Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]1=[O:34])[CH:2]=C.C1C[O:39]CC1.C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+]>O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O.CC(O)(C)C>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:5](=[O:34])[C@:4]([CH2:1][CH:2]=[O:39])([CH3:35])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCOCC2)C1=O
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottomed flask charged with (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)piperidin-2-one (Example 91, Step D) (125 mg, 0.242 mmol) was added THF (2 mL). Approximately 1 mL water was added dropwise until the solution became and remained cloudy with gentle stirring. t-BuOH (0.350 mL) was added dropwise until the solution became homogeneous. NMO (42.6 mg, 0.364 mmol) was added followed by osmium tetroxide, 4 wt. %, in water (1 drop from glass Pasteur pipette). The reaction mixture was stirred at room temperature for 16 hours. An additional drop of osmium tetroxide, 4 wt. %, in water was added. After 5 hours, two additional drops of osmium tetroxide, 4 wt. %, in water were added and the reaction mixture was stirred at room temperature for an additional 16 hours. Sodium periodate (145 mg, 0.679 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL) and filtered. The aqueous layer of the filtrate was extracted with additional ethyl acetate (10 mL) and the combined organic layers were washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [O:1]=[C:2]([C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1)[CH2:3]SC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.CC(C1C=CC(O)=CC=1)=O.BrC(C)(C)C(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(C(C)=O)C(C)C>[C:2]([C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1)(=[O:1])[CH3:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CSc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Agent: CC(=O)c1ccc(O)cc1
Agent: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)cc1

Procedure:
The ethyl 2-(4-acetylphenoxy)isobutyrate used as starting material was itself prepared as follows: 54.4 g of 4-hydroxyacetophenone, 375 ml of ethyl 2-bromoisobutyrate, 175 g of potassium carbonate, 1.2 liters of methyl isobutyl ketone and 3 g of potassium iodide are introduced into a three-necked flask equipped with a stirrer and a condenser. The whole is heated under reflux for 20 hours, then cooled, filtered and concentrated to dryness. The residue is chromatographed on 4 liters of Amicon silica (0.035-0.070 mm) while eluting with dichloromethane. The fractions retained are concentrated to dryness to yield 100 g of ethyl 2-(4-acetylphenoxy)isobutyrate in the form of a thick liquid (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].CO>C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:25]#[C:24][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[S:22][C:13]=12
Reactant: C#Cc1cccnc1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CO
Product: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4cccnc4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (160 mg, 0.33 mmol), 3-ethynylpyridine (45 mg, 0.43 mmol), 5 mg of tetrakis(triphenylphosphine)palladium(0) and 20 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture is cooled to room temperature and 5 mL of methanol is added. The solvents are removed in vacuo and the residue is treated with 50 mL of chloroform. The insoluble material is removed by filtration, washing with chloroform. The filtrate is washed with water. The residue is suspended in acetone, combined with the chloroform phase and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% methanol in dichloromethane to 10% methanol and 1% ammonium hydroxide in dichloromethane. The fractions containing product are combined and concentrated to provide 99 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile as light brown crystals, mp 249-250° C.; MS 451.0 (M+H)+.
Reaction SMILES: [CH2:1]([P:3]([OH:9])([CH2:5][C:6]([OH:8])=[O:7])=[O:4])[CH3:2].[OH-].[Na+:11]>>[Na+:11].[CH2:1]([P:3]([OH:9])([CH2:5][C:6]([O-:8])=[O:7])=[O:4])[CH3:2]
Reactant: CCP(=O)(O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCP(=O)(O)CC(=O)[O-]
Yield: 98 %

Procedure:
An aqueous solution of 304 g (2 mol) of 2-(ethylhydroxyphosphinyl)acetic acid (produced as in Example 10) is reacted with about 160 g of a 50% strength aqueous solution of sodium hydroxide and the water is distilled off in vacuo to obtain 384 g (98% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid sodium salt as a colorless solid material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[CH2:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C(O)(C)(C)C.[Li].N>C1COCC1.O.CO>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]1=[CH2:21]
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12C
Agent: N
Agent: [Li]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=C1CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@]12C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
Approximately 70 ml of anh. ammonia was distilled through a KOH tower into a 250 ml flamedried 3-neck flask fitted with an inlet adapter, magnetic stirring bar, dry ice/acetone condenser, and V ground glass stopper. See FIG. 160. A solution of 17-methylenestra-1,3,5(10)-trien-3-yl methyl ether (14, 1.1297 g, 4.0001 mmol) and t-butyl alcohol (13.21 g, 0.1782 mol) in dry THF (17 ml) was added, followed by lithium wire (0.47 g, 68 mg-atom) cut in small pieces. After refluxing under argon for 6 h anh. methanol (6.6 ml) was added and the suspension was stirred overnight while allowing ammonia to boil off. Water (100 ml) was added and the suspension was extracted three times with 50 ml portions of methylene chloride. The combined organic extracts were washed with 100 ml of brine, dried over sodium sulfate, and filtered. The residue was washed with 25 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. The resulting light yellow oil was crystallized from aqueous ethanol to give lustrous white crystals (815.0 mg, 2.865 mmol, 72%), m.p. 77-78° C., homogeneous to TLC (Rf 0.60, 10% ethyl acetate/hexanes on silica gel).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)[CH3:10]>CS(C)=O>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:20])=[CH:14][CH:15]=2)[CH2:5]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
(2S,6R)-2,6-dimethylpiperazine (6.85 g, 60.00 mmol) was added to ethyl-4-fluorobenzoate (2.20 mL, 15 mmol), in DMSO (40 mL) and warmed to 120° C. under nitrogen. The resulting solution was stirred at 120° C. for 20 h. The reaction mixture was cooled and the solvent evaporated. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane containing 1% 0.880 ammonia. Pure fractions were evaporated to dryness to afford ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (2.83 g, 71.9%) as a brown oil, which solidified on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[OH:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:28][CH2:27]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)=[CH:43][CH:42]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(O)cc2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
To 300.0 mg (0.49 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 12 ml toluene were added 11.4 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 81.5 mg (0.59 mmol) (4-hydroxyphenyl)boronic acid in 3.0 ml ethanol and 88.7 mg (1.53 mmol) potassium fluoride in 3.0 ml water. The mixture was stirred at 100° C. for 4 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 218 mg (71%) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([NH2:12])=[O:11])=[C:8]([OH:9])[C:4]=2[CH:3]=1.[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([NH:12][CH:22]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:11])=[C:8]([OH:9])[C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc2ccc(F)cc2c1O
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC=C(c1ccccc1)c1ccccc1)c1sc2ccc(F)cc2c1O
Yield: 82.1 %

Procedure:
To a solution of 5-fluoro-3-hydroxybenzo[b]-thiophene-2-carboxamide (400 mg, 1.89 mmol) in hot toluene (35 ml) were added diphenylacetaldehyde (577 mg, 2.84 mmol) and p-toluenesulfonic acid monohydrate (25 mg). The reaction mixture was stirred at reflux temperature for 2 hours with azeotropic removal of water, cooled, and evaporated under diminished pressure. The solid obtained was recrystallized from diethyl ether-hexane to yield 604 mg (82%) of 5-fluoro-3-hydroxy-N-(2,2-diphenylethenyl)benzo[b]thiophene-2-carboxamide, m.p. 186°-189° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]([CH3:24])=[N:15][CH:16]=[C:17]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[CH:18]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[C:14]([CH3:24])=[N+:15]([O-:9])[CH:16]=[C:17]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncc(C2OCCO2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C2OCCO2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 77.8 %

Procedure:
m-CPBA (626 mg, 2.72 mmol) was added to a suspension of 3-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyridine (271.4 mg, 1.359 mmol) and NaHCO3 (343 mg, 4.08 mmol) in DCM (3 ml) and stirred at room temperature. After 21 h, HPLC showed full conversion. DCM and 1M NaOH were added. It was extracted, dried (MgSO4), filtered, and concentrated yielding 3-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyridine 1-oxide (228 mg, 78%) as a pale yellow oil pure enough to be used in the next step.
Reaction SMILES: [OH:1][C@H:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1.Cl[C:23]1[N:28]=[C:27]2[S:29][C:30]([C:32]#[N:33])=[CH:31][C:26]2=[CH:25][CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[OH:1][C@H:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:23]2[N:28]=[C:27]3[S:29][C:30]([C:32]#[N:33])=[CH:31][C:26]3=[CH:25][CH:24]=2)[C:6](=[O:10])[CH2:5]1
Reactant: N#Cc1cc2ccc(Cl)nc2s1
Reactant: Cc1c([C@@H](O)CN2CCNC(=O)C2)ccc2c1COC2=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c([C@@H](O)CN2CCN(c3ccc4cc(C#N)sc4n3)C(=O)C2)ccc2c1COC2=O
Temperature: 120 °C

Procedure:
A mixture of 4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one [I-10] (33 mg, 0.11 mmol), 6-chlorothieno[2,3-b]pyridine-2-carbonitrile [I-13] (22 mg, 0.11 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), Xantphos (26 mg, 0.045 mmol), and Cs2CO3 (55 mg, 0.17 mmol) in dioxane (2 mL) was sealed in a microwave tube and purged three times with nitrogen. It was heated to 120° C. for 20 minutes in a microwave reactor. LC showed formation of the title product, which was purified by silica gel flash chromatography. LC-MS (IE, m/z): 449 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]2[O:14]CCO2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:15]([NH2:17])[CH3:16].CC(C)([O-])C.[Na+].Cl>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]>[CH2:15]([NH:17][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:10]=[O:14])[CH3:16]
Reactant: CCN
Reactant: COc1ccc(C2OCCO2)cc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CCNc1cc(C=O)ccc1OC
Temperature: 110 °C
Yield: 63 %

Procedure:
Through a solution of 2-(3-bromo-4-methoxy-phenyl)-[1,3]dioxolane (1.2 g, 4.63 mmol, 1.0 equiv; prepared as described in WO 01/74775 A1, Sanofi-Synthelabo) in toluene (6 mL) was bubbled ethylamine for 10 min. To this solution was added sodium tert-butoxide (0.67 g, 6.95 mmol, 1.5 equiv), (±)-BINAP (0.029 g, 0.046 mmol, 0.01 equiv) and Pd2(dba)3 (Tris(dibenzylideneacetone)dipailadium, 0.021 g, 0.023 mmol, 0.005 equiv) and the solution heated to 110° C. under microwave irradiation for 20 min. A few drops of a solution of 37% HCl were added and the reaction mixture heated again to 100° C. under microwave irradiation for 5 min. Evaporation of the solvent and purification of the crude reaction product by column chromatography on silica eluting with hexane/ethyl acetate (7:3) provided 0.52 g (63%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.24 (t, J=7.1 Hz, 3H), 3.16 (q, J=7.1 Hz, 2H), 3.86 (s, 3H), 4.17 (br s, 1H), 6.78 (d, J=8.1 Hz, 1H), 7.01 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.1 Hz, J=1.9 Hz, 1H). MS (ISP): 179.9 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:22]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Yield: 87.3 %

Procedure:
20 g (119.6 mmol) of carbazole, 47 g (712.0 mmol) of 85% KOH, 26.5 g (191.7 mmol) of potassium carbonate, 4.0 g (11.8 mmol) of tetra-n-butylammonium hydrogensulfate, 17.0 g (134.3 mmol) of benzyl chloride and 300 ml of toluene were allowed to react and after treated in the same manner as with Example 7 (1) to obtain 26.88 g of 9-benzylcarbazole.
Reaction SMILES: [F:1][C:2]([F:51])([C:47]([F:50])([F:49])[F:48])[CH2:3][CH2:4][C:5]([CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[C:31]2[C:26](=[CH:27][C:28]([O:32]COC)=[CH:29][CH:30]=2)[O:25][CH2:24][C:23]1([C:37]1[CH:42]=[CH:41][C:40]([O:43]COC)=[CH:39][CH:38]=1)[CH3:36])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]>C(O)C.Cl.C(OCC)(=O)C>[F:51][C:2]([F:1])([C:47]([F:48])([F:49])[F:50])[CH2:3][CH2:4][C:5]([CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[C:31]2[C:26](=[CH:27][C:28]([OH:32])=[CH:29][CH:30]=2)[O:25][CH2:24][C:23]1([C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)[CH3:36])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC(=O)C(CCCCCCCCCC1c2ccc(OCOC)cc2OCC1(C)c1ccc(OCOC)cc1)C(=O)CCC(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCCCCCCC1c2ccc(O)cc2OCC1(C)c1ccc(O)cc1)C(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a stirred solution of ethyl 2-(4,4,5,5,5-pentafluoro-1-oxopentyl)-11-[(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-yl]undecanoate (128 mg, 0.17 mmol) in ethyl alcohol (5 ml), was added concentrated aqueous hydrochloric acid (10 drops) at room temperature under N2 atmosphere. The mixture was stirred at room temperature continued for 2.5 days and diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuum. Crude product was purified by flash chromatography on silica gel (hexane:ethyl acetate=3:2) to give ethyl 2-(4,4,5,5,5-pentafluoro-1-oxopentyl)-11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]undecanoate as a colorless glassy oil. yield: 102 mg (94%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([OH:14])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.7 %

Procedure:
N-Ethyl-3-hydroxy-4-nitrobenzamide (5.23 g, 24.9 mmol) obtained in Example 312a) was dissolved in anhydrous DMF (100 ml), potassium carbonate (4.47 g, 32.3 mmol, 1.3 eq.) was added at room temperature, benzyl bromide (3.17 ml, 26.1 mmol, 1.05 eq.) was added dropwise, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with 5% aqueous sodium hydrogen carbonate solution (200 ml) and extracted with ethyl acetate-hexane (3:1, 200 ml and 150 ml). The organic layer was washed sequentially with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a yellow powder (5.42 g, 18.1 mmol, 72.5%).
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13][CH2:14]O>>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[I:1])[CH3:14]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cccc(C)c1I
Temperature: 0 °C

Procedure:
A solution of the 2-iodo-3-methylbenzoic acid (6 g-0.023 mol) in EtOH (150 mL) is treated with concentrated HCl (20 mL) and refluxed for 48 h. After removal of the EtOH in vacuo, the residue is diluted with water (125 mL) and cooled to 0° C. in an ice bath. The pH is adjusted to 10 with solid NaOH pellets and extracted with EtOAc (3×75 mL). The organic extracts are washed with water (2×50 mL) and brine (2×50 mL) and dried over MgSO4. Concentrated in vacuo to give the product as a pale yellow oil. (6 g, 90%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:19]([O:21]CC)=O)[N:8]=2)=[N:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1.C1COCC1>CC(N(C)C)=O>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:19]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:21])[N:8]=2)=[N:2]1
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccc(OC)cc2n1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(Nc3cc[nH]n3)nc(C(=O)c3ccc(F)cc3)nc2c1
Reaction time: 2 h
Yield: 60 %

Procedure:
To ethyl 4-(1H-pyrazol-3-ylamino)-7-methoxyquinazoline-2-carboxylate (30 mg, 0.10 mmol) in dry DMA (2.5 mL) cooled in a −20° C. cooling bath was added dropwise 1N 4-fluorophenylmagnesium bromide in THF (0.306 mL, 0.306 mmol). After 2 h additional 1 N 4-fluorophenyl magnesium bromide (0.050 mL) was added. After 2 h, the reaction mixture was quenched by addition of a saturated ammonium chloride solution. The solution was concentrated and H2O was added. The precipitate was washed with water and purified by preparative thin layer chromatography on silica gel eluting with 10% MeOH/DCM to give a solid (21 mg, 60%) 1H NMR (300 MHz, DMSO-d6) δ ppm 3.93 (s, 3 H) 6.73 (br. s., 1 H) 7.29 (m., 2 H) 7.38 (m, 2H) 7.63 (br. s., 1 H) 8.08 (m, 2 H) 8.64 (m., 1 H) 10.63 (br. s., 1 H) 12.47 (br. s., 1 H) LC-MS (ESI) m/z 364 (M+H)+.