Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:3]1=[O:21].Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=1[F:33].CC([O-])(C)C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:33][C:24]1[CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=[CH:28][C:23]=1[NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]2)[C:3]1=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](N)C2=O)CC1
Reactant: CS(=O)(=O)c1ccc(Br)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2CCCC(Nc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Temperature: 80 °C
Yield: 105.9 %

Procedure:
(S)-tert-Butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (Example 39, Steps A-C, 5.0 g, 17 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.0 g, 1.7 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (6.4 g, 25 mmol) and NaOtBu (1.9 g, 20 mmol) were dissolved in degassed toluene (100 mL). Pd2 dba3 (0.77 g, 0.84 mmol) was added and the reaction heated in an 80° C. oil bath for 5 hours. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2) to afford tert-butyl 3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (8.4 g, 18 mmol, 106% yield) as yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])=[C:9]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)[CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+].O>C1COCC1.CO>[C:21]([C:19]1[N:20]=[C:16]([C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:29])=[O:2])=[CH:8][C:9]=2[C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)=[O:15])[NH:17][CH:18]=1)#[N:22]
Reactant: COC(=O)C(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of 2-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-2-methyl-propionic acid methyl ester (as prepared in the previous step, 60.0 mg, 0.153 mmol) in 1 mL of 1:1 THF/MeOH was added 6 N NaOH (250 μL, 1.50 mmol). After stirring at RT for 18 h, the mixture was treated with 10 mL of H2O and washed with EtOAc (3×10 mL). The aqueous layer was acidified to a pH of 6 with 1 N aqueous HCl and extracted with 10:1 EtOAc-MeOH (3×10 mL). The combined organic layers were washed with H2O (10 mL), brine (10 mL) and dried (Na2SO4). The organic solvent was evaporated in vacuo to give the title compound (48 mg, 83%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.19 (m, 1H), 7.90 (s, 1H), 7.31 (m, 1H), 7.20 (s, 1H), 5.84 (m, 1H), 2.17-2.40 (m, 4H), 1.76-1.92 (m, 4H), 1.57 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H22N4O3, 379.2 (M+H). found 379.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19].C(=O)([O-])O.[Na+]>ClCCl>[C:18]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl indole-6-carboxylate (1.01 g) in dichloromethane (30 mL) were added aluminum chloride (1.53 g) and acetyl chloride (0.5 mL) at room temperature, and then the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (625 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].Cl.Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C(N(CC)C(C)C)(C)C>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCCNC3CCNCC3)c2c1C
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1oc2cccc(OCCCNC3CCN(Cc4cccnc4)CC3)c2c1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A mixture of 3-methyl-4-[3-(piperidin-4-ylamino)-propoxy]-benzofuran-2-carboxylic acid ethyl ester (15 mg), 3-(chloromethyl)pyridine hydrochloride (8 mg) and N,N-diisopropylethylamine (22 μl) in ethanol (1.5 ml) was stirred overnight at 70° C. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to afford 3-methyl-4-[3-(1-pyridin-3-ylmethyl-piperidin-4-ylamino)-propoxy]-benzofuran-2-carboxylic acid ethyl ester (8 mg) as a colorless oil. FAB-MS: m/z 452 (MH+); 1H-NMR (CDCl3): δ 1.43 (3H, t, J=7 Hz), 1.60 (2H, m), 2.00 (4H, m), 2.20 (2H, quintet, J=6.5 Hz), 2.70 (1H, m), 2.72 (3H, s), 2.86 (2H, br d, J=12 Hz), 2.99 (2H, t, J=7 Hz), 3.49 (2H, s), 4.15 (2H, t, J=6 Hz), 4.43 (2H, q, J=7 Hz), 6.59 (1H, d, J=8 Hz), 7.11 (1H, d, J328 Hz), 7.22 (1H, m), 7.29 (1H, t, J=8 Hz), 7.66 (1H, brd, J=8 Hz), 8.48 (1H, m), 8.51 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1F
Temperature: 28 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,5-difluoro-4-nitrotoluene (0.550 g. 3.18 mmol) in DMF (5.0 mL) was added dropwise a solution of sodium glycinate (0.308 g, 3.18 mmol, Aldrich, used as received) in water (1.0 mL). The resulting suspension was stirred at 28° C. overnight. The solid was filtered and dried under vacuum to give 0.168 g (23%) of crude product. It was purified as follows. 0.150 g material was boiled in ethyl acetate (5.0 mL) and filtered while hot to give 0.134 g (18%) of the pure (1H NMR) title compound as a yellow powder. 1H NMR (DMSO-d6): 2.213 (s, 3H), 3.428 (d, 2H, J=3.9 Hz), 6.765 (d, 1H, J=6.9 Hz), 7.700 (d, 1H, J=10.5 Hz), 8.728 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([OH:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=O)[CH:10]=[CH:11][C:12]=1[Cl:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([OH:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]2[NH:1][CH2:2][CH2:3][CH2:4][OH:5])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: NCCCO
Reactant: O=C1Nc2ccccc2C1(O)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCCNC1=Nc2ccccc2C1(O)c1ccc(Cl)c(Cl)c1

Procedure:
Reaction of 3-aminopropanol with 3-(3,4-dichlorophenyl)-3-hydroxy-3H-indol-2-one in presence of toluene-p-sulphonic acid by a procedure analogous to that of Example 1 gives 3-(3,4-dichlorophenyl)-2-(3-hydroxypropylamino)-3H-indol-3-ol
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)[CH3:21].[Li+].C(I)C>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[C:11]2[CH2:20][CH3:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc2c(Br)cncc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-c]pyridine (0.63 g, 1.86 mmol) in anhydrous THF (10 mL), at −35° C., was added a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 1.86 mL, 3.77 mmol) dropwise. The reaction mixture was stirred at −35° C. for 30 min and then ethyl iodide (0.90 mL, 11.18 mmol) was added dropwise. The resulting solution was allowed to reach room temperature and was stirred for 4 h. The reaction mixture was quenched by addition of a solution of 1N HCl (5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2×75 mL). The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane 0:100 to 70:30). The residue was triturated in EtOAc (2 mL) and collected by filtration to give the title compound as a white solid (0.27 g, 40%). LCMS (Method H): RT=4.65 min, [M+H]+ 367 (79Br), 369 (81Br)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][C:12]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[CH:4][C:3]=2[O:2]1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:21][O:20][C:18]1[C:19]2[C:6]3[CH:7]=[C:8]4[O:9][CH2:1][O:2][C:3]4=[CH:4][C:5]=3[CH2:10][CH2:11][C:12]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][C:14]=2[CH:15]=[C:16]([O:24][CH3:25])[C:17]=1[O:22][CH3:23]
Reactant: CCOC(=O)C(CCc1ccc2c(c1)OCO2)(Cc1cc(OC)c(OC)c(OC)c1)C(=O)OCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C(=O)OCC)CCc2cc3c(cc2-c2c(cc(OC)c(OC)c2OC)C1)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
In 3 ml of dichloromethane, 102 mg of diethyl 4-(3,4-methylenedioxyphenyl)-1-(3,4,5-trimethoxyphenyl)-butane-2,2-dicarboxylate [0.205 mmol, A. S. Kende and L. S. Liebeskind, J. Am. Chem. Soc., 98, 267 (1976)] were dissolved. The solution was added with 0.3 ml of trifluoroacetic acid and 210 mg (0.45 mmol) of ferric perchlorate, followed by stirring at room temperature for 1.5 hours. The reaction mixture was dissolved in 10 ml of ethyl acetate. After the resulting solution was washed with 2N-HCl and then saturated NaCl, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby brown oil was obtained. The oil thus obtained was purified by TLC (silica gel: "MERCK #5744", eluent: 1:3 mixed solvent of ethyl acetate and hexane), whereby 62 mg of the title compound were obtained as colorless oil (yield: 61%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:30]=1[N:37]=[C:38]=[O:39])[CH3:28].Cl>ClCCl>[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:30]=1[NH:37][C:38]([N:13]([CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)=[O:39])[CH3:28]
Reactant: CCc1cccc(CC)c1N=C=O
Reactant: c1ccc(C2CCC(NCC3CCCCC3)CC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)N(CC1CCCCC1)C1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
To the solution of 2 g of N-(4-phenylcyclohexyl)-N-cyclohexylmethylamine in dichloromethane was added 2 ml of pyridine and to the mixture was added a solution of 1.6 g of 2,6-diethylphenylisocyanate in 30 ml of dichloromethane dropwise. After the mixture was stirred at room temperature, to the solution was added diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine and then dried over magnesium sulfate. The solvent was distilled away in vacuo to give 2 g of crude crystals. The crystals were recrystallized from the mixture of ethyl acetate and hexane to give 1.2 g of N-(2,6-diethylphenyl)-N'-cyclohexylmethyl-N'-(4-phenylcyclohexyl)urea, melting at 166°-168° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:9]=1[CH:10]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:7][C:8]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:9]=1[CH2:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1cc(O)ccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Br)c(CN2CCOCC2)c1
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
Morpholine (1.19 mL, 13.7 mmol) was added to a solution of 2-bromo-5-hydroxybenzaldehyde (2.5 g, 12.4 mmol) in DCM (20 mL) and stirred for 20 min. Sodium triacetoxyborohydride (2.90 g, 13.7 mmol) was added and stirred for 2 h. The reaction was quenched with methanol and stirred for 1 h. The solution was concentrated in vacuo, dissolved in methanol and loaded onto a SCX (50 g) column, flushing with methanol. Eluting with methanolic ammonia and concentration of the eluant gave the 4-bromo-3-(morpholinomethyl)phenol (3 g, 11.02 mmol), which was dissolved in THF (60 mL) cooled to −78° C. and tert-butyllithium (19.45 mL, 33.07 mmol) (1.7M) was added dropwise. The reaction mixture stirred for 10 min then warmed to 0° C. for 15 min. The reaction was then cooled to −78° C. and triisopropyl borate (7.63 mL, 33.07 mmol) was added. The reaction was warmed to RT and stirred for 1 hr. Saturated aqueous ammonium hydroxide was added and the reaction stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (200 mL), the phases were separated, the aqueous was further extracted with EtOAc. The combined organic extracts were washed with saturated brine (200 mL). The organic was dried over magnesium sulfate, filtered and evaporated to give the sub-title compound. Yield: 2.45 g
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:18]2[N:27](COCCOC)[C:26](=[O:34])[C:25]3[C:20](=[CH:21][C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:23][CH:24]=3)[N:19]=2)[CH:17]=1)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:18]2[NH:27][C:26](=[O:34])[C:25]3[C:20](=[CH:21][C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:23][CH:24]=3)[N:19]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)n2COCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A solution of 4M HCl and dioxane (3.00 mL, 12.0 mmol) was added to 1-[3-(2-methoxy-ethoxymethyl)-4-oxo-7-phenyl-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (90.0 mg, 0.201 mmol). The reaction mixture was stirred at 23° C. After 18 h, the reaction mixture was concentrated under reduced pressure. Et2O was added (5 mL) and the resulting precipitate was collected by filtration and washed well with Et2O to afford the titled compound (38.0 mg, 53%). MS (ESI): mass calcd. for C20H16N4O3, 360.1; m/z found, 361.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.93 (s, 1H), 9.04 (s, 1H), 8.34 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.98 (s, 1H), 7.84 (dd, J=10.5, 4.2 Hz, 3H), 7.55 (t, J=7.6 Hz, 2H), 7.49-7.46 (m, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO.[NH:22]1[CH2:25][CH2:24][CH2:23]1>C(O)(C)C.C(OCC)(=O)C.[Cu](I)I>[N:22]1([C:7]2[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: Nc1ccc(I)cc1F
Reactant: C1CNC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: OCCO
Product: Nc1ccc(N2CCC2)cc1F
Temperature: 80 °C
Yield: 80.7 %

Procedure:
To a mixture of 2-fluoro-4-iodoaniline (1 g, 4.14 mmol), copper iodide (304 mg, 0.21 mmol) and potassium phosphate (1.75 g, 8.27 mmol) in ethylene glycol (465 μl, 8.27 mmol) and isopropanol (4 mL) in a bomb flask was added azetidine (304 mg, 5.17 mmol). The flask was sealed and heated to 80° C. for 24 hours. The reaction mixture was dissolved in ethyl acetate (50 mL), washed with water (3×50 mL), brine (50 mL), and the brine layer back extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to a brown oil. The oil was purified by chromatography over silica gel eluted with 40% v/v ethyl acetate in hexanes. The product containing fractions were combined and concentrated to give 4-azetidin-1-yl-2-fluoro-phenylamine as an orange oil (555 mg, 81% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[N:11]1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:20]1.OOS([O-])=O.[K+]>CO.CO.C1CC=CCCC=C1.C1CC=CCCC=C1.[Ir].[Ir].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:20])[CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[N:11]1
Reactant: COc1cccc(C)c1-n1cc(C(F)(F)F)cn1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: O=S([O-])OO
Solvent: CO
Solvent: O
Solvent: C1=CCCC=CCC1
Product: COc1cc(O)cc(C)c1-n1cc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 72 h
Yield: 32.9 %

Procedure:
To a flask containing 1-(2-methoxy-6-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (75.0 mg, 0.290 mmol) was added di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (2.00 mg, 0.003 mmol), bis(pinacolato)diboron (75.2 mg, 0.290 mmol), 4,4′di-tert-butyl-2,2′-dipyridyl (1.60 mg, 0.006 mmol) and degassed methyl tert-butyl ether (1.50 mL). The resulting red solution was heated to 80° C. for 18 h and then at room temperature for 3 d. The reaction was concentrated. Acetone (0.980 mL) was added to provide a homogenous solution followed by an aqueous solution of oxone (180 mg, 0.290 mmol), 0.98 mL of water) dropwise over 2 min. The reaction was stirred at room temperature for 18 h. The reaction was then quenched with aqueous sodium bisulfate and extracted three times with methylene chloride. The combined organic layers were washed with brine and water. The organic layer was then dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-25% ethyl acetate in heptane), gave 3-methoxy-5-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (26.0 mg, 33%) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.75-7.70 (m, 1H), 6.27 (dd, J=15.8, 2.5 Hz, 2H), 3.68 (s, 3H), 1.96 (s, 3H). MS (M+1): 273.2.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10]C)=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: COc1cc(C=O)c(F)cc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(Br)cc1F
Temperature: -78 °C

Procedure:
4-Bromo-2-fluoro-5-methoxy-benzaldehyde (100 mg, 0.43 mmol) is dissolved in CH2Cl2 and cooled to −78° C. and then BBr3 (2 mL, 1 M solution in CH2Cl2, 2 mmol) is added. The resulting mixture is allowed to stir at room temperature until no starting material is left. The reaction is quenched and the product is isolated after chromatography (60 mg, 57%). MS (ESI): 216.9 (M−1)−1.
Reaction SMILES: [OH-].[K+:2].C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[CH:16]=[CH:17][C:18]([N:20]([CH3:22])[CH3:21])=[CH:19][C:14]=3[S:13][C:12]=2[CH:23]=1)=[O:7])C.[K]>C(O)C>[K+:2].[CH3:21][N:20]([CH3:22])[C:18]1[CH:17]=[CH:16][C:15]2[C:11]3[CH:10]=[CH:9][C:8]([C:6]([O-:7])=[O:5])=[CH:23][C:12]=3[S:13][C:14]=2[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)sc1cc(N(C)C)ccc12
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc2c(c1)sc1cc(C(=O)[O-])ccc12

Procedure:
To a solution of 0.5 g. of potassium hydroxide in 100 ml. of ethanol was added 2.8 g. of 7-dimethylaminodibenzothiophene-3-carboxylic acid ethyl ester. The solution was stirred and refluxed for 3 hours during which time the potassium salt precipitated. The salt was filtered off, washed with ether and air dried. The yield of 7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt was 1.9 g.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([OH:27])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[C:18]=1[CH3:26])[C:13]([OH:15])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.C([Si](C)(C)Cl)(C)(C)C>CN(C=O)C>[C:1]([NH:8][C@H:9]([C@H:10]1[O:27][C:13](=[O:15])[C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[C:18]=2[CH3:26])[CH2:11]1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c(C)c1C
Reaction time: 2.25 h

Procedure:
A solution of 1.153 g (2.445 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3-dimethyl-4-methoxyphenyl)methyl]hexanoic acid, 1.372 g (20.05 mmol) of imidazole and 1.709 g (11.0 mmol) of tert-butyldimethylchlorosilane in 8.7 ml of abs. DMF is stirred at RT for 18 h under argon. After that, the reaction mixture is poured onto ice-water and the whole is extracted with ethyl acetate. The organic phase is washed with cold 10% citric acid solution and saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated on a RE at approximately 30° C. The resulting product is dissolved in 28.8 ml of methanol and 11.2 ml of THF, and this solution is treated, at RT, with 1.962 g of potassium carbonate in 11.2 ml of water. After having been stirred for 2.25 h, the reaction mixture is concentrated down to half its volume at approximately 30° C. and the residue is treated with ethyl acetate and (cold) 10% citric acid solution, and the phases are separated. The organic phase is washed a further two times with saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified by being chromatographed twice on silica gel (hexane:ethyl acetate, 1:1 and then 3:1), and the title compound is obtained. TLC Rf (hexane:ethyl acetate. 1:1)=0.42. FAB-MS (M+H)+ =586. IR (KBr) inter alia: 1711, 1485, 1260 and 1107 cm-1. 1 H-NMR (CD3OD) inter alia: 7.30-7.06 (m, 5H); 6.91 and 6.65 (each d, each 1H); 6.00 and 5.41 (each d, in all 1H from NH); 3.75 (s, 3H); 2.21 and 2.12 (each s, each 3H); 1.31 and 1.21 (each s, in all 9H from Boc); 0.89 (s, 9H); 0.12 and 0.08 (each s, each 3H).