Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[OH-:12].[Cs+]>C(OCC)(=O)C.CCCCCCC>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:12]
Reactant: [OH-]
Reactant: Brc1ccc2ccccc2c1
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Oc1ccc2ccccc2c1
Yield: 88 %

Procedure:
Following general operating mode B, 2-bromonaphthalene (207 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a white solid with a yield of 88% (eluent: ethyl acetat/heptane 20:80).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2]N.Cl.[C:8](=[NH:23])([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[O:16]([C:8]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[N:23][NH:2][C:1]([O:5][CH3:6])=[O:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)NN
Agent: Cl
Solvent: O
Product: COC(=O)NN=C(Oc1ccccc1)Oc1ccccc1
Reaction time: 4 h

Procedure:
4.31 g (46.9 mmol) of methyl carbazate were initially charged in water (40 ml) and admixed with 4.75 g (46.9 mmol) of conc. hydrochloric acid (36% strength). 10.0 g (46.9 mmol) of diphenyl imidocarbonate (preparation of diphenyl imidocarbonate similar to the method of Heydayatullah, M. Bull Soc. Chim Fr. 1967, 416) were added a little at a time to this solution, at 7° C. After 4 hours of stirring with ice-bath cooling, the mixture was extracted with ethyl acetate (4×100 ml). The combined organic phases were dried over magnesium sulphate and, after filtration, concentrated under reduced pressure. The residue was dried under reduced pressure at 25° C. This gave 7.62 g of crude product containing phenol and methyl N′-diphenoxymethylenehydrazinecarboxylate in a ratio of 10:1. The yield of methyl N′-diphenoxymethylenehydrazinecarboxylate was 693 mg (5%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[CH2:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#CCOc1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 80.4 %

Procedure:
A heterogeneous mixture of 6.0 g of (4-hydroxy-3-nitro-phenoxy)-acetonitrile, 50 ml N,N-dimethylformamide, 12.8 g of potassium carbonate, and 5.8 g of benzyl bromide was heated with stirring at 70° C. for 22 hours. The mixture was cooled to room temperature, poured into ethyl acetate, washed with water, washed with 1N sodium hydroxide, again with water, dried (MgSO4), evaporated, and obtained 7.06 g of (4-benzyloxy-3-nitro-phenoxy)-acetonitrile as a tan solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:9][NH2:10])=O)[S:5][CH:6]=1.[CH3:11][N:12]([CH:14]=O)C.[CH3:16][C:17](N(C)C)=O.C1(N)CC1.CC(O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[N:12]([CH:14]3[CH2:17][CH2:16]3)[CH:11]=[N:10][N:9]=2)[S:5][CH:6]=1
Reactant: CC(=O)N(C)C
Reactant: CN(C)C=O
Reactant: NNC(=O)c1nc(Br)cs1
Agent: NC1CC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Brc1csc(-c2nncn2C2CC2)n1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
4-bromothiazole-2-carbohydrazide (620 mg, 2.8 mmol) and toluene (9 mL) were added to a sealable vial, DMF·DMA (920 μL, 6.9 mmol) was added and the reaction was stirred for 5 minutes. Cyclopropyl amine (770 μL, 11 mmol), and AcOH (160 μL, 2.8 mmol) were added and the reaction was heated in a microwave reactor at 150° C. for 30 minutes. The reaction was concentrated and purified by flash chromatography (1→7% MeOH in CH2Cl2) to afford 740 mg of 4-bromo-2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazole (contaminated with DMF·DMA, but used directly in next step).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21](CO)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.ClCC(C1C=C2C(=CC=1)[CH2:51][N:50]([C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH2:49]2)=O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=[O:17])[C:18]2[CH:19]=[C:20]3[C:21](=[CH:22][CH:23]=2)[CH2:51][N:50]([C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH2:49]3)[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C2
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: CS(C)=O
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C2

Procedure:
4-Benzyloxy-1-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-2,3-dihydro-1H-isoindol-5-yl]-ethyl}-1H-pyridin-2-one is prepared following preparation 15b from 1.50 g (7.45 mmol) 4-benzyloxy-1H-pyridin-2-one and 2.28 g (7.83 mmol) 1-[5-(2-chloro-acetyl)-1,3-dihydro-isoindol-2-yl]-2,2,2-trifluoro-ethanone (see preparation 23) in DMSO as solvent.
Reaction SMILES: [F:1][CH:2]1C(=O)[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:18][O:19][CH:20](OC)[O:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:18][O:19][C:20]1([O:21][CH3:22])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3][CH:2]1[F:1]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC1(OC)CCN(c2ccc([N+](=O)[O-])cc2)CC1F
Temperature: 45 °C
Yield: 91 %

Procedure:
The mixture of 4-(3-fluoro-4-oxo-piperidin-1-yl)-nitrobenzene (51 mmol), trimethylorthoformate (103 mmol), p-toluene-sulphonic acid monohydrate (51 mmol) in methanol (100 ml) was heated at 45° C. for 24 hours. Solvent was removed and residual mass was taken into ethyl acetate and saturated sodium bicarbonate solution mixture. The organic layer was dried and removal of the solvent afforded title compound as a solid in 91% yield.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:16]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C@H:15]([CH3:24])[O:14][C@@H:11](OC)[C@@H:10]1[F:25])(C(C)(C)C)(C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27].S(=O)(=O)(O)O.[C:38]([OH:41])(=[O:40])[CH3:39]>>[C:38]([O:41][CH:11]1[O:14][C@@H:15]([CH3:24])[C@H:16]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[C@@H:9]([O:8][C:26](=[O:28])[CH3:27])[C@H:10]1[F:25])(=[O:40])[CH3:39]
Reactant: CC(=O)O
Reactant: CO[C@@H]1O[C@@H](C)[C@H](NC(=O)C(F)(F)F)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1F
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OC1O[C@@H](C)[C@H](NC(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@H]1F

Procedure:
Compound (7) is treated with a mixture of acetic anhydride, acetic acid and sulfuric acid at room temperature, thereby to effect simultaneously the removal of the 3-O-tert-butyldimethylsilyl group, demethylation and di-O-acetylation reactions, affording 1,3-di-O-acetyl-2,4,6-trideoxy-2-fluoro-4-(trifluoroacetylamino)-L-mannopyranose [Compound (8)] having the following formula ##STR15## The Compound (8) is a mixture or α-anomer [Compound (8-a)] and β-anomer [Compound (8-b)]. When Compound (8) is subjected to a silica gel column chromatography as developed with dichloromethane, the α-anomer [Compound (8-a)] and the β-anomer [Compound (8-b)] can be isolated from each other.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O=O.[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Product: CC(=O)OCc1ccccc1

Procedure:
A stainless steel autoclave equipped with a stirrer was charged with 3 parts of toluene, 15 parts of glacial acetic acid, and 0.42 part of palladium acetate [Pd(OAc)2 ], and the toluene was reacted for 4 hours at 90°C. with the introduction of oxygen at a partial pressure of 60 kg/cm2G. A small amount of benzyl acetate and 0.0687 part of dimethyl diphenyl were obtained, and the precipitation of palladium metal was observed. The dimethyl diphenyl so obtained was in an amount of only 20.2 mol % based on the palladium salt fed. The rate of dimerization was slow, and the palladium salt was precipitated as metal. This shows that the palladium catalyst was not regenerated by oxidation, and did not act catalytically.
Reaction SMILES: Cl.[NH:2]1[CH2:10][CH2:9][CH2:8][C@H:3]1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1>C(Cl)Cl>[Cl:27][C:25]1[CH:24]=[C:23]([S:28]([N:2]2[CH2:10][CH2:9][CH2:8][C@H:3]2[C:4]([O:6][CH3:7])=[O:5])(=[O:29])=[O:30])[CH:22]=[C:21]([Cl:20])[CH:26]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (L)-proline, methyl ester hydrochloride (838 mg, 5.06 mmol) in CH2Cl2 (25 mL) at 0° C. were added DIPEA (2.64 mL, 15.2 mmol) and a solution of 3,5-dichlorobenzenesulfonyl chloride (1.49 g, 6.07 mmol) in CH2Cl2 (5 mL). The cooling bath was removed, and the mixture was stirred overnight at rt. It was then diluted with CH2Cl2, washed with 1N hydrochloric acid, saturated NaHCO3, saturated brine solution, dried over anhydrous Na2SO4, and rotoevaporated. The product was purified by flash column chromatography on silica gel eluted with 10% acetone in hexanes to yield N-(3,5-dichlorobenzenesulfonyl)-(L)-proline, methyl ester; yield 1.49 g.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:5][CH:4]=1.[NH:28]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:33][CH:30]1[CH2:31][CH2:32][N:28]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=4[N:18]([CH3:27])[S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])=[N:5][CH:4]=2)[CH2:29]1
Reactant: OC1CCNC1
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CCl)s3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CN4CCC(O)C4)s3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.13 g) and 3-pyrrolidinol (60 mg) in N,N-dimethylformamide (8 ml) was added potassium carbonate (110 mg) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-7:3), and the obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (85 mg, yield 59%) as pale-yellow prism crystals. melting point 190-191° C. MS: 489 (MH+).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]3[CH:16]([C:17]([OH:19])=O)[CH2:15][CH2:14][N:13]3[CH3:20])[CH:9]=[C:8]([CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:46]1[C:51]2[CH:52]=[CH:53][C:54]([CH2:56][CH2:57][NH2:58])=[CH:55][C:50]=2[O:49][CH2:48][CH2:47]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[O:46]1[C:51]2[CH:52]=[CH:53][C:54]([CH2:56][CH2:57][NH:58][C:17]([CH:16]3[CH2:15][CH2:14][N:13]([CH3:20])[CH:12]3[C:10]3[CH:9]=[C:8]([CH3:21])[N:7]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:11]=3)=[O:19])=[CH:55][C:50]=2[O:49][CH2:48][CH2:47]1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1cc(C2C(C(=O)O)CCN2C)nc(-n2ccnc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2C(C(=O)NCCc3ccc4c(c3)OCCO4)CCN2C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
2-(2-Imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-methyl-pyrrolidine-3-carboxylic acid (27.0 mg, 0.094 mmol) was dissolved in DMF (1 mL). Next, the HBTU (54.0 mg, 0.141 mmol) was added. The reaction was stirred at room temperature for 30 minutes prior to addition of 2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamine (17.0 mg, 0.094 mmol) and the triethylamine (50 μL). The reaction was stirred at rt for 12 h then heated to 60° C. for 16 h. After this period, the reaction mixture was transferred to a separatory funnel with ethyl acetate (20 mL). The organic layer was washed with saturated NaHCO3 (aq) (30 mL) and H2O (30 mL), respectively. The aqueous layers were back extracted with ethyl acetate and all of the organic portions were combined, dried over Na2SO4 and concentrated under vacuum. The material was purified by Flash Chromatography (10 g, 0-10% methanol/DCM gradient) to afford 3.3 mg of 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-methyl-pyrrolidine-3-carboxylic acid [2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-amide. Product isolated as a mixture of diasteromers; [M+H]+ 449.84.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:19][O-:20].[Na+].[CH3:22][OH:23]>>[CH3:19][O:20][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:23][CH3:22])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COCc1ccc(C(=O)c2ccc(COC)cc2)cc1

Procedure:
A solution of 0.46M NaOMe/MeOH (30 mL) containing 4,4'-bis-bromomethylbenzophenone (2.1 g, 5.7 mmol) was refluxed 42 hours. After cooling, the reaction was partitioned between EtOAc and 5% aq. KHSO4. The organic layer was washed with brine, dried over Na2 SO4 and concentrated. The resulting residue was chromatographed on silica gel using 1:4 EtOAc/hexane to elute 1.11 g (70%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH:19][C@H:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[CH3:18])[CH:7]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cc(Cl)cc(Cl)n1)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 42 h
Yield: 45.8 %

Procedure:
7.2 g of 2,4,6-trichloropyridine and 2.74 g of (S)-(−)-1-(4-fluorophenyl)ethylamine were dissolved in 25 ml of 1-butanol, and 13.7 ml of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 120° C. for 42 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 2.57 g of the objective compound as yellow oil.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][C:8]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:9][CH:10]=3)[C:5]([CH3:29])([CH3:28])[C:4]=2[CH:3]=1.[CH2:30](O)[CH3:31].C(=O)([O-])[O-].[K+].[K+].[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:39]1([C:45]2[CH:31]=[CH:30][CH:29]=[CH:5][CH:28]=2)[CH:44]=[CH:43][C:42]([N:12]([C:11]2[CH:10]=[CH:9][C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:6]=2)[C:25]2[CH:26]=[CH:27][C:22]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:13]5[C:4](=[CH:3][C:2]([C:15]6[CH:2]=[CH:3][CH:4]=[CH:13][CH:14]=6)=[CH:15][CH:14]=5)[C:5]([CH3:29])([CH3:28])[C:6]=4[CH:7]=3)=[CH:23][CH:24]=2)=[CH:41][CH:40]=1
Reactant: Cc1ccccc1
Reactant: CC1(C)c2cc(Br)ccc2N(c2ccccc2)c2ccc(-c3ccccc3)cc21
Reactant: CCO
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+]
Product: CC1(C)c2cc(-c3ccccc3)ccc2N(c2ccccc2)c2ccc(-c3ccc(N(c4ccc(-c5ccccc5)cc4)c4ccc(-c5ccccc5)cc4)cc3)cc21
Temperature: 72 °C
Reaction time: 4.5 h
Yield: 64 %

Procedure:
2-Bromo-9,9-dimethyl-7,10-diphenylacridan (2.9 g), bis(biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl)phenyl]amine (4.0 g), toluene (44 ml), ethanol (11 ml), and a 2M potassium carbonate aqueous solution (8.4 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.23 g) and stirred at 72° C. for 4.5 hours. The mixture was allowed to cool to a room temperature, and an organic layer was collected by a liquid separating operation. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to obtain a red crude product. The crude product was dissolved by adding toluene (75 ml), purified by adsorption using silica gel (5.2 g), and purified by recrystallization using toluene/methanol to obtain a whitish powder of bis(biphenyl-4-yl)-[4-(9,9-dimethyl-7,10-diphenylacridan-2-yl)phenyl]amine (3.19 g; yield 64%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][N:27](C3CCCCO3)[CH:28]=2)=[CH:12][C:11]=1[F:35])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:35][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1cc(F)c(O[C@H]2CCCC[C@@H]2c2cn[nH]c2)cc1F
Yield: 125.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-(N-pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide (302 mg, 0.451 mmol) prepared in Example 33c, triethylsilane (0.40 mL), trifluoroacetic acid (4.0 mL), dichloromethane (4.0 mL) and methanol (4.0 mL), to yield the title compound (246 mg, 55%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:15][C:16]1[CH:21]=[C:20]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:19]=[CH:18][N:17]=1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: Clc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(O)c1cccc2cc(Oc3ccnc(Cl)c3)ccc12

Procedure:
6-hydroxy-1-napthoic acid (3.2 g, 17 mmol) was reacted with 2,4-dichloropyridine (2.5 g, 17 mmol) and Cs2CO3 (16.6 g, 51 mmol) under the conditions of Example 421 step a to furnish the title compound as a brown solid. MS (ESI, pos. ion) m/z: 300.4 (M+1). Mass Calc'd for C16H10ClNO3: 299.708.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14](C)[CH3:15])[CH2:9][CH2:8][CH2:7]2.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl.O.C(=O)([O-])[O-].[K+].[K+]>[F:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14]([CH3:15])[C:21](=[O:22])[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:8][CH2:7]2
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCN1CCCc2cc([N+](=O)[O-])cc(F)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(CCN1CCCc2cc([N+](=O)[O-])cc(F)c21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a stirred solution of 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethanamine (500 mg, 1.871 mmol) in Dichloromethane (8 ml) at room temperature was added phenyl chloroformate (0.352 ml, 2.81 mmol) via a syringe dropwise, slowly. The resulting solution was stirred overnight at room temperature. The reaction mixture was then diluted with water and potassium carbonate (dilute) and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 0-50% ethyl acetate in hexanes, giving the desired phenyl 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (576 mg, 1.543 mmol, 82% yield). 1H NMR (DMSO-d6) δ 7.85-7.76 (m, 1H); 7.75-7.70 (m, 1H); 7.34 (t, J=7 Hz, 1H); 7.22-7.16 (m, 1H); 6.99-6.95 (m, 2H); 3.77-3.65 (m, 3H); 3.60-3.54 (m, 1H); 3.43 (t, J=5.5 Hz, 2H); 3.02, 2.93 (2s, 3H); 2.75 (t, J=5.8, 2H); 1.90-1.81 (m, 2H). ESI-MS (m/z, %): 374 (MH+, 100).
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[CH2:15]([O:22][C:23]([NH:25][C@:26]([CH:33]([CH2:35][CH3:36])[CH3:34])([CH2:30][CH:31]=[CH2:32])[C:27](O)=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:15]([O:22][C:23]([NH:25][C@:26]([CH:33]([CH2:35][CH3:36])[CH3:34])([CH2:30][CH:31]=[CH2:32])[C:27]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CC[C@@](NC(=O)OCc1ccccc1)(C(=O)O)C(C)CC
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@](NC(=O)OCc1ccccc1)(C(=O)NCC(=O)OC)C(C)CC
Reaction time: 16 h
Yield: 99.4 %

Procedure:
Step L (1): NMM (9.8 mL, 89.1 mmol) was added to a mixture of methyl 2-aminoacetate hydrochloride (3.95 g, 31.4 mmol), (2S)-2-(benzyloxycarbonyl-amino)-2-sec-butylpent-4-enoic acid (8.0 g, 26.2 mmol) [prepared as described in WO 2004/013098] HATU (12 g, 31.4 mmol in DCM (300 mL) at room temperature. The mixture was stirred for 16 h. Poured the reaction mixture into 150 mL H2O. Extracted with DCM (3×250 mL). Washed combined organic extracts with brine, dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give methyl 2-((2S)-2-(benzyloxycarbonylamino)-2-sec-butylpent-4-enamido)acetate 9.8 g (99% yield) as a yellow-oily residue: ESI (M+H)+=377.43. 1H NMR (300 MHz, CDCl3) δ ppm 0.93-1.08 (m, 6H) 1.49-1.56 (m, 3H) 2.74-2.89 (m, 2H) 3.68 (s, 3H) 4.10-3.96 (m, 2H) 5.00-5.22 (m, 4H) 5.85-5.94 (m, 1H) 7.33-7.40 (m, 5H).