Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29](COCC[Si](C)(C)C)[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=2[F:17])[CH2:5]1)#[N:2].F[P-](F)(F)(F)(F)F.[N:47]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:51]2[CH:52]=C[CH:54]=[CH:55][C:50]=2N=N1.C1([C@@H](N)C)CC1.C(N(CC)CC)C.C([O-])(O)=O.[Na+].C(N)CN>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:47][C@H:51]([CH:50]3[CH2:55][CH2:54]3)[CH3:52])=[O:13])=[CH:10][C:9]=2[F:17])[CH2:5]1)#[N:2]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5F)C4)c3)ncnc21
Agent: C[C@H](N)C1CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)c(F)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluorobenzoic acid (20.0 mg, 0.0365 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19 mg, 0.044 mmol) in dichloromethylene (1.0 mL) was added to a mixture of (1S)-1-cyclopropylethanamine (4.7 mg, 0.055 mmol) and triethylamine (15 μL, 0.11 mmol) in methylene chloride (0.6 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with dichloromethylene (2×2 mL). The combined organic layers were washed with water (1 mL), concentrated and dried under reduced pressure. The residue was treated with methylene chloride (1.3 mL) and trifluoroacetic acid (0.6 mL), and stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in methanol (1.3 mL). Ethylenediamine (0.086 mL, 1.3 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and purified by RP-HPLC (pH=10) (the conditions are already mention before the examples) to afford the desired product. LCMS (M+H)+: m/z=485.2.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:11]1([NH:10][CH2:8][CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(COc1ccc(O)cc1)Nc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc(OCCNc2ccccc2)cc1
Temperature: 25 °C
Yield: 13.6 %

Procedure:
Compound 1b (1.5 g, 6.1 mmol) was dissolved in anhydrous THF (50 mL). LiAlH4 (500 mg, 13 mmol) was added to the mixture under argon. The reaction mixture was heated to reflux for 4 hr. After cooling to room temperature, the reaction was carefully quenched with water (50 mL). The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water and then brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography on silica gel to provide the product compound 1 (190 mg, 0.83 mmol, 14% yield) as a pale-yellow powder. HRMS (ESI, positive) m/z calcd. for C14H16NO2 [M+H]+: 230.1181, found: 230.1190; m/z calcd. for C14H15NO2Na [M+Na]+: 252.1001, found: 251.1061. 1H NMR (CDCl3, 400 MHz) δ 7.25 (t, J=8.6 Hz, 2H), 6.83-6.76 (m, 5H), 6.71 (d, J=7.2 Hz, 2H), 4.12 (t, J=5.0 Hz, 2H), 3.52 (t, J=5.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:35]4[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=4)[C:29]#[N:30])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC(F)(F)F
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(CC(F)(F)F)C2=O)c1
Temperature: 120 °C
Yield: 17.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with 2′-amino-6-bromo-2-phenyl-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.044 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 M, 0.3 mL) and 3-cyanophenylboronic acid (13 mg, 0.088 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 3-(2′-amino-5′-oxo-2-phenyl-1′-(2,2,2-trifluoroethyl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (3.7 mg, 12%). 1H-NMR (MeOD): 2.27 (m, 1H), 2.35 (m, 1H), 3.87 (m, 2H), 5.83 (m, 1H), 7.01 (d, 1H), 7.26(m, 1H), 7.32 (m, 5H), 7.59 (m, 3H), 7.76 (m, 1H), 7.81 (m, 1H).
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].CCN(CC)CC.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[CH:1]([N:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)[C:25](=[O:27])[CH3:26])([CH3:3])[CH3:2]
Reactant: CC(C)NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2.5 h
Yield: 59.6 %

Procedure:
To a 0° C. solution of tert-butyl 4-(isopropylamino)piperidine-1-carboxylate (1.2 g, 5.19 mmol) in CH2Cl2 (18 mL) was added Et3N (1.44 mL, 10.38 mmol) followed by acetyl chloride (0.55 mL, 7.78 mmol). The resulting solution was stirred for 2.5 hours, then concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 0% to 5% of EtOAc/CH2Cl2, to afford tert-butyl 4-(N-isopropylacetamido)piperidine-1-carboxylate (0.88 g, 59%).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(=O)=O.[CH2:12]([OH:15])[CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][O:15][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: Clc1ccncc1
Reactant: OCCO
Agent: O=C=O
Agent: [Na]
Product: OCCOc1ccncc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (9.2 g) in ethylene glycol (100 ml) was added portionwise 4-chloropyridine (39.6 g) under heating at 120° to 130° C. and stirring, which was continued for one hour at 130° C. after the addition. The mixture was cooled to -15° C. and dry ice (5.2 g) was added thereto. The mixture was warmed to 45° C. and allowed to stand at room temperature. The resulting precipitates were removed by filtration and washed with diisopropyl ether. The filtrate and washings were combined and evaporated. The residual oil was distilled to give 4-(2-hydroxyethoxy)pyridine (9 g), bp. 138° to 145° C. at 5 to 6 mmHg, which solidified and recrystallized from ethyl acetate. mp. 113° to 115° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[N+](=[CH2:19])=[N-]>CO.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]2[C:14]([O:16][CH3:19])=[O:15])=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: C=C1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Solvent: CO
Solvent: CCOCC
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
A 100 mL round bottom flask was equipped with a magnetic stir bar and charged with a solution of 1.188 g (5.02 mmol) of the product from Step A (the combined product of two experiments) dissolved in 20 mL of methanol was stirred and cooled to 0° C. with an external ice-water bath. A solution of diazomethane in diethyl ether was added slowly until the reaction mixture developed the persistent yellow color and TLC analysis (25% ethyl acetate-hexanes) indicated that esterification was complete. Excess diazomethane was quenched by dropwise addition of acetic acid, and volatiles were removed in vacuo. The residual clear oil was used directly in the next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[Cl:24][C:25]1[CH:26]=[C:27]([NH:32]C2C=CC=CC=2)[CH:28]=[C:29]([Cl:31])[CH:30]=1.CC(C)N=C=NC(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:21]([C:14]2([C:11]3[CH:10]=[CH:9][C:8]([I:7])=[CH:13][CH:12]=3)[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)=[O:23])[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: Clc1cc(Cl)cc(Nc2ccccc2)c1
Reactant: CN1CCC(C(=O)O)(c2ccc(I)cc2)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1CCC(C(=O)Nc2cc(Cl)cc(Cl)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
To a solution of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid pyridine salt (440 mg, 1.04 mmol, see Example 6) and 3,5-dichlorophenylaniline (0.20 g, 1.24 mmol, 1.2 eq.) in anhydrous DMF (5 mL) was added DIC (0.326 mL, 2.08 mmol, 2 eq.) followed by DMAP (0.006 g, 0.052 mmol, 5 mol %). The mixture was stirred at room temperature for 16 h and then it was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was separated, washed with H2O (3×40 mL) and saturated brine (50 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude material was purified by silica gel chromatography by eluting with 10% MeOH/EtOAc to give 175 mg (34%) of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid (3,5-dichloro-phenyl)-amide as a white solid. MS(ESI): 489.1/491.1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[O:14]1>C(O)C.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH2:13][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:15]([OH:22])=[O:14]
Reactant: O=C1OC(c2c(O)c3ccccc3oc2=O)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccccc1Cc1c(O)c2ccccc2oc1=O
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To a solution 4-Hydroxy-3-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-chromen-2-one (60mg) in ethanol was added 10% Pd/C (10 mg) then stirred under a hydrogen balloon for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give 2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid as white solid (50 mg). MS: 295[M-H].
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1(/[C:11](=[CH:14]\[F:15])/[CH2:12]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1(/[C:11](=[CH:14]\[F:15])/[CH2:12][Br:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC/C(=C/F)c1ccccc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: F/C=C(/CBr)c1ccccc1
Reaction time: 3 h
Yield: 176.3 %

Procedure:
A solution of phosphorous tribromide (227 mg) in toluene (2 ml) is slowly added to a solution of (E)-2-phenyl-3-fluoroallyl alcohol (305 mg) in toluene at about -5° so that the temperature does not rise above 0°. The cooling bath is removed and stirring is continued for 3 hours. The reaction mixture is then poured into saturated, aqueous potassium carbonate (20 ml). The mixture is extracted with ether, and the ether solution is washed with water and dried (MgSO4). Evaporation of solvent gives (E)-2-phenyl-3-fluoroallyl bromide (318 mg); colorless oil;
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:3]=1.[B:32]1(B2OC(C)(C)C(C)(C)O2)[O:36]C(C)(C)C(C)(C)[O:33]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+].Cl>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].O>[CH:11]([C:8]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[C:16]=2[CH3:25])[C:6]2[CH:5]=[C:4]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:3]=[C:2]([B:32]([OH:36])[OH:33])[C:10]=2[N:9]=1)([CH3:13])[CH3:12]
Reactant: Cc1c(Cn2c(C(C)C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(Cn2c(C(C)C)nc3c(B(O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 95 °C
Yield: 19 %

Procedure:
A mixture of 4-(4-bromo-2-isopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (1.01 g, 2.035 mmol), bis(pinacolato)diboron (1.550 g, 6.10 mmol), Pd2(dba)3 (0.093 g, 0.102 mmol), X-Phos (0.097 g, 0.203 mmol) and potassium acetate (0.599 g, 6.10 mmol) in 1,4-Dioxane (20 mL) in a 40 mL scintillation vial was heated for 1 hr at 95° C. When cooled, the reaction contents were poured into 1N HCl (3 ml) and H2O (3 mL) mixture, swirled and then extracted with EtOAc, dried over MgSO4 and concentrated in-vacuo. The residue was dissolved in MeOH and the material was purified by reverse phase chromatography eluting with a gradient 30% CH3CN to 60% CH3CN over 10 minutes. The fractions containing clean desired compound were combined and concentrated in vacuo to provide the desired product (178 mg, 0.386 mmol, 18.96% yield) as an off-white solid. Additional fractions, containing less pure desired product—contaminated with des-boronylated product as determined by LC/MS—were combined and the CH3CN was removed in-vacuo leaving the material in H2O. Upon standing a white solid fell out of the resulting solution. The white solid was collected by filtration, dried in a vacuum oven to yield (2-isopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid (296 mg, 0.642 mmol, 31.5% yield). The total yield of desired product was (474 mg, 1.03 mmol, 50.5% yield). MS (ES+) m/e: 461.2, 462.3 [M+H]+; 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.67 (d, J=7.83 Hz, 1H), 7.47-7.60 (m, 1H), 7.27 (s, 1H), 7.10 (d, J=2.27 Hz, 1H), 6.63 (d, J=7.83 Hz, 1H), 5.85 (s, 2H), 3.72-3.85 (m, 4H), 3.57 (s, 1H), 3.10-3.24 (m, 4H), 2.62 (s, 3H), 1.45 (d, J=7.07 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5]([Cl:23])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(F)cc(C(=O)O)cc1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(F)cc(C(=O)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-fluoro-4-methoxybenzoic acid (295 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.15 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (b).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)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.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1OCc1c(F)cccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(F)cccc1Cl
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine (Example I(e), 9.00 g, 27.0 mmol), 4-carboxybenzeneboronic acid (4.41 g, 27.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.99 g, 0.9 mmol), potassium carbonate (13.1 g, 95.0 mmol), dimethylformamide (72 mL) and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81° C. to 98° C. over a period of 4 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and many small impurities. The mixture was cooled to 45° C. The solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 5 mL of water. The filtrate was cooled in an ice bath and acidified to pH 7.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 2.5 g of 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid and a second compound as a brown solid in a ratio of about 1:1 by 1H-NMR. This material was discarded. The filtrate was acidified to pH 6.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 3.6 g (36% yield) of 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid as a brown solid containing a 5-10% impurity by 1H-NMR.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[C:24]([CH2:25]O)=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=[C:21]([C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=2)[N:20]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][C:24]2[C:19]([CH3:18])=[N:20][C:21]([C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:35][CH:36]=3)=[CH:22][C:23]=2[C:27]([F:28])([F:30])[F:29])=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)cc(C(F)(F)F)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc2C)cc1C
Temperature: 0 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To an ice cold solution of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (35 mg, 147 μmol; described in WO 02/092590), [2-methyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol (52 mg, 148 μmol, example 112E]) and tributylphosphine (50 μl, 178 μmol) in tetrahydrofuran (3.5 ml) was added N,N,N′,N′-tetramethyl azodicarboxamide (30 mg, 178 mmol). The cooling bath was removed and stirring continued for 14 h. The mixture was filtered over celite and the solvent removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 63 mg (110 μmol, 75%) of the title compound as colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=O)C.[OH-].[Na+]>CO>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:14]2[C@:15]3([CH2:17][CH2:18][C@H:19]4[C@@H:10]([CH2:9][CH2:8][C:7]5[CH:6]=[C:5]([OH:4])[CH:22]=[CH:21][C:20]=54)[C@@H:11]3[CH2:12][CH:13]=2)[CH3:16])[CH:24]=1
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC=C2c1cccnc1
Temperature: 80 °C
Yield: 67 %

Procedure:
The method followed that described in Example 2, but using 3-acetoxy-17-(3-pyridyl)estra-1,3,5[10],16-tetraene (2.368, 6.3 mmol), methanol (40 ml), aqueous sodium hydroxide (10% w/v, 5 ml), and the mixture was heated at 80° C. for 10 min. Chromatography, on elution with toluene-methanol (8:1 ), afforded the title compound (1.40 g, 67%) which crystallised from toluene, m.p. 256°-258° C.: 1H-NMR(DMSO) inter alia δ 1.01(3H,s, 18-CH3),
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[C:26](=[O:34])[C@@H:25]1[CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[CH3:42][N:43]([C:45]([CH2:47]Cl)=[O:46])[CH3:44].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[CH3:42][N:43]([CH3:44])[C:45]([CH2:47][O:32][C:31](=[O:33])[CH2:30][N:27]1[CH2:28][CH2:29][N:24]([C:22](=[O:23])[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C@@H:25]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:26]1=[O:34])=[O:46]
Reactant: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Reactant: CN(C)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OCC(=O)N(C)C)CCN1C(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 68 %

Procedure:
In 7.39 ml of N,N-dimethylformamide were dissolved 2.0 g of (S)-4-(N-benzyloxycarbonyl-O-methyl-L-tyrosyl)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid, 83,0 mg of sodium iodide and 563 μl of N,N-dimethylaminocarbonylmethyl chloride. To the solution was added 772 μl of triethylamine while stirring at room temperature. The mixture was stirred for 6 hours, to which was then added water. The mixture was shaken with ethyl acetate for extraction. The organic layer was concentrated under reduced pressure. The residue was purified by means of a silica gel chromatography (methylene chloride/methanol =13/1) to give 1.57 g (68.0%) of the title compound as a colorless oily product.