Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[C:34]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:28]5[CH:35]=[N:36][CH:37]=[CH:38][C:27]4=5)[N:21]=3)[CH:9]=2)=[CH:4][CH:3]=1.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.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.C(O)C>[C:2]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[C:34]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:28]5[CH:35]=[N:36][CH:37]=[CH:38][C:27]4=5)[N:21]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(-n4c5ccccc5c5cnccc54)n3)c2)cc1
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: CCO
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(-c3cc(-c4ccccn4)nc(-c4cccc(-n5c6ccccc6c6cnccc65)n4)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 58.3 %

Procedure:
To 5.1 g of the resulting 4′-(4-bromophenyl)-6-(5H-pyrido[4,3-b]indol-5-yl)-[2,2′;6′,2″]terpyridine were added 1.1 g of phenylboronic acid, 0.5 g of tetrakis(triphenylphosphine)palladium, 23 mL of a 2 M aqueous potassium carbonate solution, 72 mL of toluene, and 18 mL of ethanol, followed by heating with reflux while stirring for 5.5 hours. After cooling to room temperature, a precipitate was collected by filtration. To the precipitate, 200 mL of chloroform was added and insoluble matter was removed by filtration. The filtrate was concentrated under a reduced pressure to obtain a concentrate. The concentrate was dissolved in chloroform and subjected to adsorptive purification with NH silica gel. Thereafter, the filtrate was concentrated under a reduced pressure to obtain a crude product. The crude product was washed with methanol to obtain 2.9 g (yield, 57%) of 4′-(biphenyl-4-yl)-6-(5H-pyrido[4,3-b]indol-5-yl)-[2,2′;6′,2″]terpyridine (Compound 133) as a white powder.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].N1C2C=C[CH:12]=[C:11]([OH:16])[C:10]=2[CH:9]=[CH:8]C=1.C([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])C>C1COCC1>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:11]1[CH:10]=[C:9]2[C:20](=[CH:21][CH:12]=1)[N:19]=[CH:22][CH:23]=[CH:8]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cccc2ncccc12
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: O=P(Cl)(Cl)Oc1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (0.385 mL, 4.14 mmol.) and quinolin-5-ol (Aldrich, 600 mg, 4.14 mmol) were stirred in anhydrous THF (25 mL). Anhydrous triethylamine was added (0.576 mL, 4.14 mmol) at −78° C. and the solution was allowed to warm to room temperature. The reaction mixture was monitored by 31PNMR for completion of phosphorus oxychloride (about 30 min) and this mixture was used directly.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]([CH2:18][C:19]2[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([F:38])[CH:26]=3)=[CH:21][CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O1CCCC1.O>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([F:38])[CH:26]=3)=[CH:39][CH:40]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3CCc3ccccc3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(CCc2ccccc2)n(Cc2ccc(COc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
The oil obtained in Example 138 was dissolved in ethanol (3 mL) and tetrahydrofuran (3 mL), and 1 N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and neutralized with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:4) to give the title compound (91 mg, yield 18%, 2 steps) as colorless crystals. 1H NMR (CDCl3) δ: 1.32 (9H, s), 2.62 (2H, t, J=7.6 Hz), 2.68-2.76 (2H, m), 2.77-2.85 (2H, m), 2.89 (2H, t, J=7.6 Hz), 4.96 (2H, s), 5.22 (2H, s), 5.97 (1H, s), 6.59-6.66 (2H, m), 6.98-7.12 (5H, m), 7.16-7.34 (5H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].IC.[C:12](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(Br)c1O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(C)cccc1Br
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 2-bromo-6-methylphenol (0.520 g, 2.78 mmol) in 15 ML of acetone was added iodomethane (0.338 mL, 5.42 mmol) and potassium carbonate (0.768 g, 5.56 mmol). The reaction was heated to reflux and stirred overnight. Ammonium chloride (sat.) was added and the mixture was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford 456 mg of 1-bromo-2-methoxy-3-methylbenzene as a clear oil. To a solution of 1-bromo-2-methoxy-3-methylbenzene (0.123 g, 0.61 mmol) in 3 mL of THF at −70° C. was added n-butyllithium (1.6 M in hexanes, 0.46 mL, 0.73 mmol) dropwise. The reaction stirred at −70° C. for 30 minutes and was then allowed to warm up to −20° C. Ammonium chloride (sat.) was added and the mixture was extracted with ethyl acetate, dried over sodium sulfate and filter to give 96 mg crude material. The crude material was purified by column chromatography (3/1 hexanes/ethyl acetate) to afford 40 mg of 2-methoxy-3-methylphenylboronic acid as a white solid. MS(ES+): 167.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:25])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([CH:23]=[O:24])=[CH:12][CH:11]=3)[O:4][N:3]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[OH:24][CH2:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:25])[C:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[C:16]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(C=O)ccc3[nH]c2=O)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(CO)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
A mixture of 3-(3-methyl-isoxazol-5-yl)-2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carboxaldehyde (a) (33 mg, 0.11 mmol), sodium borohydride (NaBH4) (4 mg, 0.1 mmol) in DCM (1 mL) and methanol (1 mL) was stirred at room temperature for 1.5 h, and then concentrated. To the residue was added DCM (10 mL) and water (1 mL). The organic layer was separated from the aqueous layer, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give 6-hydroxymethyl-3-(3-methylisoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (c) (33 mg, 90%). 1H NMR (300 MHz, CD3OD) δ 7.65-7.58 (m, 1H), 7.49-7.38 (m, 4H), 7.30-7.20 (m, 3H), 6.30 (s, 1H), 4.51 (s, 2H), 2.17 (s, 3H). MS: 333.2 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:4].CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33]>CN(C)C=O>[OH:34][C@@H:32]([CH3:33])[CH2:31][C@@H:30]([CH3:29])[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.68 g of 55% sodium hydride was mixed with 10 ml of dimethylformamide. A solution of 2.50g of 4-(4'-cyanophenyl)phenol in 5 ml of dimethylformamide was added dropwise thereto under ice-cooling. Then the obtained mixture was stirred at room temperature for one hour. A solution of 3.7 g of monotosylate of (R,R)-2,4-pentanediol in 5 ml of dimethylformamide was added dropwise thereto and the obtained mixture was stirred at 80° C. for two hours. After cooling, the reaction mixture was poured into 100 ml of ice-water and extracted with diethyl ether. After washing with water, drying and desolvating, the obtained residue was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (3:2) as a developing solvent. Thus 1.8 g of (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile was obtained.
Reaction SMILES: CN[C@@H](C1C=CC=CC=1)CN1CCCCC1.[CH2:17]([Li])[CH2:18][CH2:19][CH3:20].[CH3:22][CH:23]1[CH2:28][C:27](=[O:29])[CH:26]=[CH:25][CH2:24]1>CCOCC.[Cu]I>[CH2:17]([C@H:25]1[CH2:24][C@H:23]([CH3:22])[CH2:28][C:27](=[O:29])[CH2:26]1)[CH2:18][CH2:19][CH3:20].[CH3:22][C@H:23]1[CH2:28][C:27](=[O:29])[CH:26]=[CH:25][CH2:24]1
Reactant: [Li]CCCC
Reactant: CC1CC=CC(=O)C1
Agent: [Cu]I
Agent: CN[C@H](CN1CCCCC1)c1ccccc1
Solvent: CCOCC
Product: CCCC[C@@H]1CC(=O)C[C@@H](C)C1
Product: C[C@@H]1CC=CC(=O)C1
Temperature: -65 °C
Reaction time: 0.08 h
Yield: 79 %
Yield: 54 %

Procedure:
(S)-N-methyl-1-phenyl-2-(1-piperidinyl)ethanamine (345.0 mg, 1.58 mmol) was dissolved in ether (12 mL) and n-butyllithium (2.5M in hexanes, 0.63 mL, 1.575 mmol) was added to the solution at -65° C. The solution was stirred for 5 min at -65° C., warmed to 0° C. and stirred for 10 min at 0° C. To a second flask was added CuI (251 mg, 1.32 mmol) and 10 mL of diethyl ether. This solution was cooled to -40° C. and treated with n-butyl lithium (0.53 mL, 1.323 mmol). The solution in the first flask was cooled to -35° C. and added via canula to the solution of n-BuCu in the second flask. The resulting solution was stirred for 15 min at -35° C., for 10 min at -30° C., and cooled to -78° C. After 30 min, 5-methyl-2-cyclohexenone (290 mg, 2.64 mmol) was added slowly at -78° C. The reaction mixture was quenched after 1 hr by adding 4N NH4Cl (15 mL) at -78° C. and extracted with ether (20 mL). The extract was washed with 1N HCl (15 mL), dried (Na2SO4) and concentrated. The oily residue was purified by column chromatography on silica gel (ether/pentane=1/8 followed by ether/pentane=1/5) to afford (S,S)-3-n-butyl-5-methylcyclohexanone (176 mg, 79% chemical yield, 39% ee, [α]D =5.5 (c=1.00, benzene)) and (R)-5-methyl-2-cyclohexenone (78 mg, 54% chemical yield, 28% ee, [α]D =22.8 (c=4.00, acetone)).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([C@@H](C3C=CC=CC=3)C)[CH2:14]2)=[CH:9][CH:8]=1)=[O:5].C([O-])=O.[NH4+].O1CCCC1.CO>[Pd].O>[CH3:1][N:2]([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:5]
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CN(C)C)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1ccc([C@H]2CNCCO2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of N2,N2-dimethyl-N1-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)glycinamide (0.91 g, 2.5 mmol) and ammonium formate (0.79 g, 12.5 mmol) in mixture of tetrahydrofuran (20 ml), methanol (40 ml) and water (7 ml) was added 10% palladium on carbon (wet, 300 mg) and stirred at 95° C. for 3 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give N2,N2-dimethyl-N1-(4-((2S)-morpholin-2-yl)phenyl)glycinamide (0.63 g, 96%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([CH3:22])=[C:20]([CH3:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][C:19]=1[CH3:22]
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2ccc(C)c(C)c2n1
Product: Cc1ccc2nn(CCC#Cc3ccccn3)nc2c1C
Yield: 60.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (65 mg, 0.41 mmol) and 2-but-3-ynyl-4,5-dimethyl-2H-benzo[d][1,2,3]triazole (75 mg, 0.38 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 65 mg (0.23 mmol, 63%) of 4,5-dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C.O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: c1cc2c(cn1)NCCO2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CCOc3ccncc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (100 mg, 0.73 mmol) and (4-methoxy-phenyl)-acetyl chloride (163 mg, 0.88 mmol) were dissolved in dichloromethane. Triethylamine (0.21 ml, 1.46 mmol) was added thereto and then stirred at room temperature for 2 hours. After completion of the reaction by adding water, the reaction mixture was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=9:1. The fractions containing the product were collected and evaporated to obtain the target compound, i.e., 1-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-2-(4-methoxy-phenyl)-ethanone, as yellow liquid (198 mg, 95%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:14][N:15]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][N:15]([CH:19]1[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH2:23][CH2:24]1)[C:16](=[O:18])[CH3:17]
Reactant: Fc1ccc(OCCCCBr)cc1
Reactant: CC(=O)N(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N(C)C1CCN(CCCCOc2ccc(F)cc2)CC1

Procedure:
A mixture containing 0.1 mole of the compound obtained in stage A, 0.1 mole of the compound obtained in stage C and 0.1 mole of potassium carbonate in 250 cm3 of acetone is heated to reflux.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH2:19]([N:21]([CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:28][CH3:29])[CH2:19][CH3:20])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CCN(CC)CCCCNC
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: CCN(CC)CCCCN(C)c1c2ccc(Cl)cc2nc2ccc(OC)cc12

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and N1,N1-diethyl-N4-methylbutane-1,4-diamine, the title compound was obtained; MS (Found M+1=400).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Zn+2:22].[OH-]>C(O)C>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn+2:22].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [OH-]
Agent: [Zn+2]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
1,422 parts of stearic acid is added to 10,000 parts of ethanol, and mixed together at 75° C. 507 parts of zinc hydroxide is gradually added to the mixture, and is mixed for one hour after completion of the addition. The resultant mixture is cooled to 20° C., and the reaction product is filtered to remove reaction residue and ethanol. The obtained reaction solid product is dried at 150° C. for 3 hours using a heating vacuum drier. The dried product is taken out from the drier, and is allowed to stand for cooling, as a result of which a solid product of zinc stearate is obtained. After the obtained solid product is milled using a jet mill, the milled product is classified using an ELBOW-JET CLASSIFIER (available from Matsubo Corporation), whereby powdery zinc stearate particles 1 having a volume average particle diameter of 9.6 μm are obtained. The classification cut points when the particles are classified using Elbow-jet classifier are shown in Table 1. The particle size distribution (the ratio of particles having a particle diameter of 25 μm or more, and the ratio of particles having a particle diameter of 40 μm or more) of the obtained zinc stearate particles 1 is shown in Table 1.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[N:15]([CH3:19])[C:16](=[O:18])[CH3:17].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:19][N:15]([C:14]1[CH:13]=[C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=[CH:21][CH:20]=1)[C:16](=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(=O)N(C)c1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cccc(Nc2ncccc2[N+](=O)[O-])c1
Yield: 24.6 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.96 g) and 3′-amino-N-methylacetanilide (2.03 g) in toluene (20 ml) was refluxed for 7 hours. The mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[3-(N-methylacetamido)phenylamino]-3-nitropyridine (872 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[O:65]([CH2:69][CH2:70]O)[CH2:66][CH2:67][OH:68]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:70][CH2:69][O:65][CH2:66][CH2:67][OH:68])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: OCCOCCO
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)OCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150 mg, 0.243 mmol) in methylene chloride (8 mL) was added triethylamine (72.0 mg, 0.10 mL, 0.717 mmol) followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (Aldrich, 92 mg, 0.365 mmol). The mixture was stirred at room temperature for 10 min before 2,2′-oxydiethanol (Aldrich, 154 mg, 0.14 mL, 1.45 mmol) was added. This reaction mixture was stirred at room temperature overnight. It was then diluted with methylene chloride and washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (eluting with hexane/ethyl acetate, 80/20 to 10/90) to give chiral 2-(2-hydroxyethoxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (40.8 mg, 23% yield). MS (ES+) m/z calcd. for C35H38Cl2F2N3O6 [(M+H)+]: 704. found: 704.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl[Sn](Cl)(Cl)Cl.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]2[O:22][CH2:21]2)=[CH:18][CH:17]=1.[CH2:25](OCC)C>>[C:7]1([CH3:25])[CH:8]=[CH:9][C:4]([C@H:1]2[CH2:2][O:22][C@H:20]([C:19]3[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=3)[CH2:21][O:3]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2CO2)cc1
Reactant: CCOCC
Reactant: CC(=O)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: Cc1ccc([C@@H]2CO[C@@H](c3ccc(C)cc3)CO2)cc1
Reaction time: 1 h

Procedure:
One cools 10 g. acetophenone to 2° and mixes, while stirring, below 20° with 10.4 g. SnCl4. With stirring, one adds dropwise thereto at 20°, within 1 hour, 13.4 g. p-methylstyrene oxide, warms the mixture to 28°, works up as usual with diethyl ether/10% aqueous sodium hydroxide solution and obtains trans-2,5-di-p-tolyl-1,4-dioxane, m.p. 200°, C 110°, Rf 0.45 (silica gel/toluene).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1.[CH3:26]I>>[CH3:26][N:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:4]=2)=[CH:8][CH:9]=1)[NH:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16]
Reactant: CI
Reactant: CC(C)OC(=O)NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Product: CC(C)OC(=O)NN(C)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
The product (0.4 g) of Step 4 of Example 1 was heated in methyl iodide (5 mL) at reflux for 1 day and then concentrated under reduced pressure to give a red oil (0.5 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([Br:13])[CH:9]=[CH:10][CH:11]=2)[C:6](=O)[CH2:5]1)(=O)C.BrBr.[CH2:17]([NH2:20])[CH2:18][NH2:19].C(N(CC)CC)C>C(Cl)Cl.CO>[Br:13][C:8]1[C:7]2[C:6]3[N:20]=[CH:17][CH:18]=[N:19][C:5]=3[NH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)N1CC(=O)c2c(Br)cccc21
Reactant: NCCN
Agent: BrBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Brc1cccc2[nH]c3nccnc3c12
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
1-Acetyl-4-bromo-1,2-dihydro-indol-3-one (460 mg, 1.81 mmol) was dissolved in CH2Cl2 (8 mL). Bromine (111 μL, 2.2 mmol) was added slowly, and the reaction stirred for 20 min and then was concentrated in vacuo. The residue was dissolved in THF (8 mL). Ethylenediamine (244 μL, 3.6 mmol) was added, and the reaction stirred for 16 h at r.t. Triethylamine (2 mL) and MeOH (4 mL) were added, and the reaction stirred while left open to air for 24 h. The solution was concentrated in vacuo and purified by silica gel chromatography (8% MeOH/CH2Cl2) to give 248 mg (55%) of the title compound as a red solid. MS (ES) [m+H] calc'd for C10H6BrN3, 248, 250; found 248, 250.