Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].CC1(C)COB([C:22]2[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:23]=2)OC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:3]1[C:2]([C:22]2[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:23]=2)=[C:10]([F:11])[CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]=[O:13])=[CH:6][NH:7]2
Reactant: O=Cc1c[nH]c2cc(F)c(Br)c(F)c12
Reactant: CC1(C)COB(c2ccc(OCCO)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1c[nH]c2cc(F)c(-c3ccc(OCCO)cc3)c(F)c12
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (150 mg, 0.58 mmol) and 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethanol (158 mg, 0.64 mmol) in toluene (5 mL) and EtOH (1.6 mL) was added to a solution of potassium carbonate (240 mg, 1.74 mmol) in water (1.2 mL) and Pd(dppf)Cl2 (24 mg, 0.029 mmol) at room temperature under N2. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. The reaction was cooled to room temperature, and extracted with ethyl acetate (20 mL×2). The organic layers were washed with brine (10 mL), dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography to give the title compound (70 mg, 38%) as a yellow solid.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>>[CH:18]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: C1=CCCCC1
Product: CC1(C)CC(O)CC(C)(C)N1OC1C=CCCC1
Temperature: 70 °C
Yield: 17.5 %

Procedure:
A mixture of 17.05 g (0.10 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 100 mL (0.99 mol) of cyclohexene under a nitrogen atmosphere is heated at 70° C. for 72 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine and the filtrate is washed with 5 w/v % ascorbic acid (2×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from acetonitrile to give 4.44 g (36% yield) of a white solid melting at 65-66.5° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:29]([O:31][CH3:32])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:50]2[CH:54]=[N:53][C:52]([CH2:55][C@H:56]([NH:60]C(OC(C)(C)C)=O)[C:57]([OH:59])=O)=[CH:51]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(O)=O>[NH2:60][C@H:56]([C:57]([NH:1][C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:29]([O:31][CH3:32])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:59])[CH2:55][C:52]1[N:53]=[CH:54][N:50]([S:47]([C:44]2[CH:43]=[CH:42][C:41]([CH3:40])=[CH:46][CH:45]=2)(=[O:48])=[O:49])[CH:51]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1cn(S(=O)(=O)c2ccc(C)cc2)cn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reaction time: 0.67 h

Procedure:
Stir 0.40 g (0728 mmoles) of Boc-Sta-Ile-Phe-OCH3, as prepared in Preparation XX10II above, in 6 ml of TFA-CH2Cl2 (1:1 v/v) at room temperature for 30 minutes. Remove the solvent in vacuo and extract the residue with CH2Cl2 and aq. NaHCO3. Filter the organic layers through Na2SO4 into a flask containing 0.42 g (1.02 mmoles) of Boc-His-(Tos), concentrate the solution to a volume of about 25 ml, and add 0.21 g (1.02 mmoles) of DCC. Stir for 40 minutes, then add 1 drop of HOAc and filter off DCU. Extract the filtrate with aq. NaHCO3, filter the organic layers through Na2SO4, and remove the solvent in vacuo. The crude product is applied to a silica gel chromatography column and the product is eluted with 4% MeOH-96% CH2Cl2 to give 0.566 g (93%) of Box-His(Tos)-Sta-Ile-Phe-OCH3.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]=1[C:14]([NH2:16])=[O:15].[C:21](Cl)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]=1[C:14]([NH2:16])=[O:15])(=[O:23])[CH3:22]
Reactant: CC(C)(C)c1csc(N)c1C(N)=O
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1scc(C(C)(C)C)c1C(N)=O
Yield: 80.3 %

Procedure:
21.2 g (0.21 mole) of triethylamine were first added to a suspension of 39.6 g (0.2 mole) of 2-amino-3-aminocarbonyl-4-tert.-butyl-thiophene in 300 ml of toluene, and 16.5 g (0.21 mole) of acetyl chloride were then added dropwise. After the exothermic reaction had ended, the mixture was worked up by filtering off the solid product and washing it with water. 38.6 g of 2-acetylamino-3-aminocarbonyl-4-tert.-butyl-thiophene of melting point 251° C. were obtained in this manner.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.CCCCCC.[Cl-].Cl[CH2:20]/[CH:21]=[C:22](/[F:31])\[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1>O1CCCC1>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[CH2:20][CH:21]=[C:22]([F:31])[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1
Reactant: C1CSCSC1
Reactant: F/C(=C/CCl)COC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FC(=CCC1SCCCS1)COC1CCCCO1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of 1,3-dithiane (1.55 g, 12.9 mmole) in tetrahydrofuran (60 ml) cooled to -30° C. was added dropwise a 1.32M solution of n-butyllithium in hexane (9.77 ml, 12.9 mmoles), the mixture was stirred at -30° C. for 30 min. Then the mixture was cooled to -40° C. and the chloride prepared in 1C (2.69 g, 12.9 mmoles) in tetrahydrofuran (10 ml) was added dropwise. The reaction was stirred 30 min at -40° C. and 2 hrs at 0° C. The reaction was quenched with saturated aqueous ammonium chloride and the tetrahydrofuran was evaporated under reduced pressure. The residue was diluted with ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silicagel and elution with a 8:2 mixture of hexane and ethyl acetate afforded the title dithialane as an oil (3.34 g, 90%). NMR (H1, CDCl3, 60 MHz) characetristic peaks: 4.00 (t, JHH =7 Hz, 1), 4.21 (d, JHF =20 Hz, 2), 4.7 (broad peak, 1), 5.40 (dt, JHF =20 Hz, JHH =8 Hz, 1).
Reaction SMILES: C(=O)(O)[O-].[Na+].CO.[CH3:8][CH:9]([CH3:29])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[S:19][C:18]([C:23]([O:25]CC)=[O:24])=[CH:17][C:16]2=[O:28]>O>[CH3:8][CH:9]([CH3:29])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[S:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17][C:16]2=[O:28]
Reactant: CCOC(=O)c1cc(=O)c2cc(OCCC(C)C)ccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)CCOc1ccc2sc(C(=O)O)cc(=O)c2c1

Procedure:
A mixture of 9 parts of ethyl 6-hydroxy-1-thiachromone-2-carboxylate, 15 parts of isoamyl bromide and 14 parts of anhydrous potassium carbonate in 130 parts of acetone was stirred and heated under reflux for 18 hours. Insoluble material was then filtered off and washed with acetone and the total acetone solution was evaporated to leave a yellow solid, which was crystallized from ethanol to give 4.1 parts of ethyl 6-(3-methylbutoxy)-1-thiachromone-2-carboxylate, melting point 83°-84°C. This entire product was heated under reflux for 2 hours with a solution of 1.5 parts of sodium bicarbonate in 35 parts of water and 25 parts of methanol. The methanol was then boiled off and the solution was diluted with 70 parts of water. The aqueous solution was thoroughly washed with ether, filtered then acidified with concentrated hydrochloric acid. A precipitate was obtained which was filtered off, washed with water and dried, then extracted with boiling benzene. The product was then filtered off and dried to leave 3.95 parts of 6-(3-methylbutoxy)-1-thiachromone-2-carboxylic acid, melting point 208°-209°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][N:26]=[CH:27]2>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][N:26]=[CH:27]3)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1cccc2cnccc12
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1cccc2cnccc12)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 5-aminoisoquinoline (73.7 mg, 0.51 mmol). The title compound was obtained as a yellow solid (23.0 mg, 12% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.85 (1H, br), 9.36 (1H, s), 9.00 (2H, s), 8.83 (1H, m), 8.54 (1H, m), 8.08 (1H, m), 7.84 (2H, m), 7.71 (1H, m). MS m/z: 475.17, 477.12 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.CN(OC)[C:14]([C:16]1[CH:20]=[CH:19][O:18][CH:17]=1)=[O:15]>CCOCC>[O:9]1[CH:10]=[CH:11][C:7]([C:14]([C:16]2[CH:20]=[CH:19][O:18][CH:17]=2)=[O:15])=[CH:8]1
Reactant: Brc1ccoc1
Reactant: CON(C)C(=O)c1ccoc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1ccoc1)c1ccoc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a solution of n-butyllithium (2.5M, 28 mL, 0.07 mol) in 150 mL of ether at -78° C. was added a solution of 3-bromofuran (10 g, 0.0628 mol) in 30 mL of ether over a 20 min period and the mixture was stirred at -78° C. for 20 min. To the above mixture was added 3-(N-methyl-N-methoxycarbamoyl)furan (9.16 g, 0.059 mol) in 30 mL of ether over a 15 min period and the mixture was stirred at room temperature for 1/2 h. The reaction mixture was quenched with 200 mL of ammonium chloride solution, 500 mL of methylene chloride was added and the mixture was stirred. The organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was triturated with 100 mL of hexane/TBME (9:1). The solid product was filtered and washed with TBME to afford 7.5 g (78.3%) of di-(3-furyl)ketone.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([OH:22])[C@H:5]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[OH-].[Na+].CO>O1CCOCC1>[C:18]([O:17][C:15]([NH:14][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C@H:4]([OH:22])[C:3]([OH:23])=[O:2])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@@H](O)[C@@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cccc(F)c1)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
A mixture of (2S,3R)-3-tert-Butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyric acid methyl ester (3.28 g, 10.05 mmol, 1 eq), 4N NaOH (4 mL, 16 mmol, 1.6 eq), MeOH (42 mL) and 1,4-dioxane (63 mL) was stirred at ambient temperature for 1.5 h after which the solvents were evaporated. To the residue was added 10% citric acid (100 mL) followed by extraction with EtOAc (100 mL). The organic layer was washed with H2O (100 mL), brine (50 mL), dried (Na2SO4) and concentrated to give the desired product as a cream colored solid (3.06 g, 97%). 1H NMR (DMSO) 7.33–7.26 (m, 1H), 7.02–6.97 (m, 3H), 6.78 (d, J=5.2, 1H), 3.98 (d, J=5.5, 1H), 3.99–3.86 (m, 2H), 2.77–2.82 (m, 2H), 1.27 (s, 9H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1.Br[CH2:17][CH2:18][CH3:19].C(OCC)C>CN(C)C=O.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:14][C:13](=[O:15])[N:12]([CH2:17][CH2:18][CH3:19])[N:11]=2)=[CH:8][CH:9]=1
Reactant: CCCBr
Reactant: O=C1CC(c2ccc(Cl)cc2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCCN1N=C(c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
To a suspension of 0.22 g (5.5 mmol) of 60% oily sodium hydride in 10 ml of anhydrous dimethylformamide was added dropwise a solution of 1.0 g (4.5 mmol) of 3-(4-chlorophenyl)-4, 5-dihydropyrazol-5-one in dimethylformamide (5 ml) at 0° C. After 30 minutes of stirring at room temperature, 0.83 g (6.7 mmol) of 1-bromopropane was added dropwise and stirring was continued for another 2 hours. To the reaction solution was added 50 ml of diethyl ether and 50 ml of water, and vigorously agitated. The resulting solution was separated, and the aqueous layer was extracted twice with 50 ml of diethyl ether. The organic layer was combined and washed successively with water and saturated brine solution, and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1 (v/v)) to give 1.1 g of the object compound as a colorless oil (yield 92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[O:3]1.[CH2:18]([Mg]Br)[CH3:19].B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>O1CCCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:17])([CH3:1])[O:3][B:4]([C:9]2[CH:16]=[CH:15][C:12]([C:13]3([NH2:14])[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(C3(N)CC3)cc2)OC1(C)C
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 12.4 %

Procedure:
In a 40 mL reaction tube was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (500 mg, 2.18 mmol) and titanium(IV) isopropoxide (710 μl, 2.40 mmol) in anhydrous tetrahydrofuran (11 ml) to give a colourless solution. The reaction mixture was cooled to −70° C. under a nitrogen atmosphere, followed by the dropwise addition of ethylmagnesium bromide (1M in THF, 4.80 ml, 4.80 mmol) over a period of 30 minutes. The resulting orange solution was stirred at −78° C. for 10 minutes, followed by warming to room temperature and stirring for 60 minutes. After this period, boron trifluoride diethyl etherate (540 μl, 4.37 mmol) was added and the mixture stirred at room temperature for 60 minutes. To the reaction was then added 1M HCl solution (6 ml) and stirred for 15 minutes before basification with 2M NaOH solution. The organic phase was separated and the aqueous washed with ethyl acetate (3×4 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 0:100) to give the desired product as an off-white solid (70 mg, 12% yield). 1H-NMR (500 MHz, CDCl3) δ 7.76 (2H, d), 7.29 (2H, d), 2.32 (2H, br s), 1.34 (12H, s), 1.12 (2H, dd), 1.01 (2H, dd). LCMS RT=0.68 min, M+H+=260.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:41]2[C:42](=[O:55])[N:43]([CH3:54])[C:44]([NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[N:45][CH:46]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](CC3C=CC(OC)=CC=3)[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[C:10]=12>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([C:41]2[C:42](=[O:55])[N:43]([CH3:54])[C:44]([NH:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[N:45][CH:46]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][N:16]=[C:17]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[CH:22][CH:23]=3)[C:10]=12
Reactant: COc1ccc(Cn2nc(-c3ccc(C(=O)N4CCOCC4)cc3)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(Oc3ccnc4[nH]nc(-c5ccc(C(=O)N6CCOCC6)cc5)c34)c(F)c2)c1=O
Yield: 58.8 %

Procedure:
A solution of 5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.014 g, 0.0190 mmol) in TFA (1 mL) was stirred at 60° C. for 3.5 hours. The reaction mixture was concentrated in vacuo to yield a crude yellow gum. The crude product was purified by flash column chromatography, eluting with 10:1 CH2Cl2/MeOH. The isolated product was then partitioned between EtOAc and saturated NaHCO3. The layers were separated and the aqueous layer was re-extracted with EtOAc. The combined EtOAc layers were dried over Na2SO4, filtered and concentrated to yield the desired product (6.9 mg; 59%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (br s, 1H), 8.40 (d, 1H), 8.09 (s, 1H), 8.08 (m, 2H), 7.86 (dd, 1H), 7.66 (m, 1H), 7.57-7.48 (m, 5H), 7.38 (m, 2H), 7.16 (m, 1H), 6.41 (d, 1H), 3.60 (m, 8H), 3.58 (s, 3H). LRMS (APCI pos) m/e 618 (M+1).
Reaction SMILES: OC1C=CC(C([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=CC=1.Cl[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([N:11]([CH2:10][CH2:9][CH3:8])[CH2:20][C:13]2[CH:12]=[CH:17][C:16]([O:18][CH2:40][CH2:41][N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:15][CH:14]=2)[CH:17]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CCCC1
Product: CCCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 160.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:31])[C@:16]([C@@H:24]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]2)([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)([O-])=O.[OH-].[Na+]>C(O)C.Cl.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:31])[C@:16]([C@@H:24]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]2)([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13]1
Reactant: O=C(NC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(CN2CCC(NC(=O)[C@](O)(c3ccccc3)[C@@H]3CCC(F)(F)C3)CC2)c1
Yield: 102.5 %

Procedure:
5 mg of the (2R)-N-[1-(3-nitrobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide as obtained in above step 1 was heated to 60° C. together with 2 mg of iron powder in aqueous ethanol. After adding thereto 1 drop of conc. hydrochloric acid, the heating was continued at 100° C. for about 1 hour under stirring. The reaction mixture was made basic with 4N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to provide 4.8 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][CH:28]([CH3:33])[CH2:29][C:30](Cl)=[O:31]>>[CH3:27][CH:28]([CH3:33])[CH2:29][C:30]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:31]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)CC(C)C)c4)CC3)cccc2n1
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 3-methylbutanoyl chloride.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17]C4C=CC([N+]([O-])=O)=CN=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2OC3C=CC(O)=CC=3OC2)C=CC=CC=1.Cl[C:45]1[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][N:46]=1>>[C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][C:45]4[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][N:46]=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)O3)nc1
Agent: Oc1ccc2c(c1)OCC(c1ccccc1)O2
Product: O=[N+]([O-])c1cccnc1Oc1ccc2c(c1)OCC(c1ccccc1)O2

Procedure:
2-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-3-nitropyridine was prepared in the same way as 2-(2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine above from 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg) and 2-chloro-3-nitropyridine (56 mg). Yield is 30 mg and mp <60° C. 1H NMR (DMSO-d6) δ=4.16 (dd, J=8.6, 11.4 Hz, 1H), 4.46 (dd, J=11.4, 2.5 Hz, 1H), 5.27 (dd, J=2.5, 8.6 Hz, 1H), 6.73 (dd, J=2.5, 8.6 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 7.34-7.52 (m, 6H), 8.43 (dd, J=1.9, 4.8 Hz, 1H), 8.55 (dd, J=7.8, 1,9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]=[C:10]([CH2:21][CH2:22][CH2:23]O)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:31][NH2:32]>ClCCl.CN(C1C=CN=CC=1)C.C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]=[C:10]2[CH2:21][CH2:22][CH2:23][N:32]([CH3:31])[C:11]2=[N:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1ccc(NC(=O)C(=CSc2ccc(F)cc2)CCCO)cc1
Agent: CN(C)c1ccncc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(N=C2C(=CSc3ccc(F)cc3)CCCN2C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
687 mg (1.99 mmol) of 2-{[(4-fluorophenyl)sulphanyl]methylene}-5-hydroxy-N-(4-methylphenyl)-pentanamide (prepared by the method described in WO 2010/070910) are dissolved in 25 ml of dichloromethane, and 828 mg (3.98 mmol) of phosphorus pentachloride are added. After 12 h of stirring at room temperature, all volatile components are removed under reduced pressure and the residue is suspended in 9 ml of triethylamine. 36.4 mg (0.297 mmol) of DMAP and 4.97 ml of 2M methanamine in THF are added to the reaction mixture. The mixture is stirred in a CEM microwave at 80° C. for 60 min (divided into three microwave vessels). The reaction mixture is diluted with water and extracted with ethyl acetate, and the organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate) gives 7.6 mg of N-(3-{[(4-fluorophenyl)sulphanyl]methylene}-1-methylpiperidin-2-ylidene)-4-methylaniline.