Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[N:8]([C:9]([O:11][C:12]([CH3:15])(C)C)=[O:10])[CH2:7][C@@H:6]([C:16](O)=O)[CH2:5]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[C:26]1C=C[CH:29]=[CH:28][CH:27]=1.C[N:34](C=O)C>>[CH3:1][O:2][CH2:3][C@H:4]1[N:8]([C:9]([O:11][CH2:12][C:15]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])[CH2:7][C@@H:6]([C:16]#[N:34])[CH2:5]1
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1
Reactant: COC[C@@H]1C[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
cis-5-Methoxymethyl-Boc-3-Pyrrolidine Benzyl Ester Acid {cis-Boc-(5-MOM)-PCA-OBn} 4.8. cis-5-Methoxymethyl-Boc-3-pyrrolidine carboxylic acid (1.4 g, 5.3 mmol) was dissolved in DMF (26.5 mL). Cs2CO3 (1.73 g, 5.3 mmol) and benzyl bromide (0.76 mL, 6.4 mmol) were added, and the reaction mixture was stirred 24 h at room temperature. The reaction mixture was concentrated, and the residue was dissolved in H2O. The aqueous solution was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with ethyl acetate/hexanes (1/1, v/v) to afford 1.88 g (85% yield) of the desired product as an oil.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=1[F:24].FC(F)(F)C(O)=O>C1COCC1>[CH2:10]([N:4]1[CH2:3][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([F:17])[CH:19]=2)[CH:26]([C:27]([OH:29])=[O:28])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)C1CN(Cc2ccccc2)CC1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (48.3 g, 204 mmol) and (E)-3-(3,4-difluoro-phenyl)-acrylic acid (15 g, 81.5 mmol) in THF (200 mL) was added trifluoroacetic acid (0.312 mL, 0.0041 mol) at 0° C. The mixture was gradually warmed to room temperature and stirred overnight. It was then concentrated in vaccuo and the residue was diluted with n-heptane (500 mL) followed by vigorous stirring for 1 hour. The resulted white precipitation was collected and washed with heptane affording 26 g (100%) of the title compound as a white solid. MS m/e: 318.1 (M+H+).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[OH:8][C@H:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)c1ccccc1
Reactant: [H][H]
Solvent: CO
Product: COC(=O)C[C@H](O)c1ccccc1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 94.7 %

Procedure:
Into a 1-L autoclave was introduced methanol (360 mL) in a nitrogen stream. Then, [{RuCl((R)-SEGPHOS)}2(μ-Cl)3][Me2NH2] (82 mg: 0.1 mmol) and methyl benzoylacetate (178 g: 1.0 mol) were added. After hydrogen (4.0 MPa) was forced into the autoclave, the reaction mixture was heated to 80° C. and stirred for 5.5 hours to carry out asymmetric hydrogenation reaction. After cooling, methanol was removed from the reaction mixture, and the residue was distilled under reduced pressure (94-99° C./133 Pa) to obtain 170.6 g (yield, 95.3%) of methyl (S)-3-hydroxy-3-phenylpropionate. The asymmetric yield thereof was determined with the HPLC (CHIRALCEL OD-H, 4.6 mm×250 mm; hexane/isopropyl alcohol=95/5; flow rate, 1.0 mL/min; detection wavelength, UV-254 nm), and was found to be 97.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[Cl:1][C:2]1[CH:7]=[C:6]([S:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)c1c(C)cc(I)cc1Cl
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Sc2cc(C)c(C(C)=O)c(Cl)c2)cc1
Yield: 13.5 %

Procedure:
A mixture of 1-(2-chloro-4-iodo-6-methylphenyl)ethanone (3-1, 0.720 g, 2.44 mmol), 4-methoxybenzenethiol (0.45 mL, 3.7 mmol), copper(I) oxide (17.0 mg, 0.12 mmol), and potassium hydroxide (0.34 g, 6.1 mmol) in DMF (2.2 mL) and H2O (0.5 mL) was heated at reflux for 20 h. The mixture was quenched with H2O and extracted with ethyl acetate. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide 1-(2-chloro-4-(4-methoxyphenylsulfanyl)-6-methylphenyl)ethanone (3-2, 0.10 g, 0.33 mmol) as yellow oil in 13% yield: 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J=8.7 Hz, 2 H), 6.94 (d, J=8.7 Hz, 2 H), 6.86 (d, J=8.2 Hz, 2 H), 3.85 (s, 3 H), 2.50 (s, 3 H), 2.17 (s, 3 H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28]CC)=[O:27])=[CH:18][C:17]=2[CH:31]=1>>[Cl:12][C:13]1[C:14]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:24])([F:23])[F:25])[C:19]([C:26]([OH:28])=[O:27])=[CH:18][C:17]=2[CH:31]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-(trifluoromethyl)phenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 230.9-232.0° C. 1H NMR (acetone-d6/300 MHz) 7.93 (s, 1H), 7.77 (m, 3H), 7.27 (d, 2H, J=8.7 Hz), 6.86 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −62.8 (s, 3F), −79.4 (d, 3F, J=7.2 Hz). ESLRMS m/z 437 (M−H). ESHRMS m/z 437.0008 (M−H, Calc'd 437.0015). Anal. Calc'd for Cl8H9ClF604: C, 49.28; H, 2.07; Cl, 8.08. Found: C, 49.25; H, 2.08; Cl, 8.24.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[C:22]([CH3:23])=[C:21]([CH:24]([F:26])[F:25])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN(C)C=O.C(OCC)(=O)C>[F:25][CH:24]([F:26])[C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)ncnc1C(F)F
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncnc1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 100 mg, 0.465 mmol), 4-chloro-6-(difluoromethyl)-5-methylpyrimidine (ANICHEM CAS425394-59-8, 83 mg, 0.465 mmol) and DIPEA (0.162 mL, 0.929 mmol) were added together in N,N-dimethylformamide (5 mL) and the resulting mixture was stirred at room temperature for overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (38 mg);
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11].O[CH:13]1CCN(C(C)C(OCC)=O)C1=O>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([CH3:13])[C:8]([NH2:10])=[O:9])[C:3]1=[O:11]
Reactant: CCOC(=O)C(C)N1CCC(O)C1=O
Reactant: NC(=O)CN1CCC(O)C1=O
Product: CC(C(N)=O)N1CCC(O)C1=O

Procedure:
According to the process described in paragraph (b) of Example 1, from ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)propionate there is obtained, after chromatographic filtration on silica gel (granular size 0.2-0.5 mm), elution with acetonitrile/ethanol (1:1) and crystallization from acetonitrile, (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)propionamide of melting point 139°-141°.
Reaction SMILES: [ClH:1].[C:2]([CH2:5][NH:6][C@@H:7]([C:21]([N:23]1[CH2:42][CH2:41][CH2:40][C@H:24]1[C:25]([NH:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35]([NH2:39])=[N:34][CH:33]=[CH:32]2)=[O:26])=[O:22])[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:4])=[O:3].S(Cl)([Cl:45])=O.[CH2:47](O)[CH2:48][CH3:49]>ClCCl>[ClH:45].[ClH:1].[CH2:47]([O:3][C:2](=[O:4])[CH2:5][NH:6][C@@H:7]([C:21]([N:23]1[CH2:42][CH2:41][CH2:40][C@H:24]1[C:25]([NH:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35]([NH2:39])=[N:34][CH:33]=[CH:32]2)=[O:26])=[O:22])[CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:48][CH3:49]
Reactant: CCCO
Reactant: O=S(Cl)Cl
Reactant: Nc1nccc2cc(CNC(=O)[C@@H]3CCCN3C(=O)[C@H](NCC(=O)O)C(c3ccccc3)c3ccccc3)ccc12
Agent: Cl
Solvent: ClCCl
Product: CCCOC(=O)CN[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C(c1ccccc1)c1ccccc1
Reaction time: 72 h

Procedure:
To a suspension of N-(carboxymethyl)-β-phenyl-D-phenylalanyl-N-[(1-amino-6-isoquinolyl)methyl]-L-prolinamide hydrochloride (1B; 300 mg. 0.5 mmol) in n-propanol (5 ml) was added dropwise thionyl chloride (0.4 ml). After stirring for 3 days the solution was diluted with dichloromethane, washed with 5% aqueous sodium bicarbonate solution and evaporated to dryness. The crude product was purified by reverse phase HPLC and then converted to the hydrochloride salt by dissolving in a small amount of methanol and precipitating with 1M hydrochloric acid in diethyl ether. Following addition of further anhydrous diethyl ether the resulting precipitate was collected by filtration and dried under vacuum to give 185 mg of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[Br:13].Br[CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17])=[CH:7][C:6]=2[Br:13]
Reactant: Oc1cc(Br)c2ncc(Br)cc2c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1cc(Br)c2ncc(Br)cc2c1

Procedure:
In a similar procedure, 3,8-dibromo-6-hydroxyquinoline was reacted with 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide to give 2-(3,8-dibromo-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide as a colourless gum, 1H NMR (CDCl3) δ: 1.07(3H, t); 1.59 (3H, s); 1.60(3H, s); 1.78(3H, s); 1.99–2.06(2H, m); 4.52(1H, t); 6.30(1H, s); 7.00(1H, m); 7.82(1H, dd); 8.21(1H, d); 8.88(1H, m).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][NH2:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:26][C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Reactant: NCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1csc(CNCCCOc2ccc(-c3csc4ccccc34)cc2)c1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, 2-thiophenemethylamine, potassium carbonate and acetonitrile essentially as described above in Example 118. Purity by LC/MS=97%, [M+H]+=380.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][CH:9]1[C:18]2[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)=[O:28])=[CH:23][CH:22]=1.P(O)([O-])([O-])=O.[Na+].[Na+]>CCCCCC.C1COCC1>[CH3:6][O:7][CH2:8][C@H:9]1[C:18]2[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]1[S@@:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)=[O:28]
Reactant: COCC1NCCc2c(C)cccc21
Reactant: Cc1ccc(S(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)cc1
Agent: O=P([O-])([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC[C@H]1c2cccc(C)c2CCN1[S@](=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
A solution of 1.55 M n-butyllithium in hexane (10.94 mL) was added with stirring to a solution of 1-(methoxymethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline (3.07 g) in THF (60 mL) under an argon atmosphere, over about 8 minutes, at −70° C. or below, followed by further stirring for 30 minutes. To the reaction mixture was added with stirring a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-methylbenzenesulfinate (3.375 g) in THF (25 ml) over 5 minutes at −70° C. or below, followed by further stirring for 1 hour. Thereafter, saturated disodium phosphate was added to the mixture at the same temperature and the temperature was increased to room temperature. The mixture was extracted with ether. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain (1R)-1-(methoxymethy)-5-methyl-2-[(R)-(4-methylphenyl)sulfinyl]-1,2,3,4-tetrahydroisoquinoline (2.144 g) (Rf value=0.14).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)Cl.O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CC(O)CCN1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(O)CCN1C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a cold (5° C.) solution of methyl 4-hydroxypiperidine-2-carboxylate, 13a, (5.17 g, 32.48 mmol) and triethylamine (6.00 mL, 43.05 mmol) in CH2Cl2 (135 mL) was added dropwise benzyl chloroformate (6.20 mL, 43.43 mmol) over 10 min. The resulting solution was stirred at 5° C. for 1 hour and then allowed to warm to room temperature. The reaction mixture was diluted with water and the layers were separated. The aqueous was re-extracted with CH2Cl2 and the combined organics were dried over MgSO4, filtered and evaporated to dryness. The crude was passed through a plug of silica gel, eluting with 30-80% EtOAc/Hexanes to afford the desired product, 13b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.CN.C[CH2:18][N:19]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:19][CH3:18])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
A mixture of 5-fluoro-2-nitrobenzoic acid (4.775 g, 25.8 mmol), methylamine hydrochloride (2.626 g, 38.9 mmol), EDCI (5.982 g, 31.2 mmol), HOBt (4.227 g, 31.3 mmol) and triethylamine (7.2 mL, 51.65 mmol) in DMF (50 mL) was stirred at room temperature for 24 h. It was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel chromatography (combiflash-companion; ethyl acetate/hexanes gradient) to give the title compound as a yellow solid (yield: 90%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C[O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[CH:6]=[N:5]2)[C:27]([OH:26])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: COc1ccc(O)cc1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: COc1ccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)cc1

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 4-methoxy-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(4-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as a light yellow solid (110.8 mg, 87% for the final step). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06 (br s, 2H), 1.34-1.80 (m, 7H), 1.82-2.08 (m, 1H), 2.10-2.24 (m, 1H), 3.79 (s, 3H), 5.30 (dd, J=10.9, 4.2 Hz, 1H), 5.69 (d, J=2.4 Hz, 1H), 7.05 (d, J=9.1 Hz, 2H), 7.23 (d, J=9.1 Hz, 2H), 8.07 (d, J=2.4 Hz, 1H), 12.98 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li][CH2:12][CH2:13][CH2:14]C.CCCCCC.CC(C)=O>C1COCC1>[CH3:12][C:13]1([CH3:14])[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[O:6]1
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccccc1Br
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OC(=O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.3 h
Yield: 40 %

Procedure:
To a solution of 2-bromobenzoic acid (500 mg, 2.49 mmol) in THF (12.0 ml) cooled at −78° C. was added 2.5M n-BuLi/Hexane (2.0 ml). After stirring for 18 minutes, acetone (0.91 ml, 12.4 mmol) was added. The reaction was allowed to warm to room temperature after 5 minutes at −78° C., and then quenched into 10% HCl aqueous solution (50 ml). The acidic solution was rapidly stirred for 1 hour, and then extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3, brine, dried with anhydrous Na2SO4, and rotary evaporated to give a mixture. Gradient chromatography of the mixture through silica gel column eluted with 20% to 30% EtOAc in hexane afforded 3,3-dimethyl-2-benzofuran-1(3H)-one as a white solid (161 mg, 40%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.Cl.C([N:28]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1([C:16]([NH2:28])=[O:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C1COCCN1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1CCOCC1
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The 1-(4-nitrophenyl)piperidine-4-carboxylic acid (10.1 g, 40 mmol) obtained in Example 3(1) was dissolved in N,N-dimethylformamide (25 ml), and morpholine (5.2 g, 60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.2 g, 48 mmol), and 1-hydroxybenzotriazole monohydrate (6.7 g, 44 mmol) were added thereto, followed by stirring overnight under heat at 70° C. After cooling to room temperature, water was added thereto, and the precipitate was collected by filtration and dried under heat under reduced pressure, thereby obtaining 1-(4-nitrophenyl)piperidine-4-morpholinecarboxamide (12.1 g, 95%) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC>CN(C=O)C.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>[CH2:31]([O:30][C:28]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:29])[CH3:32]
Reactant: Fc1cc2ncccc2cc1Cn1nnc2ncc(Br)nc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
A mixture of 6-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-7-fluoro-quinoline (2.0 g, 5.57 mmol), Pd(Ph3P)4(0.64 g, 0.56 mmol) and tributyl(1-ethoxyvinyl)stannane (4.02 g, 11.14 mmol) in DMF (50 mL) was flushed with nitrogen and then heated at 100° C., stirred for 7 hours. Removal of the solvent under reduced pressure, the residue was diluted with DCM, washed sequentially with KF (aq.) and water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography with gradient (DCM:MeOH=50:1) to give the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.11 (s, 1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.15 (d, 1H), 7.83 (d, 1H), 7.54 (m, 1H), 6.22 (s, 2H), 5.50 (d, 1H), 4.73 (d, 1H), 4.02 (q, 2H), 1.40 (t, 3H). LCMS (method E): [MH]+=351, tR=5.42 min.
Reaction SMILES: CSC.B.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14](O)=[O:15])[CH:10]=[CH:11][CH:12]=1.CO>C1COCC1>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][OH:15])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)Cc1cccc(CBr)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: OCCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Borane dimethylsulphide complex (2M solution in THF, 5.78 mL) was added dropwise to a solution of 2-(3-(bromomethyl)phenyl)acetic acid (1.06 g) in THF (10 mL) at 0° C. and the resulting mixture stirred for 10 min. The reaction was then allowed to warm to room temperature and stirred overnight. Methanol (5 mL) was then added and the mixture concentrated in vacuo. Purification was by silica gel chromatography eluting with isohexane to diethyl ether gradient to give the subtitled compound as a white solid. Yield 1 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]2[N:25]([CH2:33][CH3:34])[C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=2[CH:22]=1.Cl>O1CCOCC1.COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:36]=[CH:35][C:24]3[N:25]([CH2:33][CH3:34])[C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:30])([CH3:31])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc21
Yield: 26.2 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (82 mg, 0.276 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (61 mg, 0.263 mmol), 4 N HCl in dioxane (80 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 3.5 hours. Filtered off solid, then purified the solid with normal phase chromatography eluting with 9/1 methylene chloride/methanol. Washed product with saturated sodium bicarbonate solution and extracted into methylene chloride. Washed organic phase with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield an off-white solid, 2-[5-Chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (34 mg, 25%). LCMS: m/z=493.37 (M+H+), 1H NMR (400 MHz, CDCl3) δ 11.11 (s, 1H), 8.60 (d, 1H, J=8.3 Hz), 8.09 (s, 1H), 7.68 (dd, 1H, J=8.3, 2.3 Hz), 7.52 (d, 1H, J=7.3 Hz), 7.39 (m, 1H), 7.33 (d, 1H, J=2.3 Hz), 7.16 (d, 1H, J=8.8 Hz), 7.08 (m, 1H), 6.70 (br s, 1H), 3.79 (m, 2H), 3.40 (s, 1H), 3.01 (d, 3H, J=4.5 Hz), 2.38 (s, 2H), 2.27 (m, 2H), 1.29 (m, 9H).