Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:18])[N:10]([CH3:19])[C:11]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(C(F)(F)F)cnc(-c2ccc(F)cc2)c1=O
Temperature: 100 °C
Reaction time: 36 h
Yield: 69.1 %

Procedure:
First, 0.659 g of 3-(4-fluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1001) was dissolved in 3.8 ml of N,N-dimethylformamide, to which 0.529 g of potassium carbonate and 0.32 ml of methyl iodide were added, and the mixture was stirred at 100° C. for 1.5 days. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=8:1), which afforded 0.480 g (yield, 69%) of 3-(4-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-4; m.p., 121.1° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+].[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36]1>CN1CCCC1=O.C(#N)C>[N:35]1([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCc3ccccc32)nc1-c1ccc(C)cc1
Yield: 30.9 %

Procedure:
A solution of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), N,N-diisopropylethylamine (0.122 mL; 0.781 mmol), sodium iodide (0.047 mg; 0.312 mmol) and indoline (0.074 mL; 0.625 mmol) in a mixture of 1-methylpyrrolidin-2-one (0.5 mL) and acetonitrile (0.5 mL) was irradiated in a microwave oven at 160° C. for 30 min. The solution was partitioned between ethyl acetate and water and the organic layer was washed with a saturated solution of sodium thiosulphate, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica using a gradient of ethyl acetate (2-20%) in heptane furnished 0.040 g (31%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[H][H]>[Pd].C(O)C>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(N)cc1

Procedure:
Absolute ethanol (20 ml) was added to 10% palladium on charcoal (0.2 g) in a Parr hydrogenation bottle (500 ml volume). 1-(1,1-Dimethylethyl)-4-nitrobenzene (50 g) in absolute ethanol (100 ml) was added. Hydrogen was admitted to the bottle and the mixture shaken at 60 psi over night. The catalyst was removed by filtration through Celite under nitrogen, the filtrate was reduced in vacuo and the residue distilled at 96° C./0.3 mm Hg to give 4-(1,1-dimethylethyl)benzenamine as an oil.
Reaction SMILES: CS[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.S(Cl)(Cl)(=O)=[O:40].[C:44]1([CH3:50])[CH:49]=[CH:48][CH:47]=CC=1>>[OH:40][C:44]1([CH2:3][O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[CH:37][N:38]=[C:12]34)[CH2:7][CH2:6]2)[CH2:49][CH2:48][CH2:47][CH2:50]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccccc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCSC)CC2)c2ncnn12
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O)CCCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4′-[(4-{trans-4-[(Methylsulfanyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.0 g) was dissolved in toluene (10 mL), and sulfuryl chloride (0.16 mL) was added at 0° C. The mixture was stirred at room temperature for 2 hr, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was mixed with cyclopentanone (0.16 g) and tetrahydrofuran (10 mL), and samarium iodide (57 mL, 0.1 M tetrahydrofuran solution) was added dropwise at room temperature under an argon atmosphere. The mixture was stirred at room temperature for 65 hr and added to saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.026 g, 2.4%).
Reaction SMILES: BrC1N=CC(CCN2CCCCCC2)=CC=1.[N:17]1([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([O-:34])=O)=[N:30][CH:31]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Li+].S(Cl)([Cl:38])=O>>[ClH:38].[N:17]1([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([Cl:38])=[O:34])=[N:30][CH:31]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=S(Cl)Cl
Reactant: O=C([O-])c1ccc(CCN2CCCCCC2)cn1
Agent: Brc1ccc(CCN2CCCCCC2)cn1
Agent: [Li+]
Product: Cl
Product: O=C(Cl)c1ccc(CCN2CCCCCC2)cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Synthesized from 1-[2-(6-bromopyridin-3-yl)ethyl]azepane (400 mg) according to an analogous synthetic method to Preparation Example 51, to the total amount of lithium 5-(2-azepan-1-ylethyl)pyridine-2-carboxylate crude product was added thionyl chloride (8 ml), the solution was stirred for 30 minutes at 90° C., then the reaction solution was concentrated in vacuo to provide 5-(2-azepan-1-ylethyl)pyridine-2-carbonyl chloride hydrochloride (640 mg). Synthesized from this compound (320 mg) and pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) according to an analogous synthetic method to Example 152, the title compound (7 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:27])[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25]O)[C:18]=2[O:17]1>>[CH3:15][C:16]1([CH3:27])[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)[C:18]=2[O:17]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CC1(C)Cc2cccc(CO)c2O1
Product: CC1(C)Cc2cccc(COc3ccnn3-c3cc(C#N)ccn3)c2O1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,2-dimethyl-3H-1-benzofuran-7-yl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.48 (6H, s), 3.03 (2H, s), 5.21 (2H, s), 5.83 (1H, d, J=2.0 Hz), 6.83 (1H, q, J=8.0 Hz), 7.13 (1H, d, J=7.2 Hz), 7.18 (1H, d, J=8.0 Hz), 7.37 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.56 (1H, d, J=1.6 Hz), 8.07 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H18N4O2, 347; Found, 347
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:46]1[CH2:50][CH2:49][CH2:48][C@H:47]1[CH2:51][N:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1>CN(C=O)C.ClCCl>[N:52]1([CH2:51][C@@H:47]2[CH2:48][CH2:49][CH2:50][N:46]2[C:10]([C:9]2[CH:8]=[CH:7][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)=[O:12])[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: O=C(O)c1ccc(-c2cccs2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(-c2cccs2)cc1)N1CCC[C@H]1CN1CCCC1
Yield: 29.7 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 10 mL 10% DMF/dichloromethane using 4-(thiophen-2-yl)-benzoic acid (CAS 29886-62-2) (182 mg, 0.89 mmol), EDC-HCl (254 mg, 1.33 mmol), HOBt (180 mg, 1.33 mmol), DIEA (0.39 mL, 2.22 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (116 mg, 10.0 mmol) to give the title compound (90 mg, 35% yield). MS (ES+) 341.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH:5]=[C:6]([C:9]#[N:10])[C:7]#[N:8].[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][CH:6]([C:7]#[N:8])[C:9]#[N:10]
Reactant: N#CC(C#N)=Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC(C#N)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
First, 4.46 g of (3,4-dichlorobenzylidene)malononitrile was dissolved in 20 ml of tetrahydrofuran, and while stirring at room temperature, a suspension of 0.19 g of sodium borohydride in 5 ml of ethanol was added dropwise, followed by stirring at room temperature for 30 minutes. Then, 10% hydrochloride acid was added and the mixture was extracted with diethyl ether. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3.15 g of (3,4-dichlorobenzyl)malononitrile (the intermediate (12)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:24]=3[Cl:23])[N:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: C[C@H]1C[C@@H](Oc2cccc(N)n2)CCN1C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: C[C@H]1C[C@@H](Oc2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CCN1C(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
Combine 4-(6-amino-pyridin-2-yloxy)-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 64, 0.714 g) and 2-chloro-4-fluorobenzoyl chloride (0.493 g) in 1,4-dioxane (20 mL) and heat. After 2.5 hr., partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column eluting with dichloromethane-2M NH3 in methanol, gradient to give the title compound (0.678 g). Mass spectrum (electric spray) m/z=464 (M+1); 1H NMR (CDCl3): 8.45 (br, 1H), 7.89 (br d, 1H), 7.78 (dd, 1H), 7.68 (ddd, 1H), 7.24 (dd, 1H), 7.12 (ddd, 1H), 6.54 (d, 1H), 5.27 (m, 1H), 4.35 (m, 1H), 3.90 (m, 1H), 3.25 (m, 1H), 1.90 (m, 3H), 1.75 (m, 1H), 1.47 (s, 9H), 1.28 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:3]=1[NH:4][CH2:5][CH2:6][S:7][CH3:8].O.O.[Sn](Cl)Cl.Cl.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C(O)C>[CH3:1][C:2]1[C:3]2[N:4]([CH2:5][CH2:6][S:7][CH3:8])[C:27](=[O:28])[NH:13][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CSCCNc1c(C)cccc1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CSCCn1c(=O)[nH]c2cccc(C)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
To a solution of 2-methyl-N-[2-(methylthio)ethyl]-6-nitroaniline (2.6 g, 12 mmol) in ethanol (6.0 mL) was added a solution of Tin(II) chloride dihydrate (7.9 g, 35 mmol) in concd. hydrochloric acid (8.0 mL) at 0° C. and warmed to rt. After 4h, the reaction was quenched by addition of 6N sodium hydroxide (100 mL) and extracted with ethyl acetate (100 mL×2), dried over sodium sulfate, filtered and concentrated. The crude material was dissolved in THF (50 mL) and to this solution was added CDI (2.3 g, 14 mmol) and the mixture was stirred at rt. After 12 h, to the mixture was added CDI (1.5 g, 6.7 mmol) and the reaction mixture was refluxed for 5 h. Then the mixture was cooled to rt and evaporated to dryness. To this was added water (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated. The obtained material was dissolved in methanol (30 mL) and to this solution was added 2N sodium hydroxide (3 mL) and stirred at rt for 2 h. Then the mixture was quenched by addition of sat. aq. sodium bicarbonate (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20/1-10/1) to afford 1.8 g (69%) of the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[C:8]([NH:19][C:20](=[O:38])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:23][CH:22]=2)[CH:7]=1)(=[O:5])[CH3:4].CO.O1CCCC1>O>[C:3]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:8]([NH:19][C:20](=[O:38])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:23][CH:22]=2)[CH:7]=1)(=[O:5])[CH3:4]
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1ccc(OCC(=O)O)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
A 1N sodium hydroxide aqueous solution was added to a mixture of 0.5 g of ethyl 4-acetyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 53, 5 ml of methanol and 5 ml of tetrahydrofuran and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 10 ml of water. The mixture was concentrated under reduced pressure to remove methanol and tetrahydrofuran. Diluted hydrochloric acid was added to the residue to render acidic. The formed crystals were taken by filtration and recrystallized from isopropyl alcohol to obtain 0.39 g of 4-acetyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:25])[C:20]=2[O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=[C:15]([O:26][CH2:27][O:28][CH3:29])[CH:14]=3)=[CH:7][C:6]=1[O:30][CH2:31][O:32][CH3:33].CCN(C(C)C)C(C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>CCOCC>[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[O:12][C:13]4[C:18]([C:19](=[O:25])[C:20]=3[O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=[C:15]([O:26][CH2:27][O:28][CH3:29])[CH:14]=4)=[CH:7][C:6]=2[O:30][CH2:31][O:32][CH3:33])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(OCCO)c(OCOC)c3)oc2c1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(OCCOS(=O)(=O)c4ccc(C)cc4)c(OCOC)c3)oc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 2-(4-(2-hydroxyethoxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one (18 mg, 0.039 mmol) and DIPEA (15 mg, 0.11 mmol) was added 4-methylbenzene-1-sulfonyl chloride (11 mg, 0.058 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with ether (30 mL). It was washed with 0.5 M HCl(2×30 mL) and water (50 mL), and dried over MgSO4 and concentrated. The crude product was chromatographed to afford 2-(4-(3,7-bis(methoxymethoxy)-4-oxo-4H-chromen-2-yl)-2-(methoxymethoxy)phenoxy)ethyl 4-methylbenzenesulfonate (AD-C-001P-WZ01079) as a yellow wax (20 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J=8.8, 2.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.4 Hz, 2.0 Hz, 2H), 7.73 (dd, J=8.4, 2.0 Hz, 1H), 7.36 (d, J=6.8 Hz, 2H), 7.27 (d, J=2.0 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.05 (dd, J=8.8, 2.0 Hz, 1H), 6.94 (dd, J=8.8, 2.0 Hz, 1H), 5.29 (d, J=1.6 Hz, 2H), 5.22 (d, J=2.0 Hz, 4H), 4.42 (t, J=3.0 Hz, 2H), 4.32 (t, J=3.0 Hz, 2H), 3.53 (d, J=2.4 Hz, 3H), 3.52 (d, J=2.0 Hz, 3H), 3.20 (d, J=2.4 Hz, 3H), 2.46 (s, 3H); MS (ESI) m/z 617 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1.C(N(CC)CC)C.[C:21](#[N:24])[CH:22]=[CH2:23]>CO>[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH:4]([CH2:3][CH2:2][NH:1][CH2:23][CH2:22][C:21]#[N:24])[CH2:5]1
Reactant: NCCC1COc2ccccc2C1
Reactant: C=CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CCCNCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
17.7 g (0.1 mol) of 3-(2-aminoethyl)chroman are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 5.84 g (0.11 mol) of acrylonitrile are added to the solution. The reaction mixture is stirred for 15 hours at room temperature and then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-amine is thus obtained in the form of a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[S:6][N:5]=1)[CH3:2].[CH3:24][NH:25][CH3:26]>CN(C)C=O>[CH3:24][N:25]([CH3:26])[C:15]([NH:14][C:7]1[S:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:23]
Reactant: CCOC(=O)c1c(OCC)nsc1NC(=O)Oc1ccccc1
Reactant: CNC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC)nsc1NC(=O)N(C)C
Yield: 26.5 %

Procedure:
In the manner of Example II B, 8.4 g of phenyl (3-ethoxy-4-ethoxycarbonyl-5-isothiazolyl)carbamate in 20 ml of dimethylformamide were treated with 2.3 g of dimethylamine. The solid from the reaction mixture was recrystallized from ethanol to yield 1.9 g of 1,1-dimethyl-3-(3-ethoxy-4-ethoxycarbonyl-5-isothiazolyl)urea, mp 164°-165°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:35])[N:10]([CH:12]3[CH2:17][CH2:16][N:15](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:14][CH2:13]3)N=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:36]1CCC[CH2:37]1.[CH2:41](NCC)C>CO>[CH3:37][O:36][C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9](=[O:35])[N:10]([CH:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH:41]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: CCNCC
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1
Reactant: C1CCOC1
Solvent: CO
Product: COc1cccc(-c2cn(C3CCNCC3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9.0 g (0.0193 mol) of 2,4-dihydro-5-phenyl-2-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-3H-1,2,4-triazol-3-one, 50 ml of tetrahydrofuran and 70 ml of diethylamine was stirred at room temperature until the end of the reaction monitored by thin layer chromatography. The solvent was removed in vacuo, the residue remaining was mixed with 300 ml of water and subjected to ultrasound treatment for 30 minutes. The insoluble matter was separated off by suction filtering and the aqueous filtrate was evaporated down in vacuo. The residue thus obtained was boiled with a little methanol and after cooling it was suction filtered. After drying 0.58 g (12.3% of theory) of colourless crystals of melting point 294° C. (D) and Rf=0.1 (eluant 1) were obtained.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([C:12]1[CH:13]=[C:14]([S:22]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][C@@H:28]([N:32]3[CH:36]=[N:35][N:34]=[CH:33]3)[CH2:27]2)(=[O:24])=[O:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)(=[O:11])[CH3:10]>CCO>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:10]/[C:9]([C:12]1[CH:13]=[C:14]([S:22]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][C@@H:28]([N:32]3[CH:33]=[N:34][N:35]=[CH:36]3)[CH2:27]2)(=[O:23])=[O:24])[CH:15]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:17]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@H]2CCC[C@@H](n3cnnc3)C2)c1
Solvent: CCO
Product: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@H]2CCC[C@@H](n3cnnc3)C2)c1
Temperature: 100 °C

Procedure:
N,N,-Dimethylformamide dimethyl acetal (200 μL, 1.49 mmol) was added to a stirred solution of 9a (100 mg, 0.240 mmol) in EtOH (1.50 mL). The mixture was placed in a sealed tube and heated in a microwave reactor at 100° C. for 2 h. After cooling to rt, the reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by preparative thin layer chromatography on silica gel (10% MeOH/DCM as eluent) to afford the title compound, 9b. m/z (ES) 472 (MH)+
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([OH:34])=O)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:44][C@@H:45]1[NH:50][CH2:49][CH2:48][N:47]([S:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH2:46]1>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([N:50]2[CH2:49][CH2:48][N:47]([S:51]([C:54]3[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:58][CH:59]=3)(=[O:52])=[O:53])[CH2:46][C@@H:45]2[CH3:44])=[O:34])[CH:27]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
HATU (411 mg, 1.08 mmol) was added to a solution of 4-chloro-2-pyridinecarboxylic acid (142 mg, 0.90 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.394 ml, 2.25 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (333 mg, 1.082 mmol) was then added and stirring was continued for 1.5 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organics were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in isohexane, gave a pale yellow gum, shown to be impure by LCMS and NMR analysis. Further purification by MDAP gave the title compound as a colourless glass (159 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][NH2:13].[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27](OC)[CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]4[N:13]([CH3:12])[C:4](=[O:6])[C:3]5[C:2](=[CH:10][CH:9]=[CH:8][C:7]=5[F:11])[N:1]=4)=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: COc1cc(OC2CCN(C3CCC3)CC2)ccc1C=O
Reactant: CN
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2cccc(F)c2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-6-fluorobenzoic acid, methylamine and 4-[(1-cyclobutylpiperidin-4-yl)oxy]-2-methoxybenzaldehyde.