Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]([CH:16]=[CH2:17])=O>C(O)CCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:1]1[CH:17]=[CH:16][CH:14]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(N)C(=O)OCC
Reactant: C=CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CCOC(=O)c1cccnc1C(=O)OCC
Yield: 72.9 %

Procedure:
Diethyl 1-amino-1,2-ethylenedicarboxylate (1.0 g) and acrolein monomer (0.39 g) are dissolved in n-butanol (10 ml), and thereto is added p-toluenesulfonic acid (20 mg). The mixture is refluxed for 10 hours, and thereto is added additional acrolein monomer (0.1 g), and the mixture is refluxed for 5 hours (the degree of reaction of aminodiester is 91%). After distilling off the solvent, the residue is distilled under reduced pressure to give diethyl pyridine-2,3-dicarboxylate (0.86 g, 72.3%). The product has a boiling point of 135°-145° C. (3 Torr) and a purity of 96.4% by gas chromatographic analysis.
Reaction SMILES: [CH:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N#N.[ClH:13]>C1CCCCC1>[CH:1]1([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cl
Reactant: OC1CCc2ccccc21
Agent: N#N
Solvent: C1CCCCC1
Product: ClC1CCc2ccccc21

Procedure:
20 g Indanone (obtained according to Example VIII) is added to a solution of 1.5 molequivalent NaAlH2 (OC2H4OCH3)2 in a mixture of benzene and ether in the course of which the temperature raises to 35° C. Then the reaction mixture is stirred during one hour, poured out into ice and extracted with ether. The solution in ether is washed with NaCl solution, dried and evaporated. The residue is distilled under diminished pressure yielding 15.1 g indanol. B.p. 115° C./1 mm Hg. The indanol is dissolved in 100 ml cyclohexane and during 30 min. gaseous HCl is introduced followed by N2 to remove the excess of HCl. The reaction mixture is evaporated and the residue is distilled under diminished pressure yielding 12.9 g indanyl chloride. B.p. 95° C./1 mm Hg.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CNCCCC(=O)OC(C)(C)C
Agent: Cl
Product: CN(CCCC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1

Procedure:
The title compound was prepared following general procedure 10, starting from 4-cyanobenzyl bromide and tert-butyl 4-(methylamino)butanoate hydrochloride (Watanabe). It was obtained as a yellow oil (586 mg, quantitative). LC/MS (Method B): 289.2 (M+H)+. HPLC (Method A) Rt 3.02 (Purity: 91.8%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[Cl:19])[C:15](=[O:20])[NH:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1.[CH2:21]([O:23][C:24](=[O:27])[CH:25]=O)[CH3:22].C([BH3-])#N.[Na+]>CO>[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH:1][C@H:2]1[CH2:3][CH2:4][C@@H:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[Cl:19])[C:15](=[O:20])[NH:14][CH:13]=[CH:12]3)[CH2:6][CH2:7]1)[CH3:22]
Reactant: CCOC(=O)C=O
Reactant: N[C@H]1CC[C@@H](Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CN[C@H]1CC[C@@H](Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Temperature: 60 °C

Procedure:
300 mg (0.91 mmol) of 6-cis-(4-amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one (12) were dissolved in 20 ml of methanol and treated with 258 mg (1.14 mmol) glyoxylic acid ethyl ester following the general method for reductive amination reactions. To achieve complete conversion, additional 5.0 equivalents of glyoxylic acid ethyl ester and 0.5 equivalents sodium cyano borohydride were added portionwise over 34 h and the temperature was increased to 60° C. after 5 h reaction time until the reaction went to completion. After filtration, the reaction solution was evaporated. The residue was dissolved in dichloromethane, washed with 1 N NaOH and saturated NaCl-solution, dried over MgSO4 and evaporated. The so obtained crude product was used in the next reaction without further purification. Rt=0.81 min (Method C). Detected mass: 365.4 (M+H+, methyl ester, because methanol was used as solvent), 0.87 min. (Method C). Detected mass: 379.4 (M+H+, ethyl ester, title compound).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=3)([OH:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=[NH:37])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl>C1(C)C=CC=CC=1.CC(O)=O.CC(O)=O.[Pd]>[NH2:37][C:19]1[CH:18]=[C:17]([C:15]2([OH:16])[CH:13]3[CH2:12][CH2:11][CH:10]2[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14]3)[CH:22]=[CH:21][CH:20]=1
Reactant: OC1(c2cccc(Br)c2)C2CCC1CN(Cc1ccccc1)C2
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Nc1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-Benzyl-8-(3-bromo-phenyl)-3-aza-bicyclo[3.2.1]octan-8-ol (4.69 g, 7.82 mmol) was dissolved in toluene (40 mL) in a flame dried RB flask. To this was added benzophenone imine (1.57 mL, 9.38 mmol), sodium t-butoxide (1.05 g, 11.0 mmol), then BINAP (racemic, 0.487 g, 0.782 mmol). The reaction was degassed (evac./N2 purged 3×) before adding palladium II acetate (0.175 g, 0.782 mmol), then heated to 100° C. in an oil bath under N2 overnight (or until judged complete by TLC). The imine was cooled to room temperature, treated with 6 N HCl (25 mL), and heated to 100° C. After 1 h, the reaction was cooled to room temperature, filtered through a Celite pad, rinsed with ether (50 mL) then water (50 mL). The filtrate was washed with ether (2×100 mL), then the aqueous layer was basified to pH 10 with 1 N NaOH, and saturated aqueous Na2CO3 solution. The product was extracted with EtOAc (3×100 mL), washed with saturated aqueous NaCl solution (1×100 mL), dried over Na2SO4, filtered through a Silica pad (2×3 in) eluted with 100% EtOAc and concentrated to an orange foam (2.34 g, 97%). (TLC 50% EtOAc/hexanes Rf 0.30); 1H NMR (400 MHz, CDCl3) δ 7.38–7.20 (m, 5H), 7.12 (t, J=7.9 Hz, 1H), 6.86 (d, J=7.9 Hz, 1H), 6.79 (s, 1H), 6.59 (m, 1H), 3.64–3.57 (m, 2H−NH2, 2H), 2.85 (d, J=9.9 Hz, 2H), 2.58 (m, 2H), 2.34 (br s, 2H), 1.77 (d, J=7.1 Hz, 2H), 1.43 (m, 2H); APCI MS m/z 309.2 (M+1)+.
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8](Cl)[CH:9]=[CH2:10].[Sn](Cl)Cl.[I-].[Na+].C(O)(=O)C.[Al]>[Cu].O>[OH:7][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:10][CH:9]=[CH2:8]
Reactant: C=CCCl
Reactant: CCCCCC=O
Agent: [Cu]
Agent: Cl[Sn]Cl
Agent: [Al]
Solvent: O
Solvent: CC(=O)O
Product: C=CCC(O)CCCCC
Temperature: 35 °C
Reaction time: 12 h

Procedure:
To 500 ml water was added 100 g hexanal (1 mol), 184 g allylchloride (2.4 mol), 19 g tin(II) chloride (0.1 mol), 1.5 g sodium iodide (0.01 mol), 12.5 g copper powder (0.2 mol), 108 g acetic acid (1.8 mol) and 32.4 g aluminium (1.2 mol) (e.g. foil or clips). The reaction mixture was stirred vigorously for ca. 12 h at 35° C. Then the reaction mixture was separated as an aqueous and an organic layer, and the organic layer was distilled in vacuo to give 4-hydroxy-1-nonene (the conversion of starting material (based on hexanal) is typically better than 95%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18][C:19](=[N:27][OH:28])[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].CO.[OH-].[Li+].OS([O-])(=O)=O.[K+]>C1COCC1>[OH:28][N:27]=[C:19]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1)[CH2:18][CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35]
Reactant: COC(=O)c1ccc(-c2ccc(C(CC(=NO)c3ccnc(C)c3)c3ccccc3C)cc2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)=NO)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-[3-[hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid methyl ester (352 mg) in THF (7.5 mL) was added a drop of methanol and a 1 M aqueous lithium hydroxide solution (7.6 mL) at 0° C. The reaction mixture was stirred at rt for 2 hours. A 1M aqueous solution of KHSO4 (7.5 mL) was added, the phases were separated and an extraction was made with EtOAc and a saturated solution of NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH 9:1) to yield 4′-[3-[hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid as a mixture of E and Z isomers (3:1) as a white foam (288 mg, 84%), MS (ESI−): m/z=449.2 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.I[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.CN(C)CC(O)=O>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(I)cc1
Reactant: COc1ccc(O)cc1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(C)cc2)cc1
Temperature: 90 °C
Yield: 75.7 %

Procedure:
4-methoxy phenol (18 g, 0.145 mol) was taken into anhydrous dioxane (250 mL). 4-iodotoluene (47.42 g, 0.217 mol), cesium carbonate (94.49 g, 0.29 mol), N,N-dimethylglycine HCl (1.97 g, 0.014 mol), and copper iodide (0.966 g, 0.005 mol) were added to the solution. The reaction was heated to 90° C. for 12 h under nitrogen, with mechanical stirring. The reaction was concentrated to dryness and the residue was partitioned between water and ethyl acetate. The aqueous layer was washed with ethyl acetate (4×). The ethyl acetate was washed with brine, dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography (10:1 silica ratio, eluted with 3% ethyl acetate in hexane) to obtain the title product (23.50 g, 0.1097 moles, 76% yield). 1H NMR (400 MHz, DMSO-d6); δ 2.26 (s, 3H), 3.73 (s, 3H), 6.82 (d, J=8.8, 2H), 6.94 (s, 4H), 7.14 (d, J 8, 2H).
Reaction SMILES: O[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:10]1([CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: c1cn[nH]c1
Reactant: C=C(CO)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(Cn1cccn1)C(=O)OCC
Yield: 17.3 %

Procedure:
A mixture of ethyl 2-(hydroxymethyl)acrylate (4.1 g, 32 mmol), pyrazole (2.6 g, 38 mmol) and potassium carbonate (11 g, 79 mmol) in acetonitrile (30 mL) was refluxed for 20 h, quenched by the addition of water (100 mL), and extracted with ethyl acetate (40 mL×2). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (7/1) to afford 1.0 g (18%) of the title compound as a colorless oil:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12](O)[CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:24]1(=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[NH:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:34]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[C@@H:12]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=1)[CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C[C@H](O)c1ccc(C(F)(F)F)c(F)c1)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C[C@H](c1ccc(C(F)(F)F)c(F)c1)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a solution of 262 (0.98 g, 2.91 mmol) and THF (30 mL) cooled to 0° C. was added sequentially isoindoline-1,3-dione (0.470 g, 3.20 mmol) and PPh3 (1.14 g, 4.36 mmol), followed by a solution of DEAD (1.72 mL, 4.36 mmol) and THF (10 mL). The reaction was warmed to RT and stirred overnight. The reaction was concentrated to dryness, Et2O (300 mL) added and the resulting solid was filtered and discarded. The filtrate was then poured into water, and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM:MeOH (500:2) to afford 0.99 g (73.1%) of (S)-tert-butyl 2-(1,3-dioxoisoindolin-2-yl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl(methyl)carbamate (264).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH2:20])[CH:11]=1.[CH2:22]1[O:32][C:31]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][C:24]=2[O:23]1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH:20][CH2:27][C:26]2[CH:29]=[CH:30][C:31]3[O:32][CH2:22][O:23][C:24]=3[CH:25]=2)[CH:11]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1N
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
A solution of 0.80 g of N-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide in 10 ml of N,N-dimethylformamide were added 0.962 g of 3,4-methylenedioxybenzyl chloride and 0.710 g of sodium hydrogencarbonate, and the mixture was stirred at 80° C. for 4 hours. Chloroform and water were added to the reaction solution, and the chloroform extraction was conducted. The organic layer was washed with water, concentrated, and purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1) to give 0.49 g of N-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzylamino)benzamide.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([NH:7][C@H:8]([C:16](OC)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].[Cl-].[Li+].[BH4-].[Na+].CCOCC.CCCCCC>O1CCCC1.C(O)C>[CH3:3][C:2]([CH3:20])([O:4][C:5]([NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:16][OH:17])=[O:6])[CH3:1]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution containing N-[(1,1-dimethyl-ethoxy)carbonyl]-L-phenylalanine, methyl ester (10 g, 35.8 mmole) dissolved in a mixture of tetrahydrofuran (190 ml) and absolute ethanol (190 ml) is added lithium chloride (6.09 g, 143.2 mmole). The resulting homogeneous solution is treated with sodium borohydride (5.42 g, 143.2 mmole) and the reaction is stirred at room temperature under argon for 24 hours. The reaction mixture is next filtered using ether (~700 ml) to rinse the filter cake. The resulting filtrate is rinsed with water (3×200 ml) and brine (200 ml), dried over magnesium sulfate, and concentrated in vacuo to give 9 g of crude product. Recrystal-lization from ether/hexane gives 7.59 g of the title F compound; m.p. 94°-96°.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH:33][C:30]2[CH:31]=[CH:32][N:28]([CH3:27])[N:29]=2)=[O:12])[C:7](=[O:21])[CH:6]=1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.7 %

Procedure:
A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 67, 125 mg, 0.33 mmol) in N,N-dimethylformamide (3 mL) was treated with 1-methyl-1H-pyrazol-3-ylamine (40 mg, 0.40 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (300 mg, 0.67 mmol) and N,N-diisopropylethylamine (85 mg, 0.65 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-propionamide (68 mg, 45%): 1H NMR (300 MHz, DMSO-d6) δ ppm 0.60-1.36 (m, 6H) 1.42-1.91 (m, 7H) 3.73 (s, 3H) 4.25 (d, J=18.7 Hz, 1H) 4.62 (d, J=18.7 Hz, 1H) 4.90 (dd, J=10.3, 5.4 Hz, 1H) 4.96 (s, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.38-7.54 (m, 3H) 7.55 (d, J=2.1 Hz, 1H) 10.74 (s, 1H). HR-ES-MS m/z calculated for C23H26ClFN4O3 [M+Na]+ 483.1569, observed 483.1568.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:22])[CH:17]=[N:18][C:19]=1[O:20][CH3:21].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([NH:22][C:16]2[CH:17]=[N:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1cc(N)cnc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cnc1OC
Yield: 65.6 %

Procedure:
The title compound (542 mg, 1.64 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol), 5,6-dimethoxypyridin-3-amine (424 mg, 2.8 mmol) and pyridine (0.6 mL, 7.5 mmol) in DCM (10 mL) using the methods of (IntC1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:18])[S:12][C:13]=2[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>>[CH2:14]([C:13]1[S:12][C:11]([NH:18][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:21]([O:20][CH3:19])[CH:22]=2)=[N:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1sc(N)nc1-c1ccc(OC)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: CCCCc1sc(NC(=O)c2ccc(OC)c(OC)c2)nc1-c1ccc(OC)cc1
Yield: 62.8 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-n-butyl-thiazol-2-ylamine prepared in Example 62 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was recrystallized with petroleum ether and ethyl acetate at a ratio of 2:1 (V:V) to obtain a product as a white solid in a yield of 62.8%, mp: 150-151 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.93 (3H, t, J=7.2 Hz, CH3), 1.41 (2H, sextuple, J=7.20 Hz, CH2), 1.72 (2H, quintuple, J=7.20 Hz, CH2), 2.88 (2H, t, J=7.2 Hz, CH3), 3.80 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.94 (3H, s, OCH3), 6.72˜6.82 (3H, m, ArH), 7.25˜7.40 (4H, m, ArH), 11.16 (1H, br, CONH); EI-MS m/e (%): 426.1 (M+, 50), 383.1 (7), 165.1 (100); HREI-MS Calcd. for C23H26N2O4S: 426.1613. found: 426.1613. Anal. Calcd. for C23H26N2O4S: C, 64.77; H, 6.14; N, 6.57. found: C, 64.56; H, 6.23; N, 6.61.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: CC1CN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC(C)O1
Reactant: NCc1ccccc1
Solvent: O
Product: CC1CN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC(C)O1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-(2,6-dimethylmorpholin-4-yl)quinoline and 6 ml of benzylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 ml of water. The precipitated material is filtered off, washed with 20 ml of water. After drying 2.3 g of the title compound is obtained (MH+: 388).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.Cl>C(Cl)Cl>[CH3:1][C@H:2]1[N:7]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:36])[F:37])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 110.8 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-methyl-1-piperazinecarboxylate (1.5 g, 7.49 mmol, supplier Aldrich) in DCM (30 ml) was added DIPEA (1.962 ml, 11.23 mmol) and then portionwise addition of 4-(trifluoromethyl)benzenesulfonyl chloride (2.2 g, 8.99 mmol) at room temperature. The resultant mixture was stirred under an atmosphere of Ar for 2 hours before addition of 1M HCl solution (75 ml) and DCM (75 ml). The layers were separated and the aqueous layer was then re-extracted with DCM (75 ml), the organic layers were combined and washed with saturated brine solution (100 ml). The organic layers were then separated, dried (MgSO4) and concentrated to dryness giving the title compound (3.39 g).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH3:8][CH:9]([CH2:11][CH:12](O)[CH3:13])[CH3:10].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([O:7][CH:12]([CH3:13])[CH2:11][CH:9]([CH3:10])[CH3:8])(=[O:6])[CH2:2][C:3]([O:5][CH:12]([CH3:13])[CH2:11][CH:9]([CH3:10])[CH3:8])=[O:4]
Reactant: CC(C)CC(C)O
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CC(C)OC(=O)CC(=O)OC(C)CC(C)C
Yield: 83.9 %

Procedure:
Malonic acid (72.8 g, 0.7 mol) and 2-methyl-4-pentanol(286 g, 2.8 mol) in 200 ml of toluene are refluxed for 2 hours in the presence of 1.8 ml of concentrated sulfuric acid in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The organic phase is washed three times with water and dried over sodium sulfate. This solution is filtered and the solvent is evaporated off. The product obtained distils at 147° C. under 20 hPa. 160 g (79% yield) of bis(1,3-dimethylbutyl) malonate are obtained in the form of a colorless oil, which is used in the next step without further purification.