporate to provide the title compound.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](SC)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].OO.[S:37]([O-:41])([O-])(=[O:39])=S.[Na+].[Na+].[C:44](OCC)(=O)C>C1(C)C=CC=CC=1.ClCCl>[C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:29][C:30]([F:33])([CH3:31])[CH3:32])[NH:9][C@@H:10]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([S:37]([CH3:44])(=[O:41])=[O:39])=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[C:11]([F:12])([F:13])[F:14])[CH2:4][CH2:5]1)#[N:2]
Reactant: CSc1ccc(-c2ccc([C@H](N[C@@H](CC(C)(C)F)C(=O)NC3(C#N)CC3)C(F)(F)F)cc2)cc1
Reactant: O=S([O-])([O-])=S
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 0° solution of the sulfide (0.265 g) from Step 10 in toluene (5 mL) and dichloromethane (5 mL) was added Na2WO4.2H2O (0.002 g) and n-Bu4 NHSO4 (0.01 g). 30% Hydrogen peroxide (0.137 mL) was then slowly added and the mixture was stirred at room temperature for 3 hours. The mixture was poured slowly onto a mixture of ice, dilute aqueous sodium thiosulfate and ethyl acetate. The organic layer was separated and the aqueous further extracted with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue which was purified on SiO2 using ethyl acetate, hexanes and dichloromethane (1:1:0.1) as eluant. The residue was triturated in diethyl ether to yield N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:7]=1
Reactant: CN(c1ccccc1)c1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
The obtained 2,4-dichloro-6-(N-methyl-N-phenylamino)-1,3,5-triazine (956 mg, 3.75mmol) was dissolved in DMF (10 ml), added with anhydrous potassium carbonate (518 mg, 3.77 mmol), cooled to -5° C.-0° C. and gradually added dropwise with morpholine (359 mg, 4.13 mmol) dissolved in DMF (5 ml). The reaction mixture was stirred at room temperature for 24 hours and evaporated under reduced pressure. The residue was added with ethyl acetate and shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using dichloromethane and ethyl acetate (20:1) as eluant, to obtain 958 mg (yield: 83.5%) of 2-chloro-4-(N-methyl-N-phenylamino)-6-morpholino-1,3,5-triazine as colorless crystals having melting point of 93.5° C.-95.5° C.