Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:15]3[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:5][CH2:4]1.[S:34](N)([NH2:37])(=[O:36])=[O:35]>O1CCOCC1>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:14]1[N:15]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH:10][CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][NH:37][SH:34](=[O:36])=[O:35])[CH2:4][CH2:5]1)[N:19]=[CH:18][N:17]=2
Reactant: NCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: O=[SH](=O)NNCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 24.2 %

Procedure:
To a solution of N-{[4-(aminomethyl)cyclohexyl]methyl}-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-amine (6.6 mg, 0.014 mmol, 1 eq.) in 5 mL of dioxane was added 10 mg of sulfamide. The reaction was heated to 80° C. and stirred 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 1.9 mg (25%) of N-{[4-({[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}methyl)cyclohexyl]methyl}aminosulfonamide. 1H NMR (300 MHz, METHANOL-d4) δ ppm 0.80-1.17 (m, 2 H) 1.21-1.79 (m, 6 H) 1.93 (br. s., 2 H) 3.00 (d, J=7.16 Hz, 2 H) 3.59 (br. s., 2 H) 7.19-7.69 (m, 8 H) 8.13-8.35 (m, 1 H), [M+H]+ 562.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[CH:42][CH:41]=1)CCC.O>C1(C)C=CC=CC=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:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:44][N:43]=[CH:42][CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccns1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 5-(tributylstannyl)isothiazole (67.5 mg, 0.180 mmol) and tetrakis(triphenylphosphine)palladium(0) (69.5 mg, 0.060 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C26H34FN5O5S, 548. found, 548.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].I[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1>>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:1][C:2]#[C:3][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#CCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(OC(F)(F)F)cc1

Procedure:
In analogy to the procedure described for example 8 a], tert-butyl 2-propynylcarbamate was reacted with 1-iodo-4-trifluoromethoxy-benzene in the presence of PdCl2(Ph3P)2 and cuprous iodide to give the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:14][C:5]1[C:6]2[O:10][C:9]([CH3:11])([CH3:12])[C:8](=[O:13])[C:7]=2[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC1(C)Oc2c([N+](=O)[O-])ccc(Cl)c2C1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Oc2c(N)ccc(Cl)c2C1=O
Yield: 76.8 %

Procedure:
By the method of Example 1, Step E, 4.82 g (0.020 mole) of 4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-one and 5.0 g of powdered iron were reacted in 80 mL of glacial acetic acid and 10 mL of water, yielding 3.25 g of 7-amino-4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-3-one as an oil which subsequently solidified, m.p. 71°-73° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[OH:32][C:28]1[CH:27]=[C:26]([NH:25][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2cccc(O)c2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A small screw cap test tube was charged with N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 29, 70 mg, 0.217 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (28 mg, 0.257 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 76% yield (0.068 g, 0.1645 mmol).
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[N:18]=[C:17]([NH:19][C@H:20]3[C@H:24]([F:25])[CH2:23][N:22](C(OCC4C=CC=CC=4)=O)[CH2:21]3)[C:16]3[S:36][C:37]([CH3:39])=[CH:38][C:15]=3[N:14]=2)[CH2:4][CH2:3]1.[OH-].[K+]>CO>[F:25][C@@H:24]1[CH2:23][NH:22][CH2:21][C@H:20]1[NH:19][C:17]1[C:16]2[S:36][C:37]([CH3:39])=[CH:38][C:15]=2[N:14]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:1])[CH2:3][CH2:4]2)[N:18]=1
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(N[C@@H]3CN(C(=O)OCc4ccccc4)C[C@H]3F)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(N[C@@H]3CNC[C@H]3F)c2s1

Procedure:
To a suspension of benzyl trans-(±)-3-{[2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthienopyrimidin-4-yl]amino}-4-fluoropyrrolidine-1-carboxylate (320 mg, 0.57 mmol) in methanol (5 mL) was added an aqueous solution of potassium hydroxide (40%, 5 mL). The suspension was heated under reflux for 30 minutes. The organic solvent was removed by concentration in vacuo. The residue was purified by preparative HPLC to afford the pure product as a white solid. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.72 (m, 2H), 7.48 (m, 2H), 6.83 (s, 1H), 5.18-5.38 (m, 1H), 4.66-4.99 (m, 5H), 3.26-3.5 (m, 6H), 2.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:15].Cl[CH2:17][CH2:18][NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:15][CH2:17][CH2:18][NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23]
Reactant: Oc1cc(Oc2ccccc2)ccc1Cl
Reactant: CCOC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1cc(Oc2ccccc2)ccc1Cl
Temperature: 0 °C
Yield: 10.1 %

Procedure:
To a solution of 0.91 g of 2-chloro-5-phenoxyphenol in 20 ml of N,N-dimethylformamide, there were added 0.69 g of ethyl 2-chloroethylcarbamate and 1.14 g of potassium carbonate with stirring, and the resultant mixture was stirred at 50° C. for 7 hours. The reaction mixture was poured into 100 g of ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.14 g of ethyl 2-(2-chloro-5-phenoxyphenoxy)ethylcarbamate. Yield: 10%. nD22 : 1.5608.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[Br:17]N1C(=O)CCC1=O>O1CCCC1>[Br:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)o1
Yield: 15.1 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (600 mg, 2.72 mmol) [prepared in Example 116] and N-bromosuccinimide (485 mg, 2.72 mmol) in tetrahydrofuran (13 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (5-15% EtOAc in hexanes yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (130 mg, 0.41 mmol, 15% yield) as an orange oil: LCMS (ES) m/e 299, 301 (M, M+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH2:41]([NH:44][CH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[CH:42]=[CH2:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:44]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:41][CH:42]=[CH2:43])=[O:7])[CH:8]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:10]=1
Reactant: C=CCNC1CCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(C(=O)c1cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c1)C1CCCC1
Reaction time: 0.08 h
Yield: 99.4 %

Procedure:
To a solution of 3-chloro-5-(tert-butyldimethylsilyloxy)benzoic acid (17.5 g, 60 mmol), as prepared in the preceding step, and CH2Cl2 (250 mL) were added triethylamine (33.8 mL, 0.24 mol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (17.0 g, 66 mmol). The resulting mixture was stirred for 5 min, then N-allylcyclopentylamine (9.8 mL, 66 mmol) was added. After 1 h, the solution was filtered. The filtrate was washed with 10% aqueous HCl (100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, concentrated in vacuo, and flash chromatographed to provide the title compound as a colorless oil (23.5 g, 97%). 1H NMR (CDCl3) δ 6.95 (s, 1H), 6.84 (s, 1H), 6.71 (s, 1H), 5.93 (br s, 1H), 5.16 (d, 2H), 3.95 (br s, 3H), 1.4-1.9 (m, 8H), 0.97 (s, 9H), 0.20 (s, 6H). Mass spectrum (CI) calcd. for C21H32NO2SiCl: 394 (M+H). Found: 394.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#C)[C:5]2[O:9][C:8]([CH2:10][C:11]3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)=[N:7][C:6]=2[CH:26]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:26]1[C:6]2[N:7]=[C:8]([C:10]#[CH:11])[O:9][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1cc(Cl)cc2nc(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc12
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C#Cc1nc2c(-c3ccccn3)cccc2o1
Yield: 224 %

Procedure:
A suspension of 5-chloro-2-(3,5-di-t-butyl-4-hydroxy-benzyl)-7-ethynyl-benzoxazole (2.38 g, 6.0 mmol), 2-bromo-pyridine (0.66 ml, 98%, 6.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (21.1 mg, 30 μmol) and copper (I) iodide (1.2 mg, 6 μmol) in triethylamine (12 ml) was heated at 90EC, under argon, for 1.5 hours. The triethylamine was removed in-vacuo and the residue dissolved in ether (100 ml). The organics were washed with water (50 ml), 1 N HCl (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), dried (Na2SO4) and evaporated in-vacuo to give 2.96 g (104.2%) of crude pyridyl ethynyl benzoxazole. The crude benzoxazole was purified by column chromatography (SiO2; dichloromethane), and the product crystallized from methanol and suspended in hot water. The resulting crystals were collected, washed, and dried to give 1.49 g (52.5%) of the title compound (mp 138-9EC).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:8]=[CH:7][C:6]=1[CH3:24])[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=3)[C:13]=2[CH3:23])[CH:8]=[CH:7][C:6]=1[CH3:24])[CH3:2]
Reactant: CCOC(=O)c1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)ccc1C
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cc(Sc2c(C)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)ccc1C

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 5-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-2-methyl-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]2[N:14]([CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:21][C:19]1[N:20]=[C:13]2[C:12]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)=[CH:17][CH:16]=[CH:15][N:14]2[CH:18]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Cc1cn2cccc(Br)c2n1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cn2cccc(-c3ccc(O)cc3)c2n1
Yield: 25.7 %

Procedure:
A mixture of 4-hydroxyphenylboronic acid (1.1 g), 8-bromo-2-methylimidazo[1,2-a]pyridine (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.28 g), sodium carbonate (3.0 g), DME (35 ml) and water (7 ml) was heated under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (0.46 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O1CCCC1>[S:25]([O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:27])(=[O:26])[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.6 %

Procedure:
To a solution of 2-benzyloxybenzyl alcohol (2.1 g, 9.42 mmol) in tetrahydrofuran (10 mL), triethylamine (1.38 mL, 9.89 mmol) and methanesulfonyl chloride (0.766 mL, 9.89 mmol) were added under ice cooling and stirred at room temperature for 30 minutes. After filtration to remove the insoluble materials, the filtrate was concentrated to give (2-benzyloxyphenyl)methyl mesylate (3.24 g). To a suspension of methyl isobutyrylacetate (1.43 g, 9.89 mmol), sodium hydride (60% in oil; 396 mg, 9.89 mmol) and dimethoxyethane (10 mL), a solution of (2-benzyloxyphenyl)methyl mesylate (3.24 g) in dimethoxyethane (10 mL) was added and stirred at 70° C. overnight. After addition of 0.5 M HCl, the reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oil. To this oil, toluene (20 mL) and hydrazine monohydrate (317 mg, 9.89 mmol) were added and the resulting mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 8:1) to give the titled compound (750 mg, 25%) as a light-yellow amorphous substance.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[CH3:42][CH:41]([CH3:43])[C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH:30]2[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:8](=[O:9])[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:32][CH2:31]2)[CH:34]=1)=[O:44]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 59 was prepared from triphenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.40 (d, 2H, J=10.8 Hz), 7.32–7.17 (m, 17H), 6.87 (d, 1H, J=7.7 Hz), 6.32–6.26 (m, 1H), 3.41 (q, 2H, J=6.0 Hz), 2.83 (d, 2H, J=10.5 Hz), 2.48 (quintet, 1H, J=6.7 Hz), 2.43–2.33 (m, 1H), 2.26 (t, 2H, J=6.7 Hz), 1.89 (t, 2H, J=11.5 Hz), 1.73–1.62 (m, 4H), 1.56–1.44 (m, 2H), 1.22 (d, 6H, J=6.7 Hz); ESMS m/e: 574.3 (M+H)+; Anal. Calc. for C38H43N3O2.0.730 CHCl3: C, 70.38; H, 6.67; N, 6.36. Found: C, 70.42; H, 6.57; N, 6.47.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[S:9])[CH3:2].Cl([O-])(=O)(=O)=O.[Cl:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[CH:25]N(C)C)[N+:17]=1[CH2:29][CH3:30]>C(N(CC)CC)C>[Cl:15][C:16]1[N:17]([CH2:29][CH3:30])[C:18]([CH:25]=[C:6]2[S:5][C:4](=[S:9])[N:3]([CH2:1][CH3:2])[C:7]2=[O:8])=[C:19]2[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: CCN1C(=O)CSC1=S
Reactant: CC[N+]1=C(Cl)c2ccccc2C1=CN(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(=Cc2c3ccccc3c(Cl)n2CC)SC1=S

Procedure:
This dye was prepared by the interaction of 3-ethyl-rhodanine and 3-chloro-1-dimethylaminomethylene-2-ethyl-1H-isoindolium perchlorate in the presence of triethylamine. The dye after purification by recrystallization from methanol melted at 119° C. MeOH λ max 505 nm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][CH:43]([O:46][Si](C(C)C)(C(C)C)C(C)C)[C@@H:42]5[CH3:57])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:42][CH2:57][C@H:44]([CH2:43][OH:46])[CH2:45]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(O[Si](C(C)C)(C(C)C)C(C)C)[C@@H]5C)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CC[C@H](CO)C5)n4c3)c3ccccc32)cc1

Procedure:
To a solution of Intermediate 92d (240 mg, 0.300 mmol) and TBAF (1M in THF, 0.400 mL, 0.400 mmol) in THF (3 mL) was stirred at RT for 1 h. Water was added and the mixture extracted with DCM (4×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (154 mg, 81%). LCMS (Method 5): Rt 4.01 min, m/z 635.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.68-1.79 (1H, m), 1.79-1.97 (2H, m), 1.98-2.14 (3H, m), 2.36 (3H, s), 2.40-2.48 (1H, m), 3.23-3.30 (1H, m), 3.41-3.64 (5H, m), 4.71 (1H, t, J 5.3), 4.77-4.85 (1H, m), 5.51 (1H, br t, J 4.4), 6.33 (1H, s), 7.03-7.10 (2H, m), 7.25-7.40 (8H, m), 7.53 (1H, d, J 9.9), 7.82 (1H, d, J 1.8), 8.03 (1H, s).
Reaction SMILES: [C:1]1([SH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[S:17][C:16]([C:18](=[O:20])[CH3:19])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>>[C:1]1([S:11][C:13]2[S:17][C:16]([C:18](=[O:20])[CH3:19])=[CH:15][C:14]=2[N+:21]([O-:23])=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Sc1cccc2ccccc12
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2cccc3ccccc23)s1
Yield: 29.1 %

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-naphthalenethiol (320 mg, 2 mmol) and 1-(5-Chloro-4-nitro-2-thienyl)ethanone (412 mg, 2 mmol) to afforded the title compound as a yellow solid (192 mg, 29% yield). 1H NMR (300 MHz, CDCl3) δ: 8.33 (1H, m), 8.11 (1H, m), 8.08 (1H, s), 7.98 (2H, m), 7.59 (3H, m), 2.43 (3H, s).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][S:13]([C:16]1[C:17]([CH3:29])=[C:18]([CH3:28])[C:19]2[O:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]=2[C:26]=1[CH3:27])(=[O:15])=[O:14])=[NH:11])[C:3]([OH:5])=[O:4].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][S:13]([C:16]1[C:17]([CH3:29])=[C:18]([CH3:28])[C:19]2[O:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]=2[C:26]=1[CH3:27])(=[O:15])=[O:14])=[NH:11])[C:3]([OH:5])=[O:4])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)O)c(C)c2c1OC(C)(C)C2
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](CCCNC(=N)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2)C(=O)O

Procedure:
(S)-2-Amino-5-(3-(2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonyl) guanidino)pentanoic acid (H-L-Arg(Pbf)-OH) (1.0 eq.) is dissolved in pyridine (0.25 M) and acetic anhydride (1.2 eq.) is added to acylate the primary amine, after 1 h the reaction is quenched with aqueous acid, extracted with ethyl acetate, and purified by chromatography to afford (S)-2-acetamido-5-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl) guanidino)pentanoic acid (Ac-L-Arg(Pbf)-OH).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]([O:19][CH3:20])=[N:17][C:16]3[C:11]2=[N:12][C:13]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:14][C:15]=3[NH2:21])[CH2:4][CH2:3][CH2:2]1.[CH2:27](OC1N=C2C(N=C(OC)N2CCCCCCl)=C(N)N=1)CCC.N1CCCC1>>[CH2:23]([O:22][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[C:18]([O:19][CH3:20])[N:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:1]2[CH2:27][CH2:2][CH2:3][CH2:4]2)=[C:15]([NH2:21])[N:14]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCC3)c2n1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Solvent: C1CCNC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and pyrrolidine.