Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1.C1(C)C=CC(S([N:30]=[N+:31]=[N-])(=O)=O)=CC=1.Cl>CCCCCC.CCOCC.CCOCC.CCCCCC>[F:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[CH:14][CH:15]=3)[C:10](=[N+:30]=[N-:31])[C:9]=2[CH:8]=1
Reactant: Fc1ccc2c(c1)Cc1cc(F)ccc1-2
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [N-]=[N+]=C1c2cc(F)ccc2-c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
Under nitrogen, n-butyllithium (20 mL of a 2.5M solution in hexane, 1 eq) was added dropwise to a stirred, -20 ° C. solution of commercially available (Alfred Bader Library of Rare Chemicals) 2,7-difluorofluorene (24) (10 g, 49.5 mmoL) [which may also be prepared according to U.S. Pat. No. 4,436,745] in 250 mL of anhydrous ether. After 10 min., this mixture was transferred via a cannula using nitrogen pressure into a 0° C. solution of p-toluenesulfonylazide [prepared by the method described in Doering, et al. J. Am. Chem. Soc. (1953) 75, 5955] in 200 mL of anhydrous ether over 20 min. The reaction was allowed to warm to room temperature over 1.5 h and was then acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine (3×100 mL), dried (MgSO4), and concentrated to provide 10 g of crude material which was leached with ether/hexane to provide 4 g (37%) of product (25): mp 148°-150 ° C.; IR (KBr) 2070, 1600, 1575, 845 cm-1 ; 1H NMR (CDCl3, 200 MHz) 7.77 (ddd, 2H, J=0.5, 5.0, 8.7Hz), 7.14 (ddd, 2H, J=0.5, 2.5, 8.5Hz), 7.0 (ddd, 2H, J=2.3, 8.5, 9.3Hz); MS m/z 228 (M+), 200 (base peak). Anal. Calcd. for C13H6N2F2 : C, 68.42;H, 2.65; N, 12.28. Found: C, 68.25;H, 2.78; N, 12.50.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[N:16][C:15]([Br:32])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>C(Cl)Cl.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[CH2:25]([O:24][C:21]1[CH:20]=[CH:19][C:18]2[C:17]3[N:16]=[C:15]([Br:32])[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=3[NH:5][C:23]=2[CH:22]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(OCc3ccccc3)cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCCCCCCC(=O)O
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(OCc3ccccc3)ccc12
Temperature: 60 °C
Yield: 80.5 %

Procedure:
1,2-Dichloroethane (3.5 mL) was added to a mixture of methyl 3-azido-2-(4-(benzyloxy)phenyl)-6-bromoisonicotinate (2.28 g, 5.19 mmol), rhodium octanoate dimer (0.101 g, 0.130 mmol) and crushed 4 A° molecular sieves (2.2 gm). This was heated at 60° C. for 6 hr. The reaction was diluted with a mixture of DCM:MeOH=3:1 and filtered. The collected solid was washed with additional DCM:MeOH mixture to dissolve any remaining product. The solvent was removed from the filtrate and the residue was suspended in MeOH. The product was collected by filtration and washed with a little MeOH to leave methyl 7-(benzyloxy)-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (1.72 g, 4.18 mmol, 81% yield) as a yellow solid. MS (ESI) m/z 412.9 (M+H). 1H NMR (400 MHz, chloroform-d) δ ppm 9.45 (1H, br. s.), 8.22 (1H, d, J=8.81 Hz), 7.87 (1H, s), 7.43-7.50 (2H, m), 7.37-7.44 (2H, m), 7.30-7.37 (1H, m), 6.96-7.06 (2H, m), 5.18 (2H, s), 4.04 (3H, s).
Reaction SMILES: [N:1]1[C:6]([P:11]([OH:14])(=[O:13])[OH:12])([P:7]([OH:10])(=[O:9])[OH:8])[CH2:5][CH2:4][N:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=12.[H][H]>O.O=[Pt]=O>[N:1]1[C:6]([P:7]([OH:10])(=[O:8])[OH:9])([P:11]([OH:14])(=[O:12])[OH:13])[CH2:5][CH2:4][N:3]2[CH2:15][CH2:16][CH2:17][CH2:18][C:2]=12
Reactant: [H][H]
Reactant: O=P(O)(O)C1(P(=O)(O)O)CCN2C=CC=CC2=N1
Agent: O=[Pt]=O
Solvent: O
Product: O=P(O)(O)C1(P(=O)(O)O)CCN2CCCCC2=N1

Procedure:
3 g of the diphosphonic acid obtained in Example 1 were dissolved in 250 ml water and, after addition of 1.5 g PtO2, hydrogenated at atmospheric pressure up to the take-up of the calculated amount of hydrogen. After separation off of the catalyst and evaporation in a vacuum, the residue was brought to crystallisation from water/acetone. Mrel. 0.33, yield 2.61 g (85% of theory), m.p. 279°-285° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Reactant: OB(O)c1ccncc1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccncc3)c2n1C
Temperature: 140 °C
Yield: 65.4 %

Procedure:
A mixture of 4-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 4-pyridyl boronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 40 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by chromatography eluting with (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water). The relevant fractions were concentrated to approximately ⅓ volume then partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give 429 as a white solid (0.066 g, 66%). LCMS (Method K): RT 2.32 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.72 (2H, d, J=5.05 Hz), 8.03 (1H, s), 7.71-7.70 (2H, m), 7.53 (2H, d, J=13.97 Hz), 7.31 (2H, s), 7.18 (1H, dd, J=10.45, 8.79 Hz), 5.64 (1H, m), 3.21 (3H, s), 1.58 (3H, d, J=6.74 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[O:6][C:7]3[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@H:16](C(=O)C5C=CC=CC=5)[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.[OH-:34].[Na+]>CO>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[O:6][C:7]3[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@H:16]([OH:34])[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: O=C(c1ccccc1)[C@@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Agent: [Na+]
Solvent: CO
Product: O[C@@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 8-chloro-11-[(6S,8R)-8-benzoyl-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-oxazepine in methanol (5 mL) was added 1% aqueous sodium hydroxide. The reaction was stirred for 1 hour and the solvent removed under reduced pressure. The residue was dissolved in methylene chloride and washed with water, dried (MgSO4) and evaporated to dryness to give 3.5 mg (31%) of 8-chloro-11-[(6S,8R)-8-hydroxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-oxazepine as an off-white solid; mp 90°-92° C.; Rf(50% acetone/hexanes): 0.20; HRMS (FAB): MH+ of C20H20 N3O2Cl, calculated 370.1322, found 370.1327.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:48][C:49]1[CH:54]=[CH:53][C:52]([CH:55]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=2)[N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[CH:51][CH:50]=1>CN(C=O)C.C(OCC)C>[F:68][C:65]1[CH:64]=[CH:63][C:62]([CH:55]([C:52]2[CH:53]=[CH:54][C:49]([F:48])=[CH:50][CH:51]=2)[N:56]2[CH2:57][CH2:58][N:59]([C:5](=[O:7])[C@@H:4]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH2:3][CH:2]([CH3:1])[CH3:14])[CH2:60][CH2:61]2)=[CH:67][CH:66]=1
Reactant: CC(C)CC(C(=O)O)N1CCOCC1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
4-Methyl-2-morpholin-4-yl-pentanoic acid (0.200 g, 0.994 mmol, Example 23, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.346 mL, 1.99 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.379 g, 0.994 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.287 g, 0.994 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 20 minutes at ambient temperature, reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane) to provide 0.284 g (60%) of the pure titled compound as a white foam; mp 55-63° C. APCI-MS m/z 472.3.0 (MH+).
Reaction SMILES: C1(O[C:8](=[O:32])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[C:12]([CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:24])[CH:11]=2)C=CC=CC=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42]C(NC2C=CC(SC(C)C)=C(C=2)CN(C)C(=O)OC(C)(C)C)=O)=[CH:36][CH:35]=1.C1C=C(Cl)C=C(C(OO)=O)C=1>>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[C:12]([CH:11]=2)[CH2:22][N:23]([CH3:24])[C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:32])=[CH:36][CH:35]=1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: CC(C)Sc1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Yield: 97 %

Procedure:
Using a procedure analogous to that used for preparation of 16G, 18A (0.642 g, 1.20 mmol) was reacted with mCPBA (0.672 g, 3.00 mmol) to give 18B (0.660 g, 97%) as a white solid. MS (ESI) m/z 568.9 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:51]=[CH:52][C:53]=1[O:54][CH3:55])[CH2:32][O:33][C:34]([NH:36][C:37]1[NH:38][C:39](=[O:50])[C:40]2[N:41]=[CH:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=2[N:45]=1)=[O:35]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:47](=[O:48])[CH2:46][N:43]2[CH:42]=[N:41][C:40]3[C:39](=[O:50])[NH:38][C:37]([NH:36][C:34]([O:33][CH2:32][C:31]4[CH:51]=[CH:52][C:53]([O:54][CH3:55])=[C:29]([O:28][CH3:27])[CH:30]=4)=[O:35])=[N:45][C:44]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)O)c(=O)[nH]2)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)N3CCN(S(=O)(=O)c4nc5ccccc5s4)C(=O)C3)c(=O)[nH]2)cc1OC

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(3,4-dimethoxybenzyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.41 (s, 1H), 11.37 (s, 1H), 8.34 (m, 1H), 8.24 (m, 1H), 7.81 (s, 0.6H), 7.77 (s, 0.4H), 7.71 (m, 2H), 7.04 (s, 1H), 6.95 (d, 1H), 6.94 (d, 1H), 5.15 (s, 2H), 5.13 (s, 1.2H), 5.02 (s, 0.8H), 4.51 (s, 0.8H), 4.27 (s, 1.2H), 4.24 (t, 1.2H), 4.07 (t, 0.8H), 4.03 (t, 1.2H), 3.84 (t, 0.8H), 3.75 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:15])=[CH:6][CH:7]=[C:8]2[CH:13]=[O:14])[CH3:2].S(Cl)([Cl:19])(=O)=O.O>C1C=CC=CC=1>[Cl:19][C:6]1[CH:7]=[C:8]([CH:13]=[O:14])[C:9]2[C:4]([C:5]=1[OH:15])=[C:3]([CH2:1][CH3:2])[CH:12]=[CH:11][CH:10]=2
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1cccc2c(C=O)ccc(O)c12
Solvent: c1ccccc1
Solvent: O
Product: CCc1cccc2c(C=O)cc(Cl)c(O)c12

Procedure:
0.81 g of 5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde and 0.49 ml of sulfuryl chloride were heated in 30 ml of benzene under reflux for 30 minutes. The reaction solution was returned to room temperature and poured into water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate, followed by concentration under reduced pressure. The resultant crystals were washed with isopropyl ether to obtain 0.8 g of the captioned compound as yellowish brown crystals.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8].[CH2:13](Br)[C:14]#[CH:15].Cl>CS(C)=O>[CH2:15]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[C:14]#[CH:13]
Reactant: C#CCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCOc1cc(C=O)ccc1O
Temperature: 0 °C
Yield: 69.3 %

Procedure:
In a dry two-neck flask with a nitrogen inlet, NaH (4.8 g, 200 mmol, 2 equiv) was added into anhydrous DMSO (50 mL) in small portions. While stirring and cooling this solution to 0° C., anhydrous DMSO (60 mL) containing 3,4-dihydroxybenzaldehyde (13.8 g, 100 mmol, 1 equiv) was added dropwise into the flask. This reaction mixture was stirred at rt for 30 min. Propargyl bromide (11.1 mL 100 mmol, 1 equiv) was then added dropwise via syringe and the mixture was stirred at rt overnight. The mixture was poured onto ice, neutralized by a 1 M HCl solution and the product was extracted with ethyl acetate (3×250 mL). The combined organic extracts were concentrated to about 250 mL, washed with brine (5×250 mL) and dried over MgSO4. After filtration the solvent was removed under vacuum to afford crude product as a brownish powder. This was chromatographed on a silica gel column with an eluent of ethyl acetate/hexane/acetic acid (20/80/1) to give 8 as a white powder (12.2 g, yield: 69%). 1H NMR δ=9.84 (s, 1H, —CHO), 7.53 (d, J=1.7, 1H), 7.49 (dd, J1=1.7, J2=8, 1H), 7.09 (d, J=8, 1H), 6.22 (s, 1H, —OH), 4.84 (d, J=2.5, 2H, —OCH2), 2.60 (t, J=2.5, 1H, —C≡CH). 13C NMR δ=190.92 (—CHO), 152.20, 145.37, 129.96, 128.14, 115.35, 111.36, 77.41 (—C≡CH), 77.10 (—C≡CH), 57.23 (—OCH2). HRMS calculated for C10H8O3 (M+), 176.0473; found, 176.0465.
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.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[NH2:25]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[NH:25][C:4]1[C:3]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[C:22]([Cl:21])[CH:23]=2)=[C:2]([F: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]=1[F:18]
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: N#Cc1ccc(N)cc1Cl
Product: N#Cc1ccc(Nc2c(F)c3c(c(F)c2Nc2ccc(C#N)c(Cl)c2)C(=O)c2ccccc2C3=O)cc1Cl
Reaction time: 8 h

Procedure:
1,2,3,4-Tetrafluoroanthraquinone and 25 g of 3-chloro-4-cyanoaniline were charged in a 50 cc, four necked flask and then the reaction was carried out at 150° C. for about 8 hours. After completion of reaction, 3-chloro-4-cyanoaniline was distilled out from the reaction solution and a column purification using a column with a silica gel was effected to give rise to 1.14 g of 2,3-bis(3-chloro-4-cyanoanilino)-1,4-difluoroanthraquinone (Dye 22') (yield 29.3 mol %). The physical properties of Dye 22' and analytical values defining the compound are tabulated in Table 23.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].[Mg].BrC1C=CC=CC=1OC.COC1C=CC=CC=1[Mg]Br.C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1>C1COCC1.C1COCC1.CCOCC>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH:3]1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1ccccc1Br
Agent: COc1ccccc1[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Reaction time: 0.25 h

Procedure:
Ethyl (1RS)-1-Hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To dry magnesium turnings (81 mg, 3,4 mmol) under an argon atmosphere was added a solution of 2-bromoanisole (0.64 g, 3.4 mmol) in 5:1 THF/Et2O (3 ml). A portion of the resulting 2-methoxyphenyl magnesium bromide solution (0.45 ml, 0.51 mmol) was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.34 mmol) in THF (6 ml) under an argon atmosphere at 0° C. After stirring for 15 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound. (100 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH:7]=1.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[S:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)(=[O:35])=[O:34])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCCO3)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)OCCO3)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-(3-{[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12n, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.66 (m, 1H), 7.95 (d, 1H), 7.85 (m, 1H), 7.45 (m, 1H), 7.15-6.91 (m, 4H), 6.68-6.54 (m, 3H), 4.45 (s, 2H), 4.36 (s, 2H), 4.19 (s, 4H), 3.68 (s, 3H), 2.82 (t, 2H), 2.53 (t, 2H); MS 483 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([C:19]#[N:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:21]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[C:19]#[N:20])[CH2:24][CH2:23][CH2:22]1
Reactant: C1CNC1
Reactant: N#Cc1cc(OCc2ccccc2)ccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-cyanophenyl]acetic acid (0.40 g, 1.50 mmol) was dissolved in DMF (5 ml) and azetidine (0.128 g, 2.25 mmol), DIEA (0.78 ml, 4.49 mmol), and HATU (1.14 g, 2.99 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 307 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.C(P(=O)(OCC)OCC)#N>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24]([N:28]2[CH2:29][CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27]2)=[O:25])=[CH:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: c1ccc2c(c1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Product: COc1cc2c(C(=O)N3CCc4ccccc4C3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Yield: 61.4 %

Procedure:
A solution of 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (100 mg, 0.3 mmol) in 20 mL of THF was treated with 1,2,3,4-tetrahydroisoquinoline (44 mg, 0.33 mmol), TEA (56 mg, 0.552 mmol) and diethyl cyanophosphonate (55 mg, 0.33 mmol) according to the procedure described in example 1E to give [4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-6,7-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (88 mg, 66.9%). H1-NMR (CDCl3): δ, 8.31 (br s, 1H), 7.38 (br s, 1H), 7.15 (m, 5H), 6.82 (m, 1H), 6.18 (br s, 1H), 4.93 (s, 2H), 4.43 (m, 2H), 4.02 (br s, 3H), 3.92 (s, 2H), 3.58 (br s, 3H), 3.10 (br s, 1H), 2.80 (br s, 1H), 1.51 (s, 9H) [Note: broadening of peaks observed due to Boc group, rotamers also observed.]; MS: APCI (M+H) calc'd for C27H31N3O5+H 478.6; found 478.0.