Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:28][CH:29]=2)[CH:8]=[CH:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cccc(-c2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To a solution of ethyl-3-iodobenzoate (2.5 g, 1 equiv) in ethylene glycol dimethyl ether (20 mL) are added 2 M sodium carbonate solution (40 mL), 4-benzyloxybenzene boronic acid (2.5 g, 1.2 equiv) and tetrakistriphenylphosphine palladium(0) (1.05 g, 0.1 equiv). The reaction mixture is heated to reflux for 2 h. The reaction mixture is allowed to cool to room temperature and is diluted with 300 mL 50% sodium bicarbonate solution. The product is extracted three times with methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography eluting with ethyl acetate/hexanes (2:98 to 8:92) to give the desired product (2.3 g, 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([NH:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CCCC1c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 5-chloro-2-(2-phenylpyrrolidin-1-yl)nicotinic acid (D98) (150 mg, 0.5 mmol), methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (114 mg, 0.5 mmol) and N,N-Diisopropylethylamine (194 mg, 1.5 mmol) in dimethylformamide (10 ml) was stirred 1 h at room temperature, then benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (312 mg, 0.6 mmol) was added. The mixture was stirred at room temperature overnight, then poured into ice-water (20 ml) and extracted with ethyl acetate (2×20 ml). The organic solution was washed with brine (40 ml), dried over Na2SO4 and concentrated to obtain a residue which was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate (4:1). Collected fractions after solvent evaporation afforded the title compound (D142) (189 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:13])[CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:13][C:4]1[CH:3]=[C:2]([Br:1])[C:11]([CH3:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:16])[CH3:15]
Reactant: COC(=O)c1cc(C)c(Br)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(Br)cc1OC(C)=O
Reaction time: 1 h

Procedure:
To a solution of methyl 4-bromo-2-hydroxy-5-methylbenzoate (may be prepared as described in Description 14; 1.2 g, 4.90 mmol) in pyridine (10 ml) was added acetic anhydride (2.08 ml, 22.03 mmol). The solution was stirred for one hour, then the solvent was removed in vacuo and purified by column chromatography (SiO2, 6:1 cyclohexane/ethyl acetate) to yield the title compound as a white solid. 1.28 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:7][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:9]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: COc1ccc(Br)cc1C=O
Product: CCOc1ccc(Cc2cc(Br)ccc2OC)cc1

Procedure:
Preparation was performed in a similar manner as in Preparation Example 3 using 5-bromo-2-methoxybenzaldehyde and 4-bromophenetole.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[N:32]1([CH2:29][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([C:8]4[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=4[CH3:13])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:31])[CH:15]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=2)[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: C1CNCCNC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCNCC3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using product of Example 75 step i) and [1,4]diazepane.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:21][CH3:22])[C:9]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:24][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:11]2[N:10]([CH2:21][CH3:22])[C:9](=[O:23])[CH:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2ccc(OC)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2cc(Br)c(OC)cc21
Yield: 77.1 %

Procedure:
A solution of 3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3.38 g, 10.58 mmol) and N-bromosuccinimide (2.072 g, 11.64 mmol) in acetic acid (2.5 mL) and chloroform (25 mL) was heated at reflux for 2 hrs. The reaction mixture was diluted with chloroform (25 mL), washed with saturated aqueous solution of NaHCO3 and water, dried over Na2SO4, filtered and evaporated to dryness. Purification of the crude product by flash chromatography on silica gel column eluted with EtOAc/hexane (3:7) provided the desired compound (3.25 g, 77%) as white powder.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH3:13])[CH:9]=[C:10]([OH:12])[CH:11]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:16][NH:17][C:18](=[O:19])[O:12][C:10]1[CH:9]=[C:8]([CH3:13])[CH:7]=[C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])[CH:11]=1
Reactant: CN=C=O
Reactant: COC(COc1cc(C)cc(O)c1)OC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Oc1cc(C)cc(OCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2,2-Dimethoxyethoxy)-5-hydroxytoluene (2.50 grams), benzene (50 ml) and triethylamine (4 drops) were charged into a glass reaction vessel equipped with a mechanical stirrer. Methyl isocyanate (1.0 ml) was added to the vessel, and the resulting mixture was stirred at room temperature for a period of about 2 hours. The mixture was then allowed to stand at ambient temperature over the weekend. After this time the reaction mixture was stripped of benzene, leaving a viscous liquid residue. This residue was distilled under vacuum to yield the desired product O-[3-(2,2-dimethoxyethoxy)-5-methylphenyl] N-methylcarbamate as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([OH:27])=O)=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>>[C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:27])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1
Product: CS(=O)(=O)NC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared by coupling 2m and methylsulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (57%); ESI m/z: 428 (M−H−, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[C:4]([CH3:10])[N:3]=1.Cl[C:12]1C(CCl)=CC=C(Cl)[N:13]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:13][CH3:12])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: ClCc1ccc(Cl)nc1Cl
Reactant: Cc1cc(CCl)cc(C)n1
Product: CNCc1cc(C)nc(C)c1

Procedure:
The reaction according to Reference Example 11 was carried out using (2,6-dimethyl-4-pyridyl)methyl chloride in lieu of 2,6-dichloro-3-pyridylmethyl chloride to give the title compound as oil.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][C:3]=1C.[Na+:13].[C:14]1(=O)NC(=O)C2=CC=CC=C12>>[C:4]1([CH3:14])[C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:6][CH:7]=[CH:2][CH:3]=1.[Na+:13]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1C
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)[O-]

Procedure:
The procedure of Example 2 was repeated using 30.6 grams Naxonate ST, a commercially available sodium toluene sulfonate from Ruetgers-Naese (0.15 mol sodium toluene sulfonate with a content of 93%) instead of phthalimide to yield a product in which toluene sulfonic acid methyl 6,13-dihydro quinacridone having a molecular weight of 500 was detected by MALDI.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH:6]=1)=[CH2:2].C(O)C>O>[CH:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH:6]=1)=[CH2:2]
Reactant: C=C[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(=O)CC=C3[C@H]12
Solvent: O
Solvent: CCO
Product: C=C[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Reaction time: 0.83 h
Yield: 97.4 %

Procedure:
—Sodium borohydride (1.47 g) was added to a solution of (7α)-7-ethenyl-3-methoxyestra-1,3,5(10),14-tetraen-17-one (1.50 g) obtained in the previous step in a mixture of tetrahydrofliran (27.8 ml), ethanol (27.8 ml) and water (4.55 ml). The reaction mixture was stirred for 50 min. and then poured into water. The product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated, to afford (7α,17β)-7-ethenyl-3-methoxyestra-1,3,5(10),14-tetraen-17-ol (1.47 g). The product was used in the following step without fiLrther purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:12]=1[C:13]([OH:15])=[O:14]>>[Cl:23][C:16]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Product: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Reaction time: 2 h

Procedure:
To 74 g (0.60 mol) of p-anisidine, stirred mechanically at 75 degrees, was added 35.4 g (0.15 mol) of 2,6-dichloro-3-nitrobenzoic acid [Lehmstedt and Schrader, Berichte 70B, 1526 (1937)]in small portions over one-half hour. The mixture was heated at 75 degrees for 24 hours, with stirring during the first two hours. The reaction mixture was cooled, the solid mass shattered, and triturated in a mechanical blender with 300 ml of 2.4N hydrochloric acid. The solid was collected, washed with 3N hydrochloric acid, stirred in 400 ml of 0.5N sodium carbonate, and filtered. The filtrate, diluted with 250 ml of water, was gradually acidified with 4N hydrochloric acid. The precipitate was collected, washed with water, and dried to 38.5 g (79%) of the red title compound, mp 205-213 degrees. A purified sample, from toluene, melts at 212-215 degrees.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15]CCC.IC>C1COCC1>[CH3:15][CH: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
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: CI
Product: CC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of fluorene (10.0 g, 60.0 mmol) in 100 mL of THF was added n-BuLi (66.6 mmol) at -78° C. This solution was then added to a chilled solution of iodomethane (15.04 g, 90.6 mmol) in 60 mL of THF. The temperature was kept at about -20° C. to maintain a clear solution. The mixture was allowed to warm to room temperature and then quenched with saturated aqueous NH4Cl and evaporated to a residue which was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with MgSO4, filtered and evaporated to a solid. This solid was dissolved with hot pentane, stirred with decolorizing charcoal, filtered through a celite pad, and evaporated to get 10.0 g(92%) of 9-methyl fluorene was a white solid, mp 42°-43° C. FT-IR (KBr): 3065, 3039, 3016, 2962, 2926, 2864, 1478, 1445, 1309, 1023, 792 cm-1. NMR (300 MHz, CHCl3) δ 1.60-1.62(d, 3H, J=7.5 Hz), 3.93-3.97 (q, 1H, J=7.5 Hz), 7.32-7.38 (m, 4H) , 7.35-7.36 (d, 2H, J=8.0 Hz), 7.81-7.83(d, 2H, J=8.0 Hz).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O:14][B:15](OC(C)C)[O:16]C(C)C)(C)C.C([Li])CCC>C1COCC1>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([B:15]([OH:16])[OH:14])[C:7]1=2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2ccsc12
Temperature: -70 °C
Reaction time: 1 h
Yield: 75218.4 %

Procedure:
Combine 7-bromobenzo[b]thiophene (300 g, 1.41 mmol) and tri-isopropylborate (403.6 g, 2.15 mmol) in anhydrous THF (4 L) in a 12-L Morton flask fitted with a mechanical stirrer and cool under nitrogen in a dry-ice/acetone bath to −70° C. Add n-butyl lithium (1.6 M in hexane, 714 g, 1.68 mmol) dropwise at such a rate as to keep the internal temperature less than −67.5° C. After the addition is complete allow the reaction mixture to stir at this temperature for 1 h. Remove the cooling bath and slowly add 4 L of water, which causes the temperature to rise to about −5° C. Next, add concentrated HCl (75 mL) until the pH of the solution is about pH=2. Allow the slurry to stir for 1 h. Add sufficient 5 N aqueous NaOH to adjust the pH of the mixture to about pH=12 and transfer to a 22-L bottom-drop funnel Separate and save the lower aqueous layer. Dilute the upper organic layer with 4 L of methyl-tert-butyl ether and extract with 1 L of 5 N aqueous NaOH. Separate the aqueous layer, combine with the previous aqueous extract and place back in the separatory funnel Wash the aqueous layer with additional methyl-tert-butyl ether (4 L). Again, separate the aqueous layer and transfer to a 12-L, 3-neck round bottom flask fitted with a mechanical stirrer. Cool the solution to +5° C. with an ice-water bath. Add concentrated HCl slowly until the pH of the solution is about pH=2. Stir the mixture for 30 minutes and then filter off the resulting solid. Rinse the solid on the funnel twice with 2 L of water and allow to air-dry for 30 min. Place the solid in a vacuum oven at 50° C. and dry under vacuum overnight. The dried solid is slurried with 2 L of n-heptane for 30 min to remove the yellow color. Again filter off the solid, air-dry for 30 min and then vacuum-dry at 40° C. overnight to give the title compound (188.8 g, 75%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=8 Hz, 1H), 7.49-7.57 (m, 2H), 7.30-7.39 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33])#[N:26]>>[Cl:24][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:32]([F:33])=[C:27]([C:25]#[N:26])[CH:28]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:23])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Product: CC(c1ccc(-c2ccc(F)c(C#N)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with 3-cyano-4-fluorophenylboronic acid to give the title compound as a colorless foam. MS (m/e, ISP neg. ion)=463.2 [M−H+].
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:39])[NH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:26][C@H:25]2[CH3:38])=[O:23])=CC=1)([O-])=O.Cl.[CH3:41][O:42][C:43](=[O:47])[CH2:44][CH2:45][NH2:46].C(N(CC)CC)C>CO>[CH3:41][O:42][C:43](=[O:47])[CH2:44][CH2:45][NH:46][C:11]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:26][C@H:25]1[CH3:38])=[O:23])=[O:39]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CCN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)Nc1cc(Cl)ccc1OCC(=O)N1CCN(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-carbamic acid 4-nitro-phenyl ester (0.10 g, 0.18 mmol) in methanol was added β-alanine methyl ester hydrochloride (0.038 g, 0.27 mmol) and triethylamine (0.038 mL, 0.27 mmol). The reaction was stirred at ambient temperature overnight. The reaction was concentrated and purified via chromatography on silica gel to give the title compound (0.075 g).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH:12]=[CH:13][CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:16](=[O:17])[NH:7][CH:5]=[N:6][C:21]2=[O:22])[CH:12]=[CH:13][CH:14]=1
Reactant: N=CN
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: CO
Product: O=C1N=CNC(=O)C1c1cccc(Cl)c1
Reaction time: 2.5 h

Procedure:
5.97 g of formamidine acetate were added to a solution of 3.96 g of Na and 100 ml of absolute methanol. After cooling, the solution to 10° C. 15.51 g of diethyl (m-chlorophenyl)malonate were added in portions. After 2.5 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in water and the solution was adjusted to pH 5.0 with glacial acetic acid. The resulting precipitate was removed by filtration under suction, washed with water, ethanol and ether and dried at 70° C. under reduced pressure. There was obtained 5-(m-chlorophenyl)-4,6(1H,5H)-pyrimidinedione which was used directly in the next step.
Reaction SMILES: OS(O)(=O)=O.N([O-])=[O:7].[Na+].N[C@@H:11]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:12]([OH:14])=[O:13].[Na+].[Cl-]>O>[OH:7][C@@H:11]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:12]([OH:14])=[O:13]
Reactant: O=N[O-]
Reactant: N[C@@H](CC1CC1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](O)CC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A 1 L, 3-neck flask was equipped with two dropping funnels, one containing 21.3 mL of 2.0 N H2SO4 and the other containing 21.3 mL of 2.0 N NaNO2. A mixture of 5.00 g (38.7 mmol) of 2-(S)-amino-3-cyclopropyl propanoic acid in 28 mL of H2O at 0° C. was treated with a sufficient amount of the acid solution to dissolve the solids. The remaining H2SO4 solution and the NaNO2 solution were added maintaing the internal temperature at less than 5° C. The resulting mixture was stirred cold for 3 h, then warmed to rt and stirred for 20 h. The reaction mixture was saturated with NaCl and extracted with 4×100 mL of EtOAc. The extracts were dried over MgSO4 and concentrated to afford 4.30 g (85%) of the title compound: 1H NMR (300 MHz): δ 0.13-0.18 (m, 2H), 0.48-0.54 (m, 2H), 0.89 (m, 1H), 1.67-1.76 (m, 2H), 4.37 (dd, J=6.4, 4.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[C:10]([C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[CH:9]=[CH:8][C:7]=1[OH:17])([CH3:5])[CH2:3][CH3:4].[H-].[Na+].Cl[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>O1CCCC1>[N+:27]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[O:17][C:7]1[CH:8]=[CH:9][C:10]([C:12]([CH3:15])([CH3:16])[CH2:13][CH3:14])=[CH:11][C:6]=1[C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])([O-:29])=[O:28]
Reactant: CCC(C)(C)c1ccc(O)c(C(C)(C)CC)c1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(Oc2ccncc2[N+](=O)[O-])c(C(C)(C)CC)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of 2,4-bis(1,1-dimethylpropyl)phenol (9.23 g, 0.039 mol) in dry tetrahydrofuran (30 mL) was stirred at room temperature under nitrogen atmosphere. Sodium hydride (1.14 g of 80% dispersion, 0.04 mol) in dry tetrahydrofuran (10 mL) was added and the mixture stirred for 30 minutes to give a clear, green solution. 4-Chloro-3-nitropyridine (5.0 g, 0.032 mol) was added and the mixture heated to 50° C. for 4 hours. The mixture was cooled and submitted to aqueous, acidic work-up. The crude product was purified by chromatogaphy on silica gel with dichloromethane eluent to give the product 3-nitro-4-(2,4-bis(1,1-dimethylpropyl)phenoxy)-pyridine in 65% yield. Analyses by proton NMR and mass spectroscopy were consistent with the proposed structure.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 3-(4-tert-butyldimethylsilyloxy-phenyl)-1-propanol (P. A. Grieco and C. J. Markworth, Tet. Lett., 1999, 40: 665) (2.86 g, 10.73 mmol) in dry dichloromethane (25 ml), was cooled to 0-5° C. and treated with triethylamine (2.4 ml, 17.0 mmol). Then methanesulfonyl chloride (1.08 ml, 14 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at 0-5° C. for 1 hour, then quenched with sat. sodium bicarbonate, diluted with ethyl acetate (300 mL), washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was filtered aon a silica gel pad (toluene/ethyl acetate 95:5) to give the title material (3.68 g, 100%) as a clear oil.