Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.[C:9](=[O:16])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH2:10].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCCC1>[F:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:9](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(F)ccn1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A flask was charged with 2-chloro-4-fluoropyridine (20 g, 152 mmol), tert-butyl carbamate (89 g, 760 mmol), tris(dibenzylideneacetone)dipalladium (1.39 g, 1.52 mmol), X-PHOS (1.48 g, 3.10 mmol), cesium carbonate (99 g, 588 mmol), and tetrahydrofuran (500 mL) under an atmosphere of dry nitrogen. The mixture was heated at reflux under nitrogen for 7 hours. A further 1 equivalent of cesium carbonate was added and the reaction was heated a further 7 hours. The mixture was cooled to ambient temperature, filtered through Celite and washed with ethyl acetate. The filtrate was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine and dried with sodium sulfate, concentrated under vacuum, and purified by column chromatography to give tert-butyl 4-fluoropyridin-2-ylcarbamate as a pale yellow solid (22.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([O:40][CH2:41][CH2:42][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH:31]=3)=[O:28])=[C:22]([F:49])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10]CC1C=CC(OC)=CC=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[C:9](=[O:10])[NH:8][CH:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=[C:32]([O:40][CH2:41][CH2:42][N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[CH:31]=3)=[O:28])=[C:22]([F:49])[CH:21]=2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(OCCN4CCOCC4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(OCCN4CCOCC4)cc(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide (80 mg, 0.117 mmol) and TFA (10 mL, 10% in DCM) was stirred at 25° C. for 2 h. The mixture was concentrated. To the residue was added NH3 (6 mol/L in MeOH, 1 mL) and concentrated. The residue was purified by preparative TLC (DCM/MeOH=15:1, Rf=0.4) to give an off white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide (35.72 mg, 0.061 mmol, 51.7% yield): 1H NMR (400 MHz, CD3OD): δ 7.59 (s, 1H), 7.46 (s, 1H), 7.43-7.37 (m, 1H), 7.36-7.30 (m, 2H), 7.29 (d, J=2.0 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 6.96 (s, 1H), 4.23 (t, J=5.2 Hz, 2H), 4.11 (q, J=6.8 Hz, 2H), 3.79 (s, 2H), 3.78-3.69 (m, 4H), 3.02-3.00 (m, 2H), 2.80-2.79 (m, 4H), 1.45 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 564 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH2:12])[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:5]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:34][C:35]([F:39])([F:38])[S:36]Cl>ClCCl>[C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH:12][S:36][C:35]([F:39])([F:38])[F:34])[N:6]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][C:18]=2[Cl:19])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reactant: FC(F)(F)SCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NSC(F)(F)F)c1S(C)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 3-acetyl-5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulfinylpyrazole (3 g) in dichloromethane containing diisopropylethylamine (1.44 ml) was added trifluoromethylsulfenyl chloride (0.97 ml) at −30° C. The mixture was stirred (2 hours) and when at 20° C. purged with nitrogen. Water was added and the organic phase dried (sodium sulfate) and evaporated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to give 3-acetyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulfinyl-5-trifluoromethylsulfenylaminopyrazole (Compound 10, 0.5 g), m.p. 67-102° C., mass spectral analysis M+/e=499.
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:55][C@H:56]([C:58]([CH2:60][Cl:61])=[O:59])[CH3:57]>>[NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27]([NH:55][C@H:56]([C:58]([CH2:60][Cl:61])=[O:59])[CH3:57])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: C[C@H](N)C(=O)CCl
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)CCl
Temperature: -20 °C
Reaction time: 3 h

Procedure:
Boc-Ala-CH2Cl (2 g) in 5 equiv of HCl in dioxane was stirred at room temp for 1 h. After removal of solvent, the residue was triturated with diethyl ether to give crude H-Ala-CH2Cl (1.41 g). The Z-Leu-Asp(OtBu)-Leu-OH (2.68 g) and N-methylmorpholine (0.54 mL) were dissolved in ThF (25 mL), the cooled to −20° C. Isobutyl chloroformate (0.64 mL) was added to generate the mixed anhydride, which was transferred to the H-Ala-CH2Cl (1.41 g in 10 mL of DMF) solution at −20° C. The resulting mixture was allowed to come to room temp and reaction was completed in 3 h. The salt was removed by filtration. The filtrate was concentrated, redissolved in ethyl acetate (100 mL). The solution was washed with 0.2 N HCl, 5% NaHCO3, sat. NaCl; dried over Na2SO4, filtered, and concentrated to yield crude solid of 3.19 g. The crude Z-Leu-Asp(OtBu)-Leu-Ala-CH2Cl was purified by Sephadex IMO column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([N:12]=[C:13]=[O:14])=[C:4]([F:15])[CH:3]=1.[NH2:16]/[C:17](/[C:24]([F:27])([F:26])[F:25])=[CH:18]\[C:19](OCC)=[O:20].[H-].[Na+].C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:19](=[O:20])[CH:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[NH:16][C:13]2=[O:14])=[C:4]([F:15])[CH:3]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: O=C=Nc1c(F)cc(Cl)c2c1OCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(F)cc(Cl)c2c1OCCC2

Procedure:
By a method analogous to that of Example 1, Step G, 2.5 grams (0.011 mole) of 5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl isocyanate was reacted with ethyl 3-amino-4,4,4-trifluorocrotonate and 0.66 gram (0.012 mole) of sodium hydride (60% in mineral oil) in 150 mL of tetrahydrofuran. The crude reaction product was subjected to column chromatography on silica gel, with 1:2 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.0 grams of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16](Br)[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC.[F-].[K+]>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>[CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([CH:20]=[CH2:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(NCc2ccccc2)c2scc(Br)c2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 56.2 %

Procedure:
N-Benzyl-7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine (200 mg, 0.56 mmol) was dissolved in dioxane (2.5 mL) and nitrogen was flown for 20 minutes. After adding Pd(PPh3)4 (41 mg, 0.036 mmol) and tributyl(vinyl)tin (0.18 mL, 0.62 mmol), the mixture was stirred at 120° C. for 7 hours. The reaction mixture was cooled to room temperature and stirred for 2 hours after adding 10% potassium fluoride aqueous solution (5 mL). The reaction solution was filtered with celite and washed with ethyl acetate. The aqueous layer was separated from the organic layer and extracted once more with ethyl acetate. The combined organic layer was concentrated by drying with MgSO4. Purification of the mixture by silica gel chromatography (DCM/MeOH=97/3) yielded the target compound (95 mg, 55% yield).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[C:12](=O)(O)[O-].[Na+].C[Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(O)C1CNCCN1
Reactant: O=C([O-])O
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CNCCN1
Reaction time: 4 h
Yield: 28119.6 %

Procedure:
piperazine-2-carboxylic acid dihydrochloride (750 mg, 3.7 mmol) was suspended in MeOH (15 mL) and sodium bicarbonate (620 mg, 7.4 mmol) was added and stirred for 4 h. The reaction mixture was diluted with CH2Cl2 (15 mL) and cooled to 0° C. (Trimethylsilyl)diazomethane (15 mL, 2M in hexane) was added dropwise until the yellow color persisted. The solution was stirred at room temperature for 3 h and concentrated under reduced pressure. The crude product was purified by column chromatography (neutral alumina, eluent 5-6% MeOH in CHCl3) to get methyl piperazine-2-carboxylate (150 g, yield 28%). 1H NMR (300 MHz, CDCl3) δ 3.74 (s, 3H), 3.51-3.47 (dd, J=8.0 Hz, 3.4 Hz, 1H), 3.24-3.19 (dd, J=12.1 Hz, 3.3 Hz, 1H), 3.04-2.99 (m, 1H), 2.96-2.86 (m, 3H), 2.83-2.77 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:22][CH2:23][OH:24].I[C:26]1[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:26]3[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:22][CH2:23][OH:24]
Reactant: Cc1ccc(I)nn1
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(-c3nc(CCO)c(C)o3)cc2)nn1

Procedure:
To a stirring solution of 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (0.314 g, 0.952 mmol) (See Intermediate 3), 3-Iodo-6-methyl-pyridazine (0.178 g, 0.810 mmol) [CAS# 1618-47-9] and [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (1:1) (0.02 g, 0.024 mmol) in 10 mL dioxane is added aqueous sodium carbonate (2M, 1.22 mL) and the reaction is carried out substantially in accordance with the procedure of Example 9 to provide after purification by radial chromatography pure titled compound (0.208 g, 87%). MS (m/e): 296.3 (M+1).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Br:23])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41](Cl)=[O:42])[N:35]=[N:34]1>C(Cl)Cl>[NH:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41]([NH:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:15]([Br:23])[CH:14]=3)=[O:10])[CH2:7][CH2:8]2)=[O:42])[N:35]=[N:34]1
Reactant: O=C(Cl)CCCc1c[nH]nn1
Reactant: NC1CCN(C(=O)OCc2cc(Br)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Br)cc(C(F)(F)F)c2)CC1
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-bromo-5-(trifluoromethyl)benzyl 4-aminopiperidine-1-carboxylate hydrochloride salt (92 mg, 0.220 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.077 mL, 0.441 mmol). 4-(1H-1,2,3-triazol-4-yl)butanoyl chloride (38.2 mg, 0.220 mmol) in DCM (2 mL) was added and the reaction mixture stirred for 2 hours. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, a saturated solution of brine, and the organic portion was then dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH/DCM as eluent to afford the title compound;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][OH:8].[NH2:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([Cl:17])[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([NH2:9])[CH:15]=[CH:14][C:13]=1[O:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1
Reactant: OCc1cnccn1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(OCc2cnccn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.8 %

Procedure:
To a mixture of pyrazin-2-yl-methanol (62 mg, 0.56 mmol), 4-amino-2-chloro-phenol (80.8 mg, 0.56 mmol) and triphenylphosphine (148 mg, 0.56 mmol) in THF (3 ml) was added DIAD (0.11 ml, 0.56 mmol) and the mixture was stirred at rt for 20 h. The mixture was concentrated in vacuo, diluted with 1N HCl (30 ml), washed with EtOAc (3×20 ml) and basified to pH 12 by 1N NaOH. The mixture was extracted with EtOAc (4×40 ml) and the combined EtOAc extracts were washed with brine (1×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 16A (43.3 mg, 33% pure)
Reaction SMILES: C(OC1C(C(O)=O)=NC=CC=1OC)C1C=CC=CC=1.C([O:27][C:28]1[C:29]([C:38]([OH:40])=O)=[N:30][CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])C1C=CC=CC=1.CO[C:43]1[CH:56]=[CH:55][C:46]([O:47][C:48]2[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=2)=[CH:45][CH:44]=1.O(C1C=CC(N)=CC=1)C1C=CC=CC=1>>[OH:27][C:28]1[C:29]([C:38]([NH:52][C:51]2[CH:50]=[CH:49][C:48]([O:47][C:46]3[CH:55]=[CH:56][CH:43]=[CH:44][CH:45]=3)=[CH:54][CH:53]=2)=[O:40])=[N:30][CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]
Reactant: COc1cnc(C(=O)O)c(OCc2ccccc2)c1OC
Reactant: COc1ccc(Oc2ccc(N)cc2)cc1
Agent: COc1ccnc(C(=O)O)c1OCc1ccccc1
Agent: Nc1ccc(Oc2ccccc2)cc1
Product: COc1cnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c(O)c1OC

Procedure:
The procedure of Example 29 was repeated, except that 3-benzyloxy-4-methoxypicolinic acid was changed to 3-benzyloxy-4,5-dimethoxypicolinic acid and 4-(4′-methoxyphenoxy)aniline was changed to 4-phenoxyaniline. Thus, the title compound was prepared.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[C:11]1([CH:17](P(=O)(OCC)OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(C)=O.CC(C)([O-])C.[K+]>O>[C:11]1([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:5][C:4]2[CH:3]=[C:2]([Br:1])[CH:9]=[C:8]([Br:10])[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP(=O)(OCC)C(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1cc(Br)cc(C=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 73.5 %

Procedure:
Under an atmosphere of argon, 3,5-dibromobenzaldehyde (12.1 g, 46 mmole) and diethyl diphenylmethylphosphonate (15 g, 49 mmole, 1.1 eq) were dissolved into dimethyl sulfoxide (DMSO) (60 ml). To the resultant solution, potassium t-butoxide (6.2 g, 55 mmole, 1.2 eq) was added in small portions and the obtained solution was stirred at the room temperature for 9 hours and left standing for one night. After water (60 ml) was added, the reaction mixture was subjected to extraction with ethyl acetate (250 ml). The obtained organic layer was washed with water (100 ml) and a saturated aqueous solution of sodium chloride (50 ml) and dried with magnesium sulfate. Then, the solvent was removed by distillation and a deep brown oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane and hexane+3% dichloromethane, successively) and a white solid (14.0 g, 74%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Fc1ccc([C@H]2CCCN2)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC[C@@H]1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 119° C. and MS: m/e=339 (M+) was prepared in accordance with the general method of example 1e from (R)-2-(4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>ClCCl>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccc(F)cc3)cc1)N2
Yield: 37 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (70 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol,) in dichloro methane (5 mL) was added 4-fluorobenzoyl chloride (54 mg, 0.34 mmol). The resultant mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed in vacuo and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-(4-fluorobenzamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 43 mg, yield: 37%.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CN(C)C=O.C(N(CC)C(C)C)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][N:22]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(S(C)(=O)=O)CC3)cc1
Reaction time: 2 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea hydrochloride (0.1000 g, 0.2310 mmol) in dry N,N-Dimethylformamide (1.60 mL, 20.7 mmol) was added N,N-Diisopropylethylamine (0.161 mL, 0.924 mmol) followed by Methanesulfonyl chloride (0.0268 mL, 0.346 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.19 (d, J=8.7, 2H), 7.49 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.23 (dd, J=31.8, 14.8, 2H), 3.97-3.91 (m, 1H), 3.88 (d, J=11.3, 1H), 3.72 (dd, J=11.4, 2.7, 1H), 3.62 (dd, J=10.0, 7.5, 3H), 3.49-3.38 (m, 3H), 3.16-3.08 (m, 2H), 3.03 (s, 3H), 2.99 (t, J=6.3, 2H), 1.22 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+475.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].O=[C:15]([CH3:27])[CH2:16][O:17][C:18]1[C:19]([C:24]([NH2:26])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=1.[BH4-].[Na+].Cl>C(O)C>[CH3:27][CH:15]([NH:1][CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[CH2:16][O:17][C:18]1[C:19]([C:24](=[O:25])[NH2:26])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccccc1OCC(O)CN
Reactant: CC(=O)COc1cccnc1C(N)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1OCC(O)CNC(C)COc1cccnc1C(N)=O
Temperature: 25 °C

Procedure:
A solution of 4.5 g of 1-amino-3-(2-methyl-phenyloxy)-2-propanol and 4.85 g of 3-(2-oxo-propyloxy)-2-pyridinecarboxylic acid amide in 100 ml of ethanol is heated under reflux for 3 hours. After cooling to room temperature, 1.9 g of sodium borohydride are added whilst stirring; the temperature gradually rises to 45° C. After the reaction has subsided, the mixture is stirred for a further hour. The reaction mixture is then acidified with 2 N hydrochloric acid whilst cooling, and is extracted with 20 ml of ethyl acetate. The aqueous phase is rendered alkaline with a concentrated aqueous sodium hydroxide solution and is extracted with three times 50 ml of ethyl acetate. After drying over sodium sulphate and evaporation of the organic solution, oily, crude 1-[1-methyl-2-(2-carbamoyl-3-pyridyloxy)-ethyl-amino]-3-(2-methyl-phenyloxy)-2-propanol is obtained, which forms a neutral fumaric acid salt, melting point 145°-161° C. after recrystallisation from a mixture of methanol and ethyl methyl ketone.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=3[CH:12]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:11]([CH2:28]C3CCOC3)[C:10]2=[O:34])[CH:6]=[CH:7][CH:8]=1.ClC[C:39]1[O:43][C:42]([C:44]([O:46][CH3:47])=[O:45])=[CH:41][CH:40]=1>>[C:24]([C:23]1[CH:22]=[CH:21][C:20]([CH:12]2[C:13]3[C:14](=[O:19])[CH2:15][CH2:16][CH2:17][C:18]=3[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:35])([F:36])[F:1])[CH:4]=3)[C:10](=[O:34])[N:11]2[CH2:28][C:39]2[O:43][C:42]([C:44]([O:46][CH3:47])=[O:45])=[CH:41][CH:40]=2)=[CH:27][CH:26]=1)#[N:25]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC2CCOC2)cc1
Product: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C3=C(C(=O)CCC3)C2c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
The title compound is prepared in analogy to 4-(1-(3-(trifluoromethyl)-phenyl)-2,5-dioxo-3-((tetrahydrofuran-3-yl)methyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)benzonitrile (example 25), using methyl 5-(chloromethyl)furan-2-carboxylate as alkylating agent and stirring the reaction mixture at room temperature for 5 d. Yield: 50 mg; ESI mass spectrum [M+H]+=550; Retention time HPLC: 0.94 min (Z011_S03).