Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[N:11](COCC[Si](C)(C)C)[CH:10]=2)=[O:8])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl.O.C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:3][C@H:4]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:8])[CH2:5]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2C[C@@H](O)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: CCOC(C)=O
Solvent: NCCN
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4C[C@@H](O)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-hydroxy-cyclobutyl)-amide (138 mg, 0.27 mmol) was dissolved in dichloromethane (1.3 mL). Trifluoroacetic acid (0.84 mL, 10.9 mmol) was added and the orange solution was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue (light orange foam) was suspended in dichloromethane (1.3 mL) and ethylenediamine (1.1 mL, 16.3 mmol) was added. The light yellow suspension was stirred at room temperature for 1 h. The reaction mixture was diluted with water and ethyl acetate. The suspension was filtered and washed with water (hot) and ethyl acetate. The resulting off-white powder was dried under high vacuum to afford 81 mg (79%) 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-hydroxy-cyclobutyl)-amide. LC/MS: [M−H]−=379.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[NH:7][C:6](=[O:10])[CH:5]=[N:4]1.[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:1][CH2:2][N:3]2[C:8](=[O:9])[NH:7][C:6](=[O:10])[CH:5]=[N:4]2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=c1cnn(CO)c(=O)[nH]1
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OCn2ncc(=O)[nH]c2=O)cc1
Reaction time: 8 h

Procedure:
2-Hydroxymethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (1.00 g), p-methylbenzoic acid (0.95 g) and N,N-dicyclohexylcarbodiimide (2.90 g) are dissolved in pyridine, and the mixture is allowed to stand overnight. The reaction mixture is then evaporated to dryness to give a residue, which is extracted with chloroform. The chloroform extract is condensed to give an oil, which is purified by thin layer chromatography with silica gel and recrystallized from a mixture of ethanol/n-hexane. 2-(p-Methylbenzoyloxymethyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 42) is thus obtained. Yield, 1.01 g (56%). M.P. 139.3° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12]P(=O)(OC)OC)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([N-]C(C)C)(C)C.[Li+].O=[C:34]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[N:11]=[C:10]([CH:12]=[C:34]3[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COP(=O)(Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1)OC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of dimethyl (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylphosphonate (0.32 g) in anhydrous THF (3 mL) at 0° C. was added 2.0 M of lithium diisopropylamide in tetrahydrofuran (1.4 eq). The resulting solution was allowed to warm to RT (room temperature) before adding a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.4 eq) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 1 h, then partitioned between brine and DCM. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo to give 0.34 g of crude tert-butyl 3-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylene)azetidine-1-carboxylate.
Reaction SMILES: ClC1C(C)=CC(O)=CC=1.[S:10]([C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([CH3:21])=[CH:16][C:15]=1[OH:22])([OH:13])(=[O:12])=[O:11].S([C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([CH3:34])=[C:29]([Cl:35])[C:28]=1[OH:36])(O)(=O)=O.[N+:37]([O-])([OH:39])=[O:38].S(=O)(=O)(O)O>>[N+:37]([C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([CH3:34])=[C:29]([Cl:35])[C:28]=1[OH:36])([O-:39])=[O:38].[S:10]([C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([CH3:21])=[CH:16][C:15]=1[OH:22])([OH:13])(=[O:11])=[O:12]
Reactant: Cc1c(Cl)cc(S(=O)(=O)O)c(O)c1Cl
Reactant: O=[N+]([O-])O
Agent: Cc1cc(O)c(S(=O)(=O)O)cc1Cl
Agent: Cc1cc(O)ccc1Cl
Agent: O=S(=O)(O)O
Product: Cc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl

Procedure:
2-NITRO-4,6-DICHLORO-5-METHYLPHENOL IS PREPARED BY THE SULFONATION OF 4-CHLORO-5-METHYLPHENOL TO FORM 2-SULFO-4-CHLORO-5-METHYLPHENOL WHICH IS CHLORINATED TO 2-SULFO-4,6-DICHLORO-5-METHYLPHENOL WHICH IS IN TURN REACTED WITH NITRIC ACID TO FORM THE DESIRED PRODUCT. The sulfonation is carried out with concentrated sulfuric acid at elevated temperatures to form 2-sulfo-4-chloro-5-methylphenol. Thereafter the reaction mixture is diluted with water to a sulfuric acid content of 20-30%. The resulting 2-sulfo-4-chloro-5-methylphenol is chlorinated with chlorine at elevated temperature and normal or elevated pressures to form 2-sulfo-4,6-dichloro-5-methylphenol which is then reacted with nitric acid.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[CH:10]=[C:9]4[C:15]5[C:20]([C:21](=O)[C:8]4=[CH:7][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:19][CH:18]=[CH:17][CH:16]=5.O.NN.[OH-].[K+]>C(O)COCCO.O>[CH:19]1[C:20]2[CH2:21][C:8]3[CH:7]=[C:6]4[C:5]5[C:13]([CH2:12][C:11]4=[CH:10][C:9]=3[C:15]=2[CH:16]=[CH:17][CH:18]=1)=[CH:1][CH:2]=[CH:3][CH:4]=5
Reactant: O=c1c2ccccc2c2cc3c(=O)c4ccccc4c3cc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: c1ccc2c(c1)Cc1cc3c(cc1-2)Cc1ccccc1-3
Temperature: 80 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A mixture of 17 g (60 mmol) of indeno[1,2-b]fluorene-6,12-dione, 18 g (600 mmol) of hydrazine monohydrate in 350 ml of diethylene glycol was stirred at 80° C. for 3 hours and then refluxed for 1 hour. The resulting mixture was cooled to room temperature, treated with a solution of 33 g (590 mmol) of KOH in 90 mL of water, and refluxed for 3 hours. The resulting mixture was poured into 800 ml of water, and the precipitate was filtered off, washed with water, and dried in air at room temperature to give product 13.1 g (51.6 mmol, 86%) as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CN1CCCC1=O.F[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]>O>[CH:9]1([N:8]([CH3:7])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[N+:30]([O-:32])=[O:31])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CNC1CCCCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(c1ccc(F)cc1[N+](=O)[O-])C1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
Potassium carbonate (6.0 g, 43.5 mmol) and N-methylcyclohexylamine (4.6 g, 40.6 mmol) were added to a N-methylpyrolidone (NMP) solution (20 ml) of 2,5-difluoronitrobenzene (5.0 g, 31.4 mmol), and stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 7.0 g of oily yellow N-cyclohexyl-4-fluoro-2-nitro-N-methylaniline (yield: 89%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:16][CH3:17]>C(O)C.C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][N:2]([CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:16][CH3:17])[CH3:3]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a solution of dimethyl amine (0.9 mL of a 5.6 M solution in ethanol) in THF (20 mL), a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (500 mg, 2.06 mmol) was added. The mixture was stirred at rt for 35 min before it was diluted with water (150 mL) and sat. aq. Na2CO3-solution (50 mL) and extracted with EA (70 mL). The org. extract was separated, dried over Na2SO4, filtered, evaporated and dried to give methyl 4-dimethylaminomethyl-3-methoxy-benzoate as a colourless oil (420 mg). LC-MS: tR=0.61 min, [M+1]+=224.04.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][O:22][C:23]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=[C:25]([NH2:38])[N:24]=1>>[CH3:21][O:22][C:23]1[C:28]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:5]=[C:4]([O:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:3]=2)=[CH:27][N:26]=[C:25]([NH2:38])[N:24]=1
Reactant: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1nc(OC2CCOCC2)cc(N2CCOCC2)n1
Product: COc1nc(N)ncc1-c1nc(OC2CCOCC2)cc(N2CCOCC2)n1

Procedure:
According to Example 1 the reaction of 2-chloro-4-morpholino-6-(tetrahydro-2H-pyran-4-yloxy)pyrimidine (20 mg, 0.067 mmol) with 4-methoxy-5-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine (50 mg, 0.200 mmol) afforded 4′-methoxy-4-morpholino-6-(tetrahydro-2H-pyran-4-yloxy)-2,5′-bipyrimidin-2′-amine. The crude product was treated with morpholine (0.058 mL, 0.667 mmol) in NMP (2 mL) and heated under microwave irradiation (high absorption, fixed hold time) for 60 minutes at 200° C. Additional morpholine (0.058 mL, 0.667 mmol) was added and the solution heated at 200° C. under microwave irradiation for another 30 minutes, then another 60 minutes at 210° C. Upon cooling the material was directly purified by reverse-phase HPLC. After lyophilization, the TFA salt of 2-amino-5-(4-morpholino-6-(tetrahydro-2H-pyran-4-yloxy)pyrimidin-2-yl)pyrimidin-4(3H)-one was isolated as an off white solid (17.1 mg, 68%), LCMS (m/z): 375.1 (MH+). Rt: 1.74 min.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:24].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][C:23](=[O:24])[NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[CH:27][CH:28]=1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(OC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 31 %

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,6-diamine (0.070 g, 0.25 mmol) was dissolved in toluene (3 ml). 4-Methoxyphenyl chloroformate (0.042 mL, 0.28 mmol) and triethyl amine (0.053 mL, 0.38 mmol) were added and the reaction mixture was stirred at 60° C. for 10 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic phases were dried on sodium sulfate, filtered and the filtrate was evaporated. The crude product was purified by column chromatography (silica gel, heptane/ethyl acetate 4:1=>2:1) to yield the title compound as a colorless solid (33 mg, 31%); MS: m/e=326.6 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[N:3]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: O=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Reactant: C1CNCCN1
Product: O=Cc1c(N2CCNCC2)n(Cc2ccccc2)c2ccccc12
Yield: 64 %

Procedure:
2-Chloro-1-benzyl-1H-indole-3-carboxaldehyde (1.0 g, 5.5 mmol) is reacted with piperazine as described in Example 2 to yield the title compound (64%), mp 163-165° C., as a pale yellow solid. MS 320 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O-2].[Ca+2:7]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[Ca+2:7]
Reactant: NCC(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: NCC(=O)[O-]

Procedure:
Into about 1300 grams of water was dissolved 210.72 grams of glycine and 79.86 grams of calcium oxide. The solution was stirred until all of the calcium oxide appeared to be fully dissolved, i.e., about 15 minutes. The resulting reaction formed a calcium bisglycinate chelate or complex solution.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:14]>C(Cl)(Cl)Cl>[O:14]1[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C:1]12[CH2:7][OH:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCC1=CCCCC1
Solvent: ClC(Cl)Cl
Product: OCC12CCCCC1O2
Temperature: 25 °C

Procedure:
A stirred solution of 1-cyclohexenemethanol in 220 ml of chloroform was cooled to 0°-5° and 35.9 g of m-chloroperoxybenzoic acid (41.6 g of 85% pure material) in 355 ml of chloroform was added dropwise during three hours. The temperature of the reaction mixture was maintained at 0°-5° throughout the addition. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature during 24 hours. The reaction mixture was evaporated under reduced pressure to one-half the original volume and filtered. The filtrate was washed with three portions of 150 ml each of an aqueous solution saturated with sodium bicarbonate; then with three portions of 150 ml each of an aqueous solution saturated with sodium chloride. The chloroform layer was dried with sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to a residue. The residue was distilled using a Vigreux column to give 10.8 g of 1,2-epoxycyclohexanemethanol; bp 51°-52°/0.08-0.085 mm; nD25 =1.4738. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: [S-2:1].[Na+].[Na+].Cl[CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][S:1][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]
Reactant: [S-2]
Reactant: OCCOCCCl
Agent: [Na+]
Product: OCCOCCSCCOCCO

Procedure:
The reaction between sodium sulfide and two moles of 2-(2'-chloroethoxy)ethanol yields the intermediate compound 1,11-dihydroxy-3,9-dioxa-6-thiaundecane; ##STR5## Halogenation of the thiaundecane intermediate with thionyl chloride in dimethylsulfoxide (DMF) yields Intermediate A: ##STR6## Condensation of Intermediate A with 1,5-dimercapto-3-oxapentane in an aqueous-ethanol solution of sodium carbonate yields Compound 3: ##STR7##
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:29])[CH:12]=[CH:13][CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=CC=1)([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:31]=1>O1CCCC1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21](/[C:15](/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: NCCCCc1cccnc1
Reactant: CCCCCC(=CC=CC(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Solvent: C1CCOC1
Product: CCCCC/C(=C\C=C\C(=O)NCCCCc1cccnc1)c1ccc(OC)cc1
Yield: 50.6 %

Procedure:
As in Example 134, a solution of (E,E)]-5-(4-methoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester (2.5 g) and 3-pyridinebutanamine (1.12 g) in tetrahydrofuran (25 mL) was stirred overnight at room temperature. After the usual work up, the crude product was purified by HPLC (ethyl acetate) and then was crystallized from ether-hexane to provide 1.3 g of (E,E)-5-(4-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-decadienamide, mp 83.5°-84.5° C.
Reaction SMILES: N[C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[C:8]([C:16]4[O:17][C:18]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:19][C:20](=[O:22])[CH:21]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[H+].N([O:37][C:38](C)(C)C)=O.C([SiH](C(C)C)C(C)C)(C)C>C(O)C.C(OCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:23]1([C:18]2[O:17][C:16]([C:8]3[CH:9]=[CH:10][CH:11]=[C:12]4[C:7]=3[S:6][C:5]3[CH:4]=[CH:3][C:2]([CH:38]=[O:37])=[CH:15][C:14]=3[CH2:13]4)=[CH:21][C:20](=[O:22])[CH:19]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Reactant: CC(C)(C)ON=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: CCO
Solvent: CCOCC
Product: O=Cc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a suspension of 2-(7-amino-9H-thioxanthen-4-yl)-6-morpholin-4-yl-pyran-4-one (1)(0.50 g, 1.27 mmol) in ethanol (4 mL) at room temperature was added tetrafluorboric acid (supplied as 54 wt % in diethyl ether, 0.35 mL, 2.54 mmol). The solution was then cooled to 0° C., when t-butyl nitrite (750 μL, 6.33 mmol) was added. After 1 hr, the reaction was diluted with diethyl ether (10 mL), and after 20 mins the precipitate was filtered and washed with diethyl ether. The orange coloured salt was then dissolved in MeCN:Et2O (1:1) (15 mL), when triisopropylsilane (222 mg, 1.40 mmol) and Pd(OAc)2 (5.47 g, 24.37 mmol) were added successively. A CO pressure of 10 atm was then applied for 10 minutes, after which the reaction was filtered. The organic layer was washed with saturated NaHCO3 then brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting yellow/orange solid was dried under vacuum at 50° C. to give the crude title compound (0.392 g, 75%, 2 steps) which was used without any further purification. m/z (LC-MS, ESP), RT=3.40 min, (M++1)=406.3
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[C:27]([CH2:29][CH2:30][CH:31](O)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:28].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.CCOCC>[C:27]([CH2:29][CH2:30][CH:31]([O:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:28]
Reactant: Oc1cccnc1
Reactant: CCOC(=O)CCCC(O)CCC#N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCCC(CCC#N)Oc1cccnc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of triphenylphosphine (2.42 g, 9.2 mmol) and 3-hydroxypyridine (0.7 g, 7.3 mmol) in methylene chloride (20 mL) is added the ethyl 7-cyano-5-hydroxyheptanoate obtained above. The reaction mixture is stirred for 5 minutes and then diethyl azodicarboxylate (1.0 mL, 6.3 mmol) is added dropwise. The reaction mixture is stirred overnight and the solvent is evaporated. The residue is chromatographed on silica gel using ether as eluent to obtain an amber oil. The oil is dissolved in 10 mL ether, cooled to 0° C. and the precipitated triphenylphosphine oxide is filtered off. The filtrate is evaporated to give crude ethyl 7-cyano-5-(3-pyridyloxy)-heptanoate, IR (CH2Cl2): 2239, 1729, 1576, 1229, 1167, 1120 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].Cl.[NH2:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25].O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>CN(C)C=O>[CH3:19][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:16]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6])[CH3:3]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 81.5 %

Procedure:
To a solution containing N-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanine (19.89 g, 75 mmol) in dry dimethylformamide (375 mL) was added L-leucine, methyl ester, monohydrochloride (13.62 g, 75 mmol) and hydroxybenzotriazole hydrate (11.46 g, 75 mmol). The resulting mixture was cooled to 0° C. under argon and treated with diisopropylethylamine (9.69 g, 13 mL, 75 mmol) followed by 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (33.5 g, 75 mmol). The reaction was allowed to warm to ambient temperature overnight, then concentrated in vacuo to half volume followed by treatment with 800 ml of pH 4 phosphate buffer. A white solid that separated from solution was collected by filtration and dissolved in ethyl acetate (600 mL). The organic solution was rinsed with saturated aqueous sodium hydrogen carbonate, water and brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo to give 24 g of crude product. The entire product was dissolved in hot diisopropyl ether (250 mL) and the resulting solution concentrated to about half volume and refrigerated overnight. By this method, 22.2 g of the title A compound was obtained from the first crop with an additional 1.1 g from the mother liquor, m.p. 105°-106° C.
Reaction SMILES: [H-].[Na+].C(O)C.[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:8].[C:17](OCC)(=[O:20])[CH2:18][CH3:19]>CCCCCC.C(OCC)C.O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH2:6][C:17](=[O:20])[CH2:18][CH3:19])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCO
Product: CCC(=O)CC(=O)c1ccc(OC)cc1

Procedure:
To a suspension of 8.8 g (0.18 mole) of a 50% dispersion of sodium hydride in hexane was added 1 ml of ethanol followed by the addition, over a period of five minutes, of a solution of 30 g (0.2 mole) of 4-methoxyacetophenone in 50 ml of diethyl ether 50 ml of ethyl propionate was then added rapidly, and the solution was heated under reflux for three hours and then cooled. An additional 7 g of sodium hydride dispersion was added, the reaction was allowed to subside, and the mixture was then cooled and diluted with 500 ml of water with stirring. The solid which separated was collected by filtration, washed with water, then with diethyl ether and dried in a vacuum oven at 60° C. to give 18.3 g of 5-(4-methoxyphenyl)-3,5-pentanedione as the sodium salt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([CH:30]2[CH2:32][CH2:31]2)[C:12](=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[CH:5][CH:4]=1)#[N:2].[S].[CH2:34](N)[CH2:35][NH2:36]>>[CH:30]1([N:11]([CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]3[NH:36][CH2:35][CH2:34][N:2]=3)=[CH:8][CH:7]=2)[C:12](=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])[CH2:31][CH2:32]1
Reactant: NCCN
Reactant: N#Cc1ccc(CCN(C(=O)CCCNCS(=O)(=O)c2cccc(Cl)c2Cl)C2CC2)cc1
Agent: [S]
Product: O=C(CCCNCS(=O)(=O)c1cccc(Cl)c1Cl)N(CCc1ccc(C2=NCCN2)cc1)C1CC1

Procedure:
Analogously to 13b), N-cyclopropyl-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}butyramide was prepared from 0.84 g (1.70 mmol) of N-[2-(4-cyanophenyl)ethyl]-N-cyclopropyl-4-[(2,3-dichlorobenzenesulphonyl)methylamino]butyramide, 0.143 g (4.46 mmol) of sulphur and 3 ml of ethylenediamine.