Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1.O>CN(C)C(=O)C>[CH3:22][C:18]1[CH:17]=[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(Oc2ccc(N)cc2)ccn1
Temperature: 9 °C
Yield: 63.9 %

Procedure:
4-aminophenol (44.9 g, 410 mmol) was added to the 1 L 3-neck flask and dissolved with N,N-dimethylacetamide (600 mL). The stirred mixture was then cooled to 9° C. and potassium t-butoxide (46.18 g, 410 mmol) was added portionwise; the solution turned green and solidified before potassium t-butoxide addition was completed. Stirring was reestablished and a solution containing the 4-chloro-2-picoline (50 g, 390 mmol) in N,N-dimethylacetamide (400 mL) was slowly added and the mixture was heated at 90° C. for 17 h. The mixture was then allowed to cool to 45° C., filtered and concentrated to near dryness in vacuo to leave brown residue. The residue was slowly added to vigorously stirred water (1 L) and the suspension was stirred for 1 hr. The solids were then collected by suction filtration and washed with small amount of isopropanol, ether and dried to afford {4-[(2-Methylpyridin-4-yl) oxy] phenyl} amine (49.9 g, 64%) as light tan solid. 1H NMR (DMSO-d6) δ 8.21 (d, 1H), 6.78 (d, 2H), 6.57-6.63 (m, 4H), 5.10 (s, 2H), 2.35 (s, 3H); MS ES 201 (M+H)+, calcd 201, RT=1.04 min.
Reaction SMILES: COC[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH:11]=[O:12].Cl.O1CCCC1>O>[OH:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH:11]=[O:12]
Reactant: COCOCc1nc(-c2ccccc2)oc1C=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1oc(-c2ccccc2)nc1CO
Yield: 70.3 %

Procedure:
A mixture of 4-methoxymethoxymethyl-2-phenyl-1,3-oxazole-5-carbaldehyde (4.50 g), 1N hydrochloric acid (50 mL) and tetrahydrofuran (100 mL) was heated under reflux for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:1, v/v) to give 4-hydroxymethyl-2-phenyl-1,3-oxazole-5-carbaldehyde as pale-yellow crystals (2.6 g, yield 70%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 134-135° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[N:6]1[C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26])=[O:4].[OH-].[Na+]>CO.O>[Cl:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)([N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=4)[CH2:13][CH:5]3[C:3]([OH:4])=[O:2])[C:17](=[O:26])[NH:18]2)=[CH:23][CH:22]=1
Reactant: COC(=O)C1Cc2ccc(OC)cc2N1C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)N(C1(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc31)C(C(=O)O)C2
Yield: 103.4 %

Procedure:
A mixture of rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid methyl ester (250 mg, 0.5 mmol), NaOH (40 mg, 1.0 mmol) in methanol (4 mL) and water (2 mL) was heated to reflux for 3 hr. Then the mixture was concentrated in vacuo to remove methanol. Water (10 mL) was added to the residue. The resulting mixture was acidified with acetic acid, extracted with ethyl acetate. The organic layer was washed with water, dried with Na2SO4, concentrated in vacuo to give 250 mg rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid. MS: [M−H]−=481
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]([CH3:29])[CH2:23][C:24](OCC)=[O:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>C(O)(C)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]([CH3:29])[CH2:23][C:24](=[O:25])[NH:33][N:32]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: NN
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: CC1CC(=O)NN=C1c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 90 °C
Yield: 53.1 %

Procedure:
A mixture of crude 4-[4-(3-ethoxycarbonyl-2-methyl-propionyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (9 g, 21.4 mmol) and hydrazine monohydrate (3.58 ml, 71.6 mmol) in isopropanol (70 mL) was heated at 90° C. for 2 days and concentrated at reduced pressure to give a crude residue. The crude reside was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated to give a crude product. The crude product was purified by ISCO (120 g silica gel column) chromatography using 2 to 5% methanol in methylene chloride to obtain 4-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (4.4 g, 53%), MS m/z 388 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Na+:16]>O>[Na+:16].[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([O-:14])(=[O:12])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)[O-]
Reaction time: 16 h
Yield: 84 %

Procedure:
To a boiling solution of 100 g of 5-nitro-o-toluenesulfonic acid in 110 ml of water is added a solution of 53.6 g of sodium chloride in 150 ml of boiling water. The reaction mixture solidifies and is heated to boiling with the addition of sufficient water to provide solution. Then some of the water is boiled off and the mixture is allowed to stand for 16 hours. The solid formed is collected and dried to yield 92.5 g of 5-nitro-o-toluenesulfonic acid sodium salt.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:24]([O:26]CC)=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:17]([C:24]([OH:26])=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cccc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(C)cccc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg (1.1 mMol) of 2-n-propyl-4-methyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]benzimidazole are dissolved in 10 ml of ethanol and mixed with 10 ml of 1N sodium hydroxide solution. The mixture is stirred at ambient temperature for 30 minutes. Then the mixture is concentrated by evaporation and taken up in water. The solution is acidified by the addition of glacial acetic acid. The precipitate formed is suction filtered, washed with water until neutral and dried. The crude product is taken up in methylene chloride and purified over a silica gel column (particle size 0.063-0.02 mm), using as eluant a mixture of methylene chloride and methanol (19: 1). The uniform fractions are concentrated by evaporation in vacuo and the residue is triturated with hexane/ether and suction filtered.
Reaction SMILES: [BH4-].[Na+].C(O)C.[N+:6]([CH:9]=[CH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)([O-:8])=[O:7].C(O)(=O)C>O1CCOCC1>[N+:6]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)([O-:8])=[O:7]
Reactant: COc1cc(C=C[N+](=O)[O-])cc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc(CC[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C
Yield: 53.5 %

Procedure:
To a well stirred suspension of sodium borohydride (5 g) in a mixture of dioxane (100 ml) and absolute ethanol (30 ml) was added dropwise a solution of 1-(2-nitroethenyl)-3,5-dimethoxybenzene (12.6 g) in dioxane (100 ml) over a 100 ml) over a 1 hour period. Following addition the mixture was stirred for an additional 45 minutes period. To the resulting suspension were added ice-water (120 ml) and 50% aqueous acetic acid (10 ml). Agitation was maintained for 1 hour and the clear solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate/water, the organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of solvents afforded the crude title compound (10.8 g). Trap to trap distillation under high vacuum (0.05 Millibars) at 180° C. yielded 1-(2-nitroethyl)-3,5-dimethoxybenzene as a colorless oil (6.8 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.[F:17][C:18]([F:33])([F:32])[S:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+]([O-])=O)=[CH:25][CH:24]=1)(=[O:21])=[O:20].O>CN(C=O)C>[F:17][C:18]([F:33])([F:32])[S:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]2[C:25](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:24]=1[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)(=[O:21])=[O:20]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Oc1ccc2ccccc2c1C1NCCc2ccccc21)C(F)(F)F
Reaction time: 3 h

Procedure:
Powdered K2CO3 (2.30 g, 17 mmol) was added to a solution of 1 (2.30 g, 8.4 mmol) and 4-nitrophenyl trifluoromethanesulfonate (2.28 g, 8.4 mmol) in DMF (70 mL). After 3 hours, the mixture was poured into water (300 mL) and extracted with CH2Cl2 (250 mL, 3 times). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to provide crude 2 as an oil which was purified by column chromatography on silica gel (5:1 hexanes/EtOAc). The fractions containing the product (Rf=0.50, 5:1 hexanes/EtOAc) were collected and concentrated under reduced pressure to yield the title product 2 (3.15 g, 92% yield) as an oil. 1H NMR (CDCl3, 400 MHz, ppm): δ 8.18 (d, J=8.8 Hz, 1H), 7.92-7.83 (m, 2H), 7.46-7.11 (m, 5H), 6.92 (t, J=7.2 Hz, 1H), 6.51 (d, J=7.6 Hz, 1H), 5.97 (s, 1H), 3.54-3.28 (m, 3H), 2.94 (d, J=14.8, 1H), 2.31 (s, 1H); 13C NMR (CDCl3, 75 MHz, ppm): δ 146.03, 137.81, 134.57, 133.68, 131.97, 131.48, 131.02, 129.22, 128.45, 128.07, 126.71, 126.59, 126.32, 126.11, 120.75, 118.98, 116.51, 55.86, 44.96, 29.67.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:38])[CH:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][C:46]1[CH:47]=[C:48](Br)[CH:49]=[CH:50][CH:51]=1>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:50]2[CH:49]=[CH:48][CH:47]=[C:46]([O:45][CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44][O:39]3)[CH:51]=2)([OH:38])[CH:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCCOCCOCc2ccccc2)cc1)C(CCOC1CCCCO1)c1ccccc1
Reactant: Brc1cccc(OC2CCCCO2)c1
Product: OC(c1ccc(OCCOCCOCc2ccccc2)cc1)(c1cccc(OC2CCCCO2)c1)C(CCOC1CCCCO1)c1ccccc1

Procedure:
is prepared by using the method described in the example 4e starting from 1-{4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}-2-phenyl-4-(tetrahydropyran-2-yloxy)butan-1-one (10 g, 19.2 mmol) and 3-(tetrahydropyran-2-yloxy)phenyl bromide (9.8 g, 38 mmol). The product is purified by flash chromatography with toluene-methanol (50:1) as eluent. Yield 5.7 g, 43%.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1>[Pd].[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=[Pt]
Agent: [Pd]
Product: c1ccc2c(C3CCNCC3)c[nH]c2c1

Procedure:
For example, a 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole of formula (3) may be hydrogenated over a catalyst, such as palladium on carbon or platinum oxide, to give a 3-(piperidin-4-yl)-1H-indole of formula (4). Such hydrogenations are generally carried out in a solvent and a variety of solvents are suitable, for example methanol, ethanol, or isopropanol, tetrahydrofuran, or mixed solvents, such as tetrahydrofuran and ethyl acetate. The hydrogenation may be performed at an initial hydrogen pressure of 20-180 psi (137-1241 kPa), preferably from 50-60 psi (345-413 kPa). The reaction is typically carried out at temperature of about 0° C. to about 60° C., preferably at temperatures of about 40° C. to 60° C. The reaction typically requires 1 hour to 3 days. The product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, precipitation, chromatography, and recrystallization.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][S:10]C(=O)C2C=CC=CC=2)[C:5]([CH:19]=[CH2:20])=[CH:4][N:3]=1.[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][SH:10])[C:5]([CH:19]=[CH2:20])=[CH:4][N:3]=1
Reactant: C=Cc1cnc(C)c(O)c1CSC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1cnc(C)c(O)c1CS

Procedure:
A mixture of 1 g. of 2-methyl-3-hydroxy-4-benzoylthiomethyl-5-vinylpyridine, 10 ml. of tetrahydrofuran, and 10 ml. of 2.5 N aqueous sodium hydroxide was aged at room temperature overnight. The solution was acidified to about pH 6 with hydrochloric acid and then adjusted to pH 7.5 with solid sodium bicarbonate. The mixture was extracted with 3 × 100 ml. of ethyl acetate: isopropanol (9:1 v/v). The extract was dried over magnesium sulfate and concentrated to give 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]=[C:32]=[O:34])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N=C=O)cc2)COC1(C)C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 253.7 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (600 mg, example 14 (b)) in dichloromethane (10 ml) were added sequentially triethylamine (0.52 ml) and triphosgene (206 mg) and the mixture was heated at 50° C. for 18 h. The mixture was then concentrated in vacuo and to the residue was added diethyl ether. After stirring for 10 min at room temperature the resulting crystals were removed by filtration. The filtrate was concentrated in vacuo to give (S)-4-[2-(4-isocyanato-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (610 mg, 94%) as a yellow oil which was used immediately in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9])=[O:17]
Reactant: Nc1ccc(O)cc1F
Reactant: O=C(Cl)CCCCCBr
Product: O=C(CCCCCBr)Nc1ccc(O)cc1F
Yield: 98 %

Procedure:
The 10.9 g (0.09 mol) of 4-amino-3-fluorophenol from above was reacted with 8.96 g (0.04 mol) of 6-bromo-hexanoyl chloride according to the procedure of Example 3, part a. 6-Bromo-N-(2-fluoro-4-hydroxyphenyl) hexanamide was obtained in 98% yield after crystallization from acetonitrile, mp 66°-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]1=[O:20].Cl.[F:32][C:33]([F:41])([F:40])[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:21][C:6]1[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:37]3[CH2:38][CH2:39][CH:34]([C:33]([F:41])([F:40])[F:32])[CH2:35][CH2:36]3)=[O:30])=[CH:24][CH:23]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:10]1=[O:20]
Reactant: FC(F)(F)C1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCOCC4)C3=O)c(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCOCC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.4 %

Procedure:
Treat a solution of 3′,5′-dichloro-4′-[(R)-2-oxo-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.25 g, 0.56 mmol), 4-(trifluoromethyl)piperidine hydrochloride (0.13 g, 0.67 mmol), 1-hydroxybenzotriazole (0.23 g, 0.67 mmol), and 4-methylmorpholine (0.18 mL, 1.67 mmol) in dichloromethane (10 mL) with N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.13 g, 0.67 mmol) and stir at room temperature for 6 hr. Quench the reaction with 1N hydrochloric acid and extract with ethyl acetate. Wash the organic layer with brine, dry over magnesium sulfate, and filter. Purify the crude material by silica gel column chromatography using hexanes:ethyl acetate to afford 0.23 g (72%) of desired product: MS (m/z): 583 (M+).
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl>[CH3:19][Si:20]([C:23]#[C:24][N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1)([CH3:22])[CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(I)cnc-2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc2c(O)n(C#C[Si](C)(C)C)cnc-2n1

Procedure:
A mixture of 2.0 g of 3-iodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine, 1.2 g. of trimethylsilylacetylene, 0.1 g of palladium chloride, 0.23 g of triphenylphosphine, 0.06 g of cuprous iodide, and 2.6 g of triethylamine in 100 mL of acetonitrile is heated in a sealed tube for 1.5 hours at 50° C. and then at reflux for 3 hours. The solvent is removed under reduced pressure and the residue triturated with 1:1 ethyl acetate:hexanes and filtered. The solid thus collected is dissolved in methylene chloride and this solution is passed through a pad of silica gel eluting with 1% methanol on methylene chloride. The eluate is concentrated to yield 3-trimethylsilylethynyl-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)CCC>>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]4)[N:9]=3)=[CH:4][CH:3]=2)[CH:31]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: CC1(C)CC(Nc2nccc(-c3ccc(-c4cccnc4)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Step D of Example 172, starting from [4-(4-bromophenyl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 3-tributylstannanyl-pyridine. Yield: 45 mg (24%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24]C(=O)C)[CH2:21][O:20]C(C)(C)[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([SH:36])[CH:33]=[CH:34][CH:35]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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.C(Cl)(Cl)Cl.[Pd].[Pd].O>[NH2:24][C:16]([CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=3)=[CH:3][C:4]=2[F:28])=[CH:13][CH:12]=1)([CH2:21][OH:20])[CH2:17][OH:18]
Reactant: Fc1cccc(S)c1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NC(CO)(CO)CCc1ccc(-c2ccc(Sc3cccc(F)c3)cc2F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (225 mg) of Reference Example 10, 3-fluorobenzenethiol (64 mg), diisopropylethylamine (129 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (14.9 mg) in 1,4-dioxane (2 mL) was heated under reflux for 6 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (4 mL). Concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated, aqueous potassium carbonate solution was added to the residue, and the precipitated crystals were collected by filtration. The crude crystals were purified by preparative HPLC to give the title compound (47 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=2)[C:12]#[N:13])[CH:5]=[N:6][CH:7]=1.O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.[Fe]>[NH2:17][C:15]1[CH:14]=[C:11]([CH:10]=[C:9]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cc(Oc2cncc(Cl)c2)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(N)cc(Oc2cncc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
Iron powder (6.3 g, 112 mmol) was added to a mixture of 3-(5-chloro-pyridin-3-yloxy)-5-nitro-benzonitrile (3.1 g, 11.2 mol) in acetic acid (100 mL) and the reaction was stirred at RT for 6 h. Water (200 mL) was added and the mixture was neutralized to pH 7 with saturated Na2CO3 solution and was extracted with EtOAc (3×150 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified on silica gel to give 3-amino-5-(5-chloropyridin-3-yloxy)benzonitrile (1.92 g, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=1.6 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 7.80 (t, J=2.4 Hz, 1H), 6.77 (s, 1H), 6.72 (d, J=1.6 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 5.92 (s, 2H); MS (ESI) m/z: 246.2 [M+H]+.