Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl>C(O)CCC>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][O:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: ClCCOCCCl
Reactant: Oc1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCOCCOc1ccc(I)cc1

Procedure:
A mixture prepared by adding 3.08 g of sodium hydroxide and 40 ml of n-butanol to 15.4 g of 4-iodophenol was refluxed. 2 ml of n-butanol solution of 5.01 g of 1,5-dichloro-3-oxapentane was added dropwise to the above prepared mixture over a period of 5 minutes.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:6][NH2:7].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C(Cl)Cl.[OH-].[Na+]>[C:13]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([F:11])=[C:3]([Br:2])[CH:4]=1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(Br)c1
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-4-fluorobenzylamine hydrochloride (10 g, 42 mmol) and TEA (10.5 g, 103 mmol) in 200 mL of CH2Cl2 was added BOC2O (9.1 g, 42 mmol) at RT. The resulting solution was stirred for 16 h. The solution was diluted with aq. 1 N NaOH and CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give N-Boc-(3-bromo-4-fluoro-benzyl)amine. MS (ES+): 305 (M+H)+; (ES−): 303 (M−H). Calc'd C12H15BrFNO2-304.16.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[O:7])=[CH:4][CH:3]=1.[CH:20]1[C:28]2[N:23]([CH:24]=[CH:25][C:26](=O)[CH:27]=2)[CH2:22][CH:21]=1>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[C:10]([C:26]3[CH2:27][CH:28]4[N:23]([CH2:22][CH2:21][CH2:20]4)[CH2:24][CH:25]=3)=[CH:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(ccn2C(=O)c2ccc(F)cc2)c1
Reactant: O=c1ccn2c(c1)C=CC2
Product: Nc1ccc2c(c1)c(C1=CCN3CCCC3C1)cn2C(=O)c1ccc(F)cc1

Procedure:
The N-(4-fluorobenzoyl)-5-amino-1H-indole (813 mg, 3.20 mmol) and the 7-indolizinone (560 mg, 4.00 mmol) were converted to product by the procedure of Example 2 to give 818 mg. (68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>COCCOC.CCOC(C)=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:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:12][O:11][C:10]([NH2:13])=[N:9]3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC1=NC(c2ccc(Br)cc2)CO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: NC1=NC(c2ccc(-c3ccc(F)cc3)cc2)CO1
Temperature: 85 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
To a stirred solution of (RS)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine (80 mg; example 20) at r.t. in 1,2-dimethoxyethane (4 ml) under an argon atmosphere were added PdCl2(dppf) (24 mg), 10% aq. Na2CO3 (1 ml) and 4-fluorophenylboronic acid (186 mg). The mixture was heated to 85° C. and stirring at that temperature was continued for 18 h. The dark brown mixture was cooled to r.t., diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give (RS)-4-(4′-fluoro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine (46 mg) as off-white solid. MS (ISP): 257.0 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C([Al](CC)CC)C.[N-:24]=[N+:25]=[N-:26].C([Al+]CC(C)C)C(C)C.Cl.N([O-])=O.[Na+]>C(OC(C)C)(=O)C>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[NH:26][N:25]=[N:24][N:16]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccccc1-c1ccc(CO)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)C[Al+]CC(C)C
Agent: CC[Al](CC)CC
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: OCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
2.1 g of 4′-hydroxymethyl-biphenyl-2-carbonitrile (10 mmol), are treated, in a drop wise manner at 0° C. with 5.52 ml of triethyl aluminium (10 mmol, 1.8M in toluene). The reaction mixture is stirred for 5 minutes. After that, the clear colourless reaction mixture is added to the solution of diisobutyl aluminium azide (19 mmol), gradually warmed to an internal temperature of about 100° C. and stirred over the night (conversion 95.7%). For the work up the reaction mixture is cooled to 0° C. and added dropwise to a solution of 30 ml of HCl (2 N) containing 1.38 g of NaNO2 (20 mmol) (cooled to 0° C.). 40 ml of iso-propyl acetate are added and the mixture is extracted once with 15 ml of HCl 2N, once with 20 ml of water. The combining aqueous layers are extracted twice with 10 ml of isopropyl acetate. The organic phase is extracted three times with 15 ml portions of an aqueous solution of K2CO3 (10%). The aqueous phase is washed once with 15 ml of isopropyl acetate. HCl (2 N) is added to the aqueous phase to adjust the pH to 2, and the solution is extracted three times with 20 ml portion of isopropyl acetate. The combining organic phase is washed once with 20 ml of water and the solvent is removed to give the crude product. The crude product is crystallized from ethyl acetate and isopropyl ether to give the pure product.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:12][C@@H:11]([N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:16])[CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[C:23]([C:25]1[S:29][C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[N:27][C:26]=1[CH3:36])=[O:24])C.O1C=CC=C1C(Cl)=O>>[CH3:1][C@H:3]1[CH2:12][C@@H:11]([N:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14](=[O:16])[CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[C:23]([C:25]1[S:29][C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[N:27][C:26]=1[CH3:36])=[O:24]
Reactant: CC[C@H]1C[C@@H](N(C(C)=O)c2ccccc2)c2ccccc2N1C(=O)c1sc(-c2cnccn2)nc1C
Agent: O=C(Cl)c1ccco1
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2sc(-c3cnccn3)nc2C)c2ccccc21

Procedure:
(±)-Cis-N-[2-ethyl-1-(4-methyl-2-pyrazin-2-yl-thiazole-5-carbonyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-acetamide was made following general procedure A, substituting 4-methyl-2-(2-pyrazinyl)-1,3-thiazole-5-carbonyl chloride for 2-furoyl chloride.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]1([CH:12]2[C:15]3([CH2:17][O:16]3)[O:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[OH:16][CH2:17][C:15]1([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][O:14]1
Reactant: c1ccc(C2COC23CO3)cc1
Reactant: c1c[nH]nn1
Solvent: ClCCl
Product: OCC1(n2nccn2)OCC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1H-1,2,3-triazole (0.043 g, 0.62 mmol) in dry CH2Cl2 (2 mL) was introduced to a stirred solution under N2 of 3-phenyl-1,5-dioxaspiro[3.2]hexane (0.10 g, 0.62 mmol) in dry CH2Cl2 (2 mL) at −78° C. After 3 hours at −78° C., the reaction was allowed to warm to room temperature; then, the solvent was evaporated in vacuo. The resultant oil was purified by flash chromatography on silica gel (CH2Cl2/EtOAc 95:5). 2-Hydroxymethyl-3-phenyl-2-(1,2,3-triazol-2-yl)oxetane was isolated as a pale yellow solid (0.076 g, 59%): mp 77.0-78.3° C.; IR (CDCl3) 3145, 3031, 2969, 1496, 1452, 1323, 1049 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 2H), 7.41 (m, 2H), 7.35 (m, 3H), 5.41 (dd, J=8.2, 7.7 Hz, 1H), 5.08 (dd, J=8.5, 6.0 Hz, 1H), 4.98 (dd, J=7.0, 6.0 Hz, 1H), 4.15 (dd, J=13.0, 7.6 Hz, 1H), 4.10 (dd, J=13.0, 7.6 Hz, 1H), 2.51 (t, J=7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 135.3, 134.1, 128.8, 128.1, 128.0, 99.7, 68.5, 62.9, 47.9; MS (EI) m/z 200 (M+—CH2O), 185, 104 (100), 78; Anal. calculated for C12H13N3O2: C, 62.33; H, 5.67; N, 18.17. Found: C, 62.58; H, 5.30; N, 17.94.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:4].[BH4-].[Na+]>C(O)C>[F:29][C:26]([F:27])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:16]2[NH:15][C:14]3[CH:30]=[CH:31][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[CH:3]([OH:4])[CH2:2][OH:1])=[CH:12][C:13]=3[N:17]=2)=[CH:21][CH:22]=1
Reactant: O=C(CO)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
A solution of 2-hydroxy-1-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-ethanone (0.082 g, 0.192 mmol) in ethanol (6 mL) was added sodium borohydride (0.029 g, 0.769 mmol) at 0° C. After stirring for 20 min, the reaction was quenched by water. EtOAc was added to dilute and the organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to provide a residue, which was purified by chromatography (silica, CH2Cl2: MeOH, 10:1) to afford the title compound as a pale yellow oil (0.075 g, 91%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.64-7.61 (m, 4H), 7.40 (dt, 1H, J=8.4 Hz, J=1.6 Hz), 7.32 (dt, 1H, J=8.2 Hz, J=1.6 Hz), 7.26-7.23 (m, 5H), 5.45 (s, 2H), 4.86 (dd, 1H, J=6.8 Hz, J=1.2 Hz), 3.58-3.55 (m, 1H), 1.60-1.57 (m, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H20F3N2O3: 429.4 (M+H), Found 429.1.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:40](O)(=O)C>CO>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:40])[CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: CN1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 18 h
Yield: 73 %

Procedure:
The 2-[4-tert-butyl-2-(piperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (450 mg, 0.86 mmol) was placed in a dry flask and diluted with dry MeOH (0.95 mL). Paraformaldehyde (54.0 mg, 1.8 mmol) and NaCNBH4 (167.0 mg, 2.7 mmol) were added, followed by acetic acid (0.5 mL). The reaction was allowed to stir for 18 h. More paraformaldehyde (54.0 mg), NaCNBH4 (107.0 mg) and acetic acid (1.0 mL) were added, and the reaction was stirred another 18 hrs under N2 at room temperature. The solvents were removed in vacuo, and the residue was diluted with H2O (5.0 mL). The flask was cooled in an ice bath while the pH was adjusted to 8 using saturated sodium bicarbonate. This solution was extracted with EtOAc (5×90 mL). The organics were combined and washed with a saturated solution of sodium bicarbonate and then brine. The organic layer was dried over MgSO4 and the solvents were removed in vacuo to obtain the desired product as a white solid (338.2 mg, 0.63 mmol, 73%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][N:7]=[C:8]([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[O:16]CC1C=CC(Cl)=CC=1.C1(OC)C=CC=CC=1>C(=O)(O)[O-].[Na+]>[CH3:5][O:6][N:7]=[C:8]([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[OH:16]
Reactant: CON=C(c1noc(C)n1)c1cc(Cl)ccc1OCc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: CON=C(c1noc(C)n1)c1cc(Cl)ccc1O
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Aluminium chloride (0.27 g, 2 mmol) was added to a mixture of 5-chloro-2-(4-chlorobenzyloxy)phenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.39 g, 1 mmol) and anisole (3 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, aqueous sodium bicarbonate solution (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 5-chloro-2-hydroxyphenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.22 g, 82.2%) as colorless crystals. A part of the crystals was recrystallized from ether/n-hexane to give crystals (mp. 92-93.5° C.).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(NC2CCCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A solution of (±)-cis-4-(-2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.53 g, 2 mmol) from Example 4, triethylamine (2.00 g, 20 mmol), cyclopentylamine (267 mg, 3.1 mmol) and ethanol (10 mL) was stirred at reflux for 9 hours. The solution was allowed to cool to room temperature before the addition of 2 mL of 1.0N NaOH. Concentration of the solution afforded the crude product which was purified by elution from a silica gel column using 5% methanol in chloroform (0.430 g, 68.4%). Crystallization of such a sample from ethanol-acetonitrile gave an off-white powder, m.p. 143°-146° C.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][C:9]1([CH3:19])[O:16][CH2:15][C@H:14]2[C@:12]([CH2:17][OH:18])([CH2:13]2)[CH2:11][O:10]1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>CCCCCC>[CH2:20]([O:18][CH2:17][C@:12]12[CH2:13][C@H:14]1[CH2:15][O:16][C:9]([CH3:19])([CH3:8])[O:10][CH2:11]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)OC[C@@H]2C[C@]2(CO)CO1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H]2C[C@]2(COCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a suspension of 1.2 g (30 mmol) of sodium hydride, previously washed with hexane, in 80 ml of DMF 4.07 g (23.6 mmol) of (1S,7R)-4,4-dimethyl-3,5-dioxabicyclo[5,1,0]oct-1-yl methanol was added and the mixture was stirred for 5 min. at room temperature. 3.97 ml (30 mmol) of benzyl bromide was added and the mixture was stirred for 14 hours at room temperature. Saturated aqueous solution of ammonium chloride was added and the mixture was extracted with hexane-ethyl acetate (1:1). The organic layer was washed with water and dried over anhydrous sodium sulfate, and evaporated in vacuo. The resultant residue was subjected to silica gel chromatography (hexane:ethyl acetate/5:1) to obtain 5.56 g (21.1 mmol, 90%) of (1S,7R)-1-benzyloxymethyl-4,4-dimethyl-3,5-dioxabicyclo[5,1,0]octane. Colorless oil; 1H-NMR(CDCl3) δ 0.67 (dd, J=4.2, 8.4 Hz, 1H), 0.92 (m, 1H), 1.00 (m, 1H), 1.28 (s,3H), 1.37 (s,3H), 3.13 (d, J=10.2 Hz, 1H), 3.50 (d, J=10.2 Hz, 1H), 3.70 (dd, J=3.9, 13.2 Hz, 1H), 3.78 (d, J=13.1 Hz, 1H), 4.12 (dd, J=5.1, 13.2 Hz, 1H), 4.15 (d, J=13.1 Hz, 1H), 4.50 (d, J =12.0 Hz, 1H), 4.55 (d, J=12.0 Hz, 1H), 7.32 (m, 5H); FD MASS, m/z 262 (M+).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH:7]=1)C.[CH3:22][O:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH3:22][O:23][C:24]1[C:29]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:21])[CH:11]=[CH:10][CH:9]=3)=[CH:19][CH:18]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COc1ncccc1B(O)O
Reactant: CCOC(=O)Cc1cccc(COc2ccc(I)cc2)c1
Product: COc1ncccc1-c1ccc(OCc2cccc(CC(=O)O)c2)cc1

Procedure:
{3-[4-(2-Methoxy-pyridin-3-yl)-phenoxymethyl]-phenyl}-acetic acid was prepared using general procedure 4 from [3-(4-iodo-phenoxymethyl)-phenyl]-acetic acid ethyl ester (of intermediate 4) and 2-methoxy-pyridine-3-boronic acid (available from Lan-caster Synthesis Ltd., Lancashire, UK). Mass spectrum MH+=350.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1.Br[CH2:27][CH3:28]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:27][CH3:28])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(O)cc1
Reactant: CCBr
Product: CCOc1ccc(CN2C(=O)CCCC2c2c(OC)cccc2OC)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)piperidin-2-one with commercially available bromoethane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.76 min.; [M+H]+: 370.17 g/mol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][C:23]([C:29](O)=[O:30])=[CH:22]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][O:15][C:29]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][C:19]([O:18][CH3:17])=[CH:28][CH:27]=3)=[O:30])[CH2:12][CH2:13]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ncc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)cc2c1
Temperature: 30 °C
Reaction time: 15 h

Procedure:
trans-(4-Hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (480 mg, 2.46 mmol, 1.0 eq) is added at room temperature to a stirred solution of 6-methoxy-quinoline-3-carboxylic acid (564 mg, 2.46 mmol, 1.0 eq) in dichloromethane (15 mL), followed by 1-hydroxybenzotriazole (532 mg, 3.94 mmol, 1.6 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.04 g, 5.41 mmol, 2.2 eq) and triethylamine (754 μL, 5.41 mmol, 2.2 eq). After 15 hours stirring at 30° C., solvent is evaporated and the residue is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 4:1, v/v) to afford 6-methoxy-quinoline-3-carboxylic acid trans-4-tert-butoxycarbonylamino-cyclohexylmethyl ester as a white powder (787 mg, 77% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([F:49])[CH:48]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:10]=[C:9]2[NH:34][C:35](=[O:45])[C:36]1[CH:41]=[C:40]([CH:42]=[O:43])[CH:39]=[CH:38][C:37]=1[F:44].CC(=CC)C.Cl([O-])=[O:56].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([F:49])[CH:48]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:10]=[C:9]2[NH:34][C:35](=[O:45])[C:36]1[CH:41]=[C:40]([CH:39]=[CH:38][C:37]=1[F:44])[C:42]([OH:56])=[O:43]
Reactant: O=Cc1ccc(F)c(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(Cc4cc(F)cc(F)c4)cc23)c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(F)c(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(Cc4cc(F)cc(F)c4)cc23)c1
Yield: 117.6 %

Procedure:
N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2-fluoro-5-formyl-benzamide (88 mg, 0.135 mmol) in tert-butanol (1.8 mL) at room temperature was treated first with 2-methyl-2-butene (0.079 mL, 1.082 mmol) and then with sodium chlorite (37 mg, 0.405 mmol) and sodium dihydrogenphosphate in water (0.8 mL) drop-wise. The reaction was stirred over-night, EtOAc was then added (30 mL) and washed with water (25 mL). The aqueous layer was extracted twice with EtOAc (2×10 mL). The combined organic layers were washed with brine, evaporated to dryness to leave 106 mg of title compound which was employed in the following step with no need of further purification.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][S:6][CH:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li+].[OH-]>C1COCC1.CO>[C:11]1([CH2:10][CH2:9][CH2:8][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:39])[C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[S:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CCSC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(C(=O)C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCSC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(C(=O)C(F)(F)F)cc2)cc1
Reaction time: 12 h
Yield: 82 %

Procedure:
A mixture of 300 mg of the product from Step 5 and 1.5 mL of 1M LiOH in 12 mL of 5:1 THF/MeOH was stirred for 12 hrs. at r.t. The reaction mixture was then treated with 10 mL of PH-7 buffer and extracted with EtOAc (50 mL). The extract was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 2:1 Hexane/EtOAc containing 1% AcOH to give 240 mg of the title compound.
Reaction SMILES: CC([O-])(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[NH:34][C:33]=2[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:28][CH:27]=1.Br[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=1.OS([O-])(=O)=O.[K+]>C1COCC1.O>[Cl:54][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][CH:51]=1)[CH2:47][N:34]1[C:35]([C:37]([F:39])([F:40])[F:38])=[CH:36][C:32]([C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=2)=[C:33]1[C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: Clc1cccc(CBr)c1
Reactant: CCOC(=O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
KOt-Bu (265 mg, 2.36 mmol) and 18-crown-6 (catalytic amount) were added to ethyl 3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate [for synthesis see ACI-06] (500 mg, 1.57 mmol) in dry THF (5 mL). The reaction mixture was stirred for 30 min. and 1-(bromomethyl)-3-chlorobenzene (647 mg, 3.15 mmol) was added to the reaction mixture. The reaction mixture was stirred at reflux temperature overnight. The reaction mixture was acidified with aqueous 1M KHSO4 (4 mL), diluted with H2O (4 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated to give crude product as a colourless oil (732 mg).