Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19].BrC(C)C>CN(C=O)C>[CH3:1][C:2]1[C:10]2[N:9]([CH:18]([CH3:20])[CH3:19])[CH:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(C)c2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)Br
Product: COC(=O)c1ccc(C)c2c1ccn2C(C)C
Temperature: 70 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A cooled (ice/water bath) solution of methyl 7-methyl-1H-indole-4-carboxylate (260 mg, 1.374 mmol) in DMF (20 mL) was added sodium hydride (43.4 mg, 1.718 mmol). After 10 minutes 2-iodopropane (0.151 mL, 1.512 mmol) was added and the reaction was stirred for 16 h. LCMS showed reaction only 10% complete. Added sodium hydride (43.4 mg, 1.718 mmol) followed by 2-iodopropane (0.151 mL, 1.512 mmol). After 2 hours LCMS showed reaction was 15% compete. Added more sodium hydride (43.4 mg, 1.718 mmol) and let stir for 5 minutes, then added more 2-bromopropane (0.142 mL, 1.512 mmol). Heated to 70° C. for 16 h. LCMS showed reaction 50% complete. Concentrated reaction mixture. Added DCM and washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (Biotage; 0% to 100% DCM:Hex; 25 g-HP-silica gel column) to give 137 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.60 (m, 6H), 2.78 (s, 3H), 3.94-4.02 (m, 3H), 5.17 (dt, J=13.20, 6.66 Hz, 1H), 6.96 (d, J=7.83 Hz, 1H), 7.28 1H, 7.40 (d, J=3.28 Hz, 1H), 7.81 (d, J=7.58 Hz, 1H). MS(ES) [M+H]+ 232.1
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([Br:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[C:14](Cl)(Cl)=[S:15]>O>[Br:13][C:4]1[C:3]([N:2]=[C:14]=[S:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[N:6]=[CH:7][CH:8]=[N:9]2
Reactant: Nc1ccc2nccnc2c1Br
Reactant: S=C(Cl)Cl
Agent: Br
Solvent: O
Product: S=C=Nc1ccc2nccnc2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-amino-5-bromoquinoxaline hydrobromide (10 g) in distilled water (150 ml) is added thiophosgene (3 ml). The solution is stirred for two hours at room temperature and the resultant precipitate is collected by filtration, washed with water, and dried to afford 5-bromo-6-isothiocyanato-quinoxaline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)CCOc4ccccc4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCCOc4ccccc4)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-3-phenoxypropaneamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[F:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[C:16]([F:18])[CH:17]=1>C1C=CC=CC=1.C1COCC1>[F:11][C:12]1[CH:13]=[C:14]([CH:5]2[NH:4][C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[C:7](=[O:8])[CH2:6]2)[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CC1(C)C(=O)C=CNC1=O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC1(C)C(=O)CC(c2cc(F)cc(F)c2)NC1=O

Procedure:
To a solution of 3,3-dimethylpyridine-2,4(1H,3H)-dione (978 mg, 7.03 mmol) [U.S. Pat. No. 2,525,231] in benzene (10 mL) was added 3,5-difluorophenylmagnesium bromide (50 mL of a 0.5 M solution in THF, 25 mmol) and the resulting mixture was heated to reflux for 1.5 h. The mixture was cooled, quenched with 1 N aqueous HCl (10 mL), made basic with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with H2O (50 mL), then brine (50 mL), and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 60:40, to give the title compound. MS: m/z=254 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[CH3:25])=[C:4]([CH:12]=[C:13]([F:16])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C1COCC1>[F:1][C:2]1[C:3]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[CH3:25])=[C:4]([C:5]([NH:7][O:8][CH2:9][CH2:10][O:11][C:33](=[O:35])[CH3:34])=[O:6])[CH:12]=[C:13]([F:16])[C:14]=1[F:15]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOCCO)cc(F)c(F)c1F
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCONC(=O)c1cc(F)c(F)c(F)c1Nc1ccc(I)cc1C
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a 0° C. solution of 3,4,5-trifluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)-benzamide (0.25 g, 0.536 mmol) in THF (10.72 mL) was added triethylamine (0.113 mL, 0.804 mmol). After 5 min, acetyl chloride (0.039 mL, 0.536 mmol) was added to the cold solution, which immediately produced a precipate. After stirring for 50 min between 0-5° C., the reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were combined and dried over anhydrous magnesium sulfate. The resultant mixture was filtered and the filter cake was thoroughly rinsed with ethyl acetate. The filtrate was concentrated in vacuo to obtain a yellow oil (0.1755 g). Chromatographed crude oil using a gradient of hexanes and ethyl acetate. Combined fractions and removed the solvent in vacuo to obtain a solid. The solid was recrystalized in a mixture of hexanes/acetone to afford 0.0221 g (8%) of a solid; 1H NMR (400 MHz, Acetone-d6): δ 10.15 (br s, 1H), 8.49 (br s, 1H), 7.88 (t, J=0.9 Hz, 1H),7.56 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 6.69 (dd, J=8.55, 5.86 Hz, 1H), 4.53 (br s, 2H), 4.19 (br s, 2H), 2.33 (s, 3H), 1.81 (br s, 3H). 19F NMR (375 MHz, Acetone-d6): δ −139.52 (br t, 1F), −146.62 (br q, 1F), −153.43 (br s, 1F). Anal. Calcd/Found for C18H16F3IN2O4: C, 42.54/40.87; H, 3.17/2.98; N, 5.51/5.17.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:31][CH3:32])=[C:24]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)[CH:23]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (65 mg, 0.199 mmol) and 5-chloro-2-methoxyphenylboronic acid (42 mg, 0.22 mmol) as a colourless gum. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.91 (dd, 1H), 8.18 (d, 1H), 8.13 (m, 3H), 7.98, (d, 2H), 7.86 (d, 1H), 7.66 (d, 2H), 7.36 (dd, 2H), 7.32 (m, 2H), 6.94 (d, 1H), 3.82 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[N:10]=2)=[CH:4][C:3]=1[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH:40][CH3:41])=[O:39])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:32]4[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH:40][CH3:41])=[O:39])[CH:33]=4)[CH:15]=3)[N:10]=2)=[CH:4][C:3]=1[CH3:20]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Cc1cc(Nc2ccc3cc(O)ccc3n2)ccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4ccc(Br)c(C)c4)ccc3c2)ccn1

Procedure:
The mixture of 2-[(4-bromo-3-methylphenyl)amino]quinolin-6-ol and potassium bis(trimethylsilyl)amide (2 eq), was stirred in dimethylformamide for 30 min at room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-methylcarboxamide (1 eq) and potassium carbonate (1.2 eq) and microwaved for 6 mins at 170° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([O-:10])=[O:9]
Reactant: OCCc1ccccn1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCCc1ccccn1

Procedure:
7.05 g (50 mmol) of 2-fluoronitrobenzene, 6.77 g (50 mmol) of 2-(2-hydroxyethyl)pyridine and 16.62 g (50 mmol) of cesium carbonate in 30 mL of dimethyformamide were stirred at room temperature for 7 days. The mixture was then filtered, and the filtrate was subjected to fractional distillation. The solvent and unreacted 2-fluoronitribenzene distilled below 100° C. at 8 to 4 mbar. The product distilled in a bulb tube still at 170 to 180° C. of furnace temperature under a vacuum of 3 mbar.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under atmosphere of argon, to a suspension of sodium hydride (63%, 57.1 g) in anhydrous N,N-dimethylformamide (540 ml) was added a solution of 3,4-dihydroxybenzaldehyde (103.5 g) in anhydrous N,N-dimethylformamide (500 ml) dropwise slowly under cooling with ice. The reaction mixture was stirred for 30 minutes at room temperature, and to the mixture was added benzyl chloride (104 ml) under cooling with ice and it was stirred for 15 hours at room temperature. To the mixture was added water under cooling with ice, and was concentrated under reduced pressure. The residue was diluted by water and it was washed by methylene chloride. The methylene chloride layer was extracted by a 1N aqueous solution of sodium hydroxide. Combined aqueous layers were acidified by 2M hydrochloric acid and it was extracted by ethyl acetate. The organic layer was washed by a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from chloroform to give the title compound (99.4 g) having the following physical data.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3(O)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][C:25]([C:28]#[N:29])=[CH:26][N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:30][S:31]([O-:33])=[O:32].[Na+].C(O)(C(F)(F)F)=O>CO>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][C:25]([C:28]#[N:29])=[CH:26][N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: N#Cc1cnc(C(=O)Nc2ccc(C3(O)CCOCC3)cc2C2=CCCCC2)[nH]1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)C1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)CCOCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
To a mixture of 5-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (as prepared in Example 27, 75 mg, 0.19 mmol) and sodium methylsulfinate (195 mg, 1.90 mmol) in 4 mL of methanol was added 0.28 mL (3.80 mmol) of TFA. The mixture was stirred overnight at 70° C. and then concentrated in vacuo. The crude residue was partitioned in EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was dried (Na2SO4) and then concentrated in vacuo. The residue was purified by preparative TLC on silica gel (20% ethyl acetate-hexane) to afford the title compound as a light brown oil (18 mg, 21%). 1H-NMR (CDCl3; 400 MHz): δ 9.64 (s, 1H), 8.32 (d, 1H, J=8.0), 7.71 (s, 1H), 7.33 (m, 1H), 7.23 (d, 1H, J=1.8 Hz), 5.87 (s, 1H), 3.90-3.81 (m, 4H), 3.01 (s, 3H), 2.30-2.25 (m, 4H), 2.07-1.79 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=[C:7]([Br:23])[CH:6]=2.C(N(CC)CC)C.[Cl:31][CH2:32][C:33](Cl)=O>C(O)C>[Br:23][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:33]([CH2:32][Cl:31])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cc(Br)ccc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3cc(Br)ccc3c21
Yield: 50 %

Procedure:
A modification of the method described in Part C of Example 365 was used to treat tert-butyl 2-[(3-amino-7-bromoquinolin-4-yl)amino]ethylcarbamate (66.69 g, 174.9 mmol, U.S. patent application publication no. US 2004/0147543, Example 386, Parts A and B) with triethylamine (35.4 g, 350 mmol) and chloroacetyl chloride (20.7 g, 183 mmol). After the reaction in ethanol was complete, a precipitate was present and was isolated by filtration to provide 38.42 g of tert-butyl 2-[7-bromo-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as white crystals. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 33-minute gradient from 0:100 to 5:95) to provide an additional 4.89 g of product.
Reaction SMILES: [CH2:1]([O:8][N:9]=[CH:10][C:11]1[C:12]([F:22])=[C:13]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](O)[CH3:24].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:23]([O:15][C:14](=[O:16])[C:13]1[CH:17]=[C:18]([F:21])[C:19]([F:20])=[C:11]([CH:10]=[N:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]=1[F:22])[CH3:24]
Reactant: O=C(O)c1cc(F)c(F)c(C=NOCc2ccccc2)c1F
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)c(F)c(C=NOCc2ccccc2)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
3-(Benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid (0.117 g, 0.378 mmol), 4-dimethylaminopyridine (0.023 g, 0.189 mmol), anhydrous ethanol (0.030 mL, 0.517 mmol) are mixed in dichloromethane (6 mL), cooled to 0° C., and treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.082 g, 0.427 mmol). After 2 hours at 0° C. and room temperature for 21 hours, the solvents are evaporated. The residue is dissolved in chloroform, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by chromatography (1:8 ethyl acetate/hexanes) provided the title compound (0.068 g). 1H NMR (200 MHz, CDCl3): δ 8.27 (s, 1H), 7.87–7.66 (m, 1H), 7.49–7.28 (m, 5H), 5.27 (s, 2H), 4.48–4.29 (q, 2H), 1.46–1.31 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[C:28](O)(=[O:32])[C@H:29]([CH3:31])[OH:30].ON1C2C=CC=CC=2N=N1.C(Cl)CCl>C1COCC1.O.C(OCC)(=O)C>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:28](=[O:32])[C@@H:29]([OH:30])[CH3:31])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](O)C(=O)O
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C[C@H](O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(S)-7-Amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one (50 mg, 0.14 mmol) and L-(+)-lactic acid (14 mg, 0.15 mmol) were dissolved in THF (2 ml), cooled to 0° C. and under exclusion of moisture subsequently treated with 1-hydroxybenzotriazole (21 mg, 0.15 mmol), EDC (33 mg, 0.17 mmol) and N-diisopropyl-ethylamine (0.05 ml, 0.28 mmol). After stirring for 30 min. at 0° C. and 3 h at ambient temperature, the mixture was diluted with water and ethyl acetate (10 ml each), the phases separated and the organic layer extracted with water, 1N aqueous HCl and saturated aqueous NaCl. After drying over magnesium sulphate and evaporation of the solvent, the title compound was afforded as colourless oil (98%). MS: m/e=431(M−H+).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1>>[CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=3)[CH2:27][CH2:28]2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(N2CCNCC2)nc1
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)C)cc3)CC2)nc1
Yield: 32.1 %

Procedure:
By reaction and treatment in the same manner as in Example 29 and using (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (374 mg) described in Preparation Example 18 and 1-(5-methylpyridin-2-yl)piperazine (250 mg), the title compound (185 mg) was obtained.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:12][NH:13][C:14]([C:16]2[N:17]=[C:18]([C:36]#[N:37])[C:19]3[C:24]([C:25]=2[OH:26])=[CH:23][CH:22]=[C:21]([O:27][C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[CH:20]=3)=[O:15])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:36]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([O:27][C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])[CH:20]=2)[C:25]([OH:26])=[C:16]([C:14]([NH:13][CH2:12][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11]2)=[O:15])[N:17]=1)#[N:37]
Reactant: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4c(F)cccc4F)ccc3c2O)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCC2)c(O)c2ccc(Oc3c(F)cccc3F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
A mixture of 1-({[1-cyano-7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-methyl)-cyclobutanecarboxylic acid tert-butyl ester (13 mg), TFA (0.3 mL) and DCM (1 mL) was stirred at rt for 1 h; then concentrated, the residue was treated with water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (10 mg). LC MS ESI+: 454 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][NH:20][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCCO
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCO)s2)c(C)[nH]c1=O
Yield: 38 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-aminoethanol as described in Step 5, Example 24 to give the title compound as a yellow solid (38% yield). LC/MS: RT 2.20 min; m/e 343 (M+H); 1H NMR (δ, ppm): 11.80 (1H, br), 7.80 (1H, s), 7.53 (1H, d), 7.32 (1H, s), 7.13 (1H, d), 4.72 (1H, t), 3.26-3.42 (2H, m), 2.90 (2H, t), 2.30-2.60 (3H, s), 2.4 (2H, q), 1.10 (3H, t).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>C(OCC)(=O)C>[CH2:30]([O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1cc(O)n(-c2ccccc2C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(C)C)n(-c2ccccc2C)n1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a mixture of ethyl 5-hydroxy-1-(2-methylphenyl)-1H-pyrazole-3-carboxylate (1.0 g, 4.06 mmol), potassium carbonate (0.84 g, 6.09 mmol) and N,N-dimethylformamide (10 mL) was added isobutyl bromide (0.49 mL, 4.47 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and 5% aqueous potassium hydrogensulfate solution, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (1.07 g, yield 87%) as pale-yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:35][CH:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[CH3:24][CH:22]([S:19]([NH:18][CH2:17][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][S:38]([CH:36]([CH3:37])[CH3:35])(=[O:40])=[O:39])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH3:25])(=[O:21])=[O:20])[CH3:23]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCNS(=O)(=O)C(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 137.8 %

Procedure:
To a 10 mL round-bottomed flask, in an ice bath, fitted with a thermometer, and under a nitrogen atmosphere, of (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (150 mg, 0.3984 mmol, prepared in example 39) dissolved in methylene chloride (2.7 mL) was added triethylamine (0.07 mL, 0.478 mmol). Once the mixture was cooled to 0° C., 2-propanesulfonyl chloride (0.05 mL, 0.4382 mmol) was added by syringe, and the mixture was gradually warmed to room temperature, with stirring overnight. The reaction was quenched with excess water, and the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum, yielding 265 mg viscous oil. Purification was conducted using a Chromatotron®, on a 4000 μm rotor and eluting with a 1:1 hexane:ethyl acetate solvent system, yielding the title compound (200 mg, 100%) as a slow crystallizing foam.