Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[C:12]([O:16][C:17]([NH:19][C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][C:20]1([C:23]([NH:1][N:2]2[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]2[C:8]([O:10][CH3:11])=[O:9])=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: COC(=O)c1c(Cl)ccn1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(Cl)ccn1NC(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.9 %

Procedure:
To a stirred solution of methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (1.50 g, 8.59 mmol) in DCM (50 mL) was added 1-((tert-butoxycarbonyl)amino) cyclopropanecarboxylic acid (2.59 g, 12.9 mmol), HOBT (1.58 g, 10.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.47 g, 12.9 mmol) and DIPEA (3.00 mL, 17.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by CombiFlash ISCO (REDISEP®, SiO2, 12 g, 50% EtOAc/petroleum ether) to give methyl 1-(1-((tert-butoxycarbonyl)amino)cyclopropanecarboxamido)-3-chloro-1H-pyrrole-2-carboxylate (950 mg, 30.9%) as a white solid. LCMS Condition B-16: retention time 0.87 min, [M+1]=358.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.06 (m, 2H), 1.30-1.38 (m, 2H), 1.41 (s, 9H), 3.74 (s, 3H), 6.27 (s, 1H), 6.99 (d, J=2.4 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 11.08 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[C:22]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[C:23]=2[N:24]=[CH:25][N:26]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]([CH2:16][CH3:17])[C:21]2[C:22]3[O:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=4)[C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)c1ccc(-c2noc3c(Cl)ncnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ncnc2c(-c3ccc(S(C)(=O)=O)cc3)noc12
Reaction time: 0.17 h
Yield: 324.6 %

Procedure:
4-Ethylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.49 mmol) was dissolved in anhydrous THF (5 mL) and treated with NaH, 60% oil dispersion (20 mg, 0.49 mmol) at ambient temperature. After stirring for 10 min, 7-chloro-3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidine (0.15 g, 0.49 mmol) was added. The reaction was stirred for 3 h and concentrated under vacuum. The residue was subjected to SiO2 with ethyl acetate and hexane (1/1) to afford Compound D2 (0.82 g, 61%). 1H NMR (400Mz, DMSO-d6) δ 8.49 (s, 1H), 8.41 (d, J=7.1, 2H), 8.34 (d, J=7.1, 2H), 4.10˜3.74 (m, 7H), 3.52 (m, 1H), 3.25 (t, 3H), 1.41˜1.22 (m, 4H). LCMS 516.3[M+H].
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[OH:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:23]3[CH:24]=[CH:25][C:20]([OH:19])=[CH:21][CH:22]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Product: Oc1ccc(C=C2c3ccccc3CCc3c(Cl)cccc32)cc1

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-1-chloro-10,11dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 4-hydroxyphenylboronic acid (47 mg, 0.344 mmol), affords 84 mg (81%) of a mixture of geometric isomers of the title compound as a brown oil. MS (ES) 331 (M−H); HPLC shows 97% purity.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11][O:12][C:13](=[O:18])[CH:14]=[CH:15]OC.CC(C)([O-])C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OC)(C)(C)C>[CH3:11][O:12][C:13](=[O:18])[CH2:14][CH:15]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:9]#[N:10]
Reactant: N#CCc1ccccc1Br
Reactant: COC=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COC(=O)CC=C(C#N)c1ccccc1Br
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of 2-bromo-phenylacetonitrile (6.62 mL, 51.0 mmol) and methyl-3-methoxyacrylate (5.32 mL, 49.5 mmol) in tetrahydrofuran (10 ml) was added to a suspension of sodium tert-butoxide (5.05 g, 51.0 mmol) in tetrahydrofuran (70 mL) at 0° C. over 10 minutes under a stream of nitrogen. The reaction mixture was warmed to room temperature and after 15 minutes diluted with methyl tert-butyl ether (240 mL). To the mixture was added 0.2 N aqueous citric acid until the aqueous layer had a pH of 2 (80 mL). The organic layer was separated and washed with a saturated aqueous solution of sodium chloride (2×80 mL), dried over anhydrous sodium sulfate, filtered through a pad of Celite and silica (4:1) and concentrated in vacuo to provide 4-(2-bromo-phenyl)-4-cyano-but-3-enoic acid methyl ester as a pale yellow oil (13.8 g, 96%). Major isomer 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, 1H, J=7.6, 1.2), 7.57–719 (m, 3H), 6.71 (t, 1H, J=7.1), 3.71 (s, 3H), 3.61 (d, 2H, J=7.1); 13C NMR (100 MHz , CDCl3) δ 169.7, 144.4, 133.7, 131.4, 131.1, 128.3, 122.5, 118.1, 117.3, 115.3, 52.7, 36.6; IR (ATR, neat) 1737, 1434, 1319, 1199, 1171, 1026, 755 cm−1. Minor isomer 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, 1H, J=7.6, 1.0), 7.57–7.19 (m, 3H), 6.9 (t, 1H, J=7.5), 3.64 (s, 3H), 3.06 (d, 2H, J=7.5).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1.[I:12]I.[OH-].[K+]>CN(C)C=O>[I:12][C:3]1[C:4]2[C:9](=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1cccc2c(I)c[nH]c12

Procedure:
To a starting material (indole-7-carbaldehyde), a solution of 24 g of I2 in 125 ml of DMF (dimethylformamide) was added with stirring, and 5.3 g of KOH was added, after which the mixture was allowed to react. The termination of the reaction was confirmed with thin layer chromatography (TLC), after which layer separation was conducted with 354 ml of EA and 354 ml of purified water. The organic layer was washed with aqueous 10% Na2S2O3, dried with Na2SO4 (sodium sulfate), filtered and concentrated at 40, thus obtaining P10 as a concentrated residue.
Reaction SMILES: NC1C([N+:8]([O-:10])=[O:9])=CC=CC=1C.[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13].[N+]([O-])(O)=O>C(OC(=O)C)(=O)C>[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:8]([O-:10])=[O:9])[CH:15]=1)[CH3:13]
Reactant: CCc1ccc(N)cc1
Reactant: Cc1cccc([N+](=O)[O-])c1N
Solvent: CC(=O)OC(C)=O
Solvent: O=[N+]([O-])O
Product: CCc1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 69.32 %

Procedure:
According to the method of synthesis for 2-amino-3-nitrotoluene (Organic Syntheses Collective Volume IV P.42-45) 6 g of 4- ethylaniline was added dropwise to 30 ml of acetic anhydride and then, the mixture was treated dropwise with 6.3 ml (100 m mol) of 70% nitric acid at 12°-13° C. After the mixture was stirred for some time at 10°-12° C., the reaction solution was poured into an ice water. Oily product was separated and heated with 15 ml of concentrated hydrochloric for one hour. The reaction solution was alkaline with dilute aqueous sodium hydroxide and then, partitioned with 100 ml of chloroform. The organic layer was washed with water and dried on anhydrous sodium sulfate. Removal of the solvent in vacuo gave 5.76 g (69.32%) of 4-ethyl-2-nitroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([OH:22])[C:3]=1I.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:3]2[CH:31]=[C:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][C:4]=2[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:6]([F:8])[CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(I)c2O)c1=O
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(-c4ccccc4)oc23)c1=O
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 23.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 1.5 grams (0.003 mole) of 3-(4-chloro-6-fluoro-2-hydroxy-3-iodophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 0.41 gram (0.004 mole) of phenylacetylene, and 0.71 gram (0.007 mole) of triethylamine in 25 mL of DMF was stirred. To this was added 0.09 gram (0.00013 mole) of dichlorobis(triphenylphosphine)pallidium (II) and 0.05 gram (0.00026 mole) of copper (I) iodide. Upon completion of addition, the reaction mixture was heated to 70° C. where it stirred for 2.5 hours. After this time, the reaction mixture was cooled to ambient temperature and then poured into 150 mL of an aqueous 10% ammonium chloride solution. The resulting precipitate was collected by filtration and washed with water. The precipitate was taken up in 120 mL of ethyl acetate. The resulting solution was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a brown solid. The solid was recrystallized using 1:1 chloroform and petroleum ether, yielding 0.31 gram of Compound 280. The mother liquor was concentrated to a residue. The residue was recrystallized using petroleum ether to yield an additional 0.21 gram of Compound 280, m.p. 215-216° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:42])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([S:14]CCC(OCC(CC)CCCC)=O)[C:11]([NH:28][C:29](=O)[C:30]2[CH:35]=[CH:34][C:33]([O:36]CC3CC3)=[CH:32][CH:31]=2)=[CH:10][N:9]=1)(=[O:3])[CH3:2].[O-]CC.[Na+].FC(F)(F)C(O)=O>C1COCC1>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]2[S:14][C:12]3[CH:13]=[C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:42])[N:9]=[CH:10][C:11]=3[N:28]=2)=[CH:31][CH:32]=1
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OC[C@H](C)NC(C)=O)ncc1NC(=O)c1ccc(OCC2CC2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](C)COc1cc2sc(-c3ccc(O)cc3)nc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A mixture of 2-ethylhexyl 3-((2-(((2S)-2-acetamidopropyl)oxy)-5-((4-(cyclopropylmethoxy)benzoyl)amino)pyridin-4-yl)sulfanyl)propanoate (740 mg), sodium ethoxide (20% ethanol solution, 840 mg) and THF (10 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C., trifluoroacetic acid (0.475 mL) was added thereto, the obtained mixture was stirred at 70° C. for 1 hr. The reaction mixture was cooled to 0° C., and the precipitate was collected by filtration, and washed with diisopropyl ether. The obtained residue was dissolved in trifluoroacetic acid (5 mL), and the obtained solution was stirred at 70° C. for 1 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (379 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][C:38]([N:42]([CH2:47][C:48]3[S:49][CH:50]=[CH:51][CH:52]=3)[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:40]=2)[C:35](=[O:53])[N:34]1[CH2:54][C:55](O)=[O:56]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:55](=[O:56])[CH2:54][N:34]1[C:35](=[O:53])[C:36]2[C:41](=[CH:40][CH:39]=[C:38]([N:42]([CH2:47][C:48]3[S:49][CH:50]=[CH:51][CH:52]=3)[S:43]([CH3:46])(=[O:45])=[O:44])[CH:37]=2)[C:33]1=[O:32]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)N(Cc1cccs1)c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)N(Cc1cccs1)c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (200 mg, 0.476 mmol), DMAP (116 mg, 0.952 mmol), and EDC (182 mg, 0.952 mmol) in DCM (10 ml), 2-(1,3-dioxo-5-(N-(thiophen-2-ylmethyl)methylsulfonamido)isoindolin-2-yl)acetic acid (225 mg, 0.571 mmol) was added portion wise, and the resulting mixture was stirred at room temperature for 18 hours. The solvent was evaporated, and the crude was purified by flash chromatography on silica gel (DCM/MeOH 10/0.5). The resulting product was triturated with iPr2O affording after filtration 227 mg of crude desired product. A further purification by flash chromatography on silica gel (DCM/acetone 8/1) was performed to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(1,3-dioxo-5-(N-(thiophen-2-ylmethyl)methylsulfonamido)isoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (155 mg, 0.195 mmol, 40.9% yield, MS/ESI+ 796.02 [MH]+, [αD]=−30.31, c=0.415, DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (s, 2H), 7.96 (d, 1H), 7.91 (d, 1H), 7.86 (dd, 1H), 7.40 (dd, 1H), 7.19 (d, 1H), 7.08 (d, 1H), 6.92-6.99 (m, 1H), 7.08 (t, 1H), 6.86 (d, 1H), 6.84 (d, 1H), 6.00 (dd, 1H), 5.25 (s, 2H), 4.39 (s, 2H), 3.81-4.09 (m, 2H), 3.37 (dd, 1H), 3.21 (s, 3H), 3.21 (dd, 1H), 1.17-1.37 (m, 1H), 0.50-0.69 (m, 2H), 0.21-0.46 (m, 2H)
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:34][N:35]([CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>CN(C=O)C>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:19])[CH3:20])[C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:41])[CH3:34])[CH3:40])[CH:4]=2)[CH:10]=1)=[O:22]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CBr)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CNCCCN(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CN(C)CCCN(C)C)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
6-(3-(Bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was suspended in DMF and N1,N1,N3-trimethylpropane-1,3-diamine (5 equiv.) was added to it. The reaction mixture was stirred at room temperature for overnight. On completion of reaction, solvent was removed under reduced pressure and the residue was purified by prep. HPLC chromatography to provide the desired compound (25% yield). LCMS: 544.30 (M+1)+; HPLC: 99.90% (@ 254 nm) (Rt;4.765); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 10.2-9.6 (m, 1H), 8.92 (bs, 1H), 8.38 (s, 2H), 8.14 (s, 1H), 7.70-7.66 (m, 2H), 5.91 (s, 1H), 5.36-5.35 (m, 1H), 4.41 (d, 2H), 3.39 (4H merged in DMSO peak), 3.08-2.98 (m, 2H+3H), 2.79 (s, 6H), 2.24 (s, 3H), 2.13 (s, 3H), 2.13 (m, 2H), 1.55 (d, 6H, J=4.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:9]=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])[CH3:2].[CH3:27][C@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:29]2[C@@H:28]([CH3:27])[C@@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][C:30]2=[O:39])[CH:9]=[CH:8][C:7]=1[C:22]([F:23])([F:25])[F:24])[CH3:2]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)ccc1C(F)(F)F
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)ccc1C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [5-(4-Bromo-2-bromomethyl-phenoxy)-2-trifluoromethyl-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH2:19])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.C([O:23][C:24](=O)[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:34]Br)C.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1)[N:19]1[CH2:34][C:26]2[C:25](=[C:30]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:28][CH:27]=2)[C:24]1=[O:23]
Reactant: CCOC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CCOc1cc(C(N)CC(=O)OC)ccc1OC(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC(F)F
Yield: 80.8 %

Procedure:
3-(4-Difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester was prepared by the procedure of example 11 from 3-amino-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (7.3 g, 0.025 mol), 2-bromomethyl-6-nitro-benzoic acid ethyl ester (7.6 g, 0.028 mol) and triethyl amine (7 ml, 0.05 mol) in DMF (50 ml) to provide 3-(4-difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester as yellow oil (9.1 g, 81% yield). 1HNMR (CDCl3): δ 1.42 (t, J=7.5 Hz, 3H, OCH2CH3), 3.09 (dd, J=6.8, 15 Hz, 2H, CH2CO), 3.29 (dd, J=6.8, 15 Hz, 1H, CH2CO), 3.65 (s, 3H, OCH3), 4.10 (q, J=7.5 Hz, 2H, OCH2CH3), 4.26 (d, J=17 Hz, 2H, CH2N), 4.46 (d, J=17 Hz, 2H, CH2N), 5.80-5.86 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, OCF2H), 6.92 (dd, J=1.8, 8.2 Hz, 1H, Ar), 7.06 (d, J=1.8 Hz, 1H, Ar), 7.14 (d, J=8.25, 1H, Ar), 7.58-7.76 (m, 3H, Ar).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13].[CH3:25]I.O>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([O:24][CH3:25])([C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSC(F)(F)C(Cn1cncn1)(OC)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 60% sodium hydride (0.16 g, 4.0 mmol) in N,N-dimethylformamide (50 ml), 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazole-1-yl)-2-propanol (1.0 g, 3.0 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. Methyl iodide (0.56 g, 3.9 mmol) was then added dropwise to the reaction mixture under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ether. The ether solution was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to a silica gel column and from the chloroform eluate fraction, 1-[2-(2,4-difluorophenyl)-3-ethylthio-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole (0.81 g, yield: 78%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1F.[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:25]=1[NH2:26])([CH3:23])[CH3:22]>>[CH:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:24]([CH:21]([CH3:23])[CH3:22])[C:25]=1[NH:26][C:3]1[C:4]([NH:26][C:25]2[C:27]([CH:31]([CH3:32])[CH3:33])=[CH:28][CH:29]=[CH:30][C:24]=2[CH:21]([CH3:23])[CH3:22])=[C:5]([F:18])[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]=1[F:1])([CH3:33])[CH3:32]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Product: CC(C)c1cccc(C(C)C)c1Nc1c(F)c2c(c(F)c1Nc1c(C(C)C)cccc1C(C)C)C(=O)c1ccccc1C2=O
Reaction time: 6 h
Yield: 69.7 %

Procedure:
2 g of 1,2,3,4-Tetrafluoroanthraquinone and 25 g of 2,6-diisopropylaniline were charged in a 50 cc, four necked flask and the reaction was carried out at 180° C. for about 6 hours. After completion of reaction, 2,6-diisopropylaniline was distilled out from the reaction solution and a column purification using a column with a silica gel was effected to give rise to 2.96 g of 2,3-bis(2,6-diisopropylanilino)-1,4-difluoroanthraquinone (Dye 24') (yield 69.7 mol %). The physical properties of Dye 24' and analytical values defining the compound are tabulated in Table 24.
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[H-].[Na+]>CN(C=O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:21]=1
Reactant: OCc1ccccc1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(OCc3ccccc3)nc(N)nc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 500 mL of dry round-bottomed flask were added (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (4, 8.0 g, 15.2 mmol) and anhydrous benzyl alcohol (128 mL). To another 250 mL of dry round-bottomed flask were charged NaH (60% in mineral oil, 2.44 g, 60.8 mmol) and anhydrous DMF (40 mL). The suspension was stirred at 0° C. in an ice-water bath. Benzyl alcohol (27 mL) was added drop-wise via a syringe. A solution was slowly formed and it was transferred to the nucleoside suspension quickly under a nitrogen atmosphere at room temperature. The mixture was heated to 50° C. and stirred. The reaction was complete after 3 h and cooled to ambient temperature. It was neutralized by the addition of 4 NHCl to ca. pH=7 (12 mL). The solution was concentrated under reduced pressure (4 mbar, 90° C. bath). The cloudy residue was diluted with dichloromethane (100 mL) and washed with water (3×30 mL), brine (30 mL) and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated under reduced pressure to an oily residue. This was purified by column chromatography (Analogix, 0 to 8% gradient of MeOH in DCM). The product eluted at 4% MeOH in DCM. The product containing fractions were combined, concentrated under reduced pressure and dried (50° C., 0.2 mmHg, 17 h) to a white foam solid (4.57 g, 11.7 mmol, 77.2%).