Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.CCCCCC.C([Li])CCC.[N:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([C:21]3=[O:28])[CH2:19]1)[CH2:25]2>O1CCCC1.CO>[C:22]([C:21]1([OH:28])[CH:20]2[CH2:19][N:18]3[CH2:25][CH:24]([CH2:5][CH:6]1[CH2:27]3)[CH2:26]2)#[CH:23]
Reactant: C#C[Si](C)(C)C
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: C#CC1(O)C2CC3CC1CN(C3)C2
Reaction time: 0.5 h

Procedure:
To a solution of 0.2 ml of trimethylsilylacetylene in 2 ml of tetrahydrofuran was added dropwise 0.64 ml of a 1.56 mol hexane solution of n-butyllithium in a dry ice-acetone bath. After stirring for 30 minutes, a solution of 50 mg of 1-azaadamantane-4-one in 1 ml of tetrahydrofuran was added dropwise to the mixture. After further stirring for 30 minutes, 1 ml of methanol was added to the mixture and the temperature was elevated to room temperature. The solvent was removed and water was added to the resulting solid. Crystals that remained were collected by filtration, to give 17 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7](=O)[CH2:8][CH3:9])[CH3:2].O=C(CC)C(C(=O)CC)CC(OC(C)(C)C)=O.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([NH:42][NH2:43])[CH3:41])=[CH:36][CH:35]=1.O>CO>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([CH2:12][CH3:13])=[N:43][N:42]([CH:40]([C:37]2[CH:38]=[CH:39][C:34]([Br:33])=[CH:35][CH:36]=2)[CH3:41])[C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CC(NN)c1ccc(Br)cc1
Reactant: CCOC(=O)CC(C(=O)CC)C(=O)CC
Agent: CCC(=O)C(CC(=O)OC(C)(C)C)C(=O)CC
Solvent: O
Solvent: CO
Product: CCOC(=O)Cc1c(CC)nn(C(C)c2ccc(Br)cc2)c1CC
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of 4-oxo-3-propionyl-hexanoic acid ethyl ester (500 mg) (preparation analagous to that of 1,1-dimethylethyl 4-oxo-3-propanoylhexanoate in WO2007/141267) in methanol (20 ml) at room temperature was added [1-(4-bromo-phenyl)-ethyl]-hydrazine (0.75 g). After overnight stirring, water was added and the mixture extracted 3 times with ethyl acetate. The organic layer was separated; washed with water and brine solution, then dried and concentrated to afford 792 mg of the title compound. Retention time HPLC: 1.58 min (Method D), ESI mass spectrum: (Br) [M]+=393/395.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:19]([NH:21][N:22]1[C:26](=[O:27])[C:25]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[NH:24][C:23]1=[O:33])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38]=O.[H][H]>[Pd].CO>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:19]([NH:21][N:22]1[C:26](=[O:27])[C:25]2([CH2:32][CH2:31][N:30]([CH3:38])[CH2:29][CH2:28]2)[NH:24][C:23]1=[O:33])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCNCC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCN(C)CC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A mixture of 0.403 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-[2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]valeramide, 0.145 ml of 38% aqueous formaldehyde solution and 0.093 g of 10% palladium-on-charcoal catalyst in 4 ml of methanol was shaken in a hydrogen atmosphere for 2 days. The catalyst was filtered off and the methanol evaporated. The residue was re-evaporated from toluene and the solid obtained triturated with diethyl ether. There was obtained 0.348 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-(8-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl)valeramide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[NH2:48][CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:48][CH2:49][CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)=[O:19])=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCCC1)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 57.9 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and aminomethylcyclohexane (30 μl, 0.23 mmol). The resulting mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with dichloromethane and washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (58 mg, 0.11 mmol, 59%) as a white powder.
Reaction SMILES: CCN(C(C)C)[CH:4]([CH3:6])[CH3:5].[CH3:10][CH:11]([CH3:37])[CH:12]([NH:24][C:25]([CH:27]1[CH2:31][CH:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][NH:28]1)=[O:26])[CH:13]1[CH:18]([OH:19])[CH:17]([OH:20])[CH:16]([OH:21])[CH:15]([S:22][CH3:23])[O:14]1.C[OH:39]>>[CH3:10][CH:11]([CH3:37])[CH:12]([NH:24][C:25]([CH:27]1[CH2:31][CH:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][N:28]1[CH2:5][CH:4]([OH:39])[CH3:6])=[O:26])[CH:13]1[CH:18]([OH:19])[CH:17]([OH:20])[CH:16]([OH:21])[CH:15]([S:22][CH3:23])[O:14]1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: CO
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CC(C)O)C1
Temperature: -4 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
DIEA (0.1 mL, 0.58 mmol, 1 equiv) and R(+)-propylene oxide (3 mL) were added to a stirred cool solution of crude 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (307.6 mg, 0.58 mmol, 1 equiv), prepared as in Example 10, in anhydrous methanol (10 mL), at 0° C. and under nitrogen. The resulting solution was stirred at −4° C. for 18 h and evaporated to dryness. The residue obtained was purified by chromatography over silica gel, with an eluent of 6% methanolic ammonia in dichloromethane. The desired fractions were evaporated, and lyophilized (deuterium oxide/anhydrous acetonitrile, 1:1, v/v, 20 mL) to furnish the title compound as a fluffy white powder (91 mg, 48%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]1([C:14]#[N:15])[CH2:13][CH2:12]1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>O1CCCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:19][CH:20]=1
Reactant: N#CC1CC1
Reactant: COc1ccc(CCl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CC2(C#N)CC2)cc1
Reaction time: 0.33 h

Procedure:
Sodium bis(trimethylsilyl)amide (2 M in tetrahydrofuran (THF), 37.5 mL, 75.0 mmol) was slowly added to a solution of cyclopropanecarbonitrile (3.35 g, 49.9 mmol) in THF (30 mL) at room temperature. The reaction mixture was stirred for 20 minutes and then a solution 1-chloromethyl-4-methoxy-benzene (7.83 g, 50.0 mmol) in THF was added. The mixture was heated to reflux for 3 hours and then quenched with a saturated aqueous solution of ammonium chloride (50 mL). The separated aqueous layer was extracted three times with ethyl acetate (50 mL). The combined organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give crude 1-(4-methoxy-benzyl)-cyclopropanecarbonitrile, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16](=[O:24])[NH:15][C:14]3=[O:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16](=[O:24])[N:15]([CH3:28])[C:14]3=[O:25])=[CH:11][CH:12]=2)=[CH:26][CH:27]=1
Reactant: O=C1NC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)[C@H](c2ccccc2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(4-chloro-phenoxy)-phenyl]-5-(S)-phenyl-imidazolidine-2,4-dione (10.0 mg, 0.026 mmol) in anhydrous DMF (0.5 mL) are added K2CO3 (7.3 mg, 0.052 mmol) and MeI (4.93 μL, 0.078 mmol). The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by preparative LC/MC to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.42-7.31 (m, 7H), 7.26 (d, 2H), 6.90 (m, 4H), 5.42 (s, 1H), 3.16 (s, 3H); HPLC-MS calculated for C22H17ClN2O3 (M+H+) 393.1, found 393.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])(=[O:4])=[O:3].[Cr]([O-])(OCl)(=O)=O.[NH+]1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(CO)c1
Agent: O=[Cr](=O)([O-])OCl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-methylsulfonyl benzyl alcohol (3.5 g, 28.6 mmol) in dichloromethane (50 mL) was added pyridinium chloro chromate (PCC) (9.1 g, 42.2 mmol). The mixture was stirred at room temperature for 3 hours. After workup and column chromatography on silica gel eluting with hexane:ethyl acetate, 1:1, 3-methylsulfonylbenzaldehyde was obtained as white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[N+:15]([C:18]1[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]([OH:28])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C=O)C.O>[CH2:2]([O:28][C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)c2cccnc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c2cccnc12
Temperature: 90 °C
Yield: 68.5 %

Procedure:
Bromomethyl-benzene (424 μl, 3.57 mmol) and K2CO3 (493 mg, 3.57 mmol) were added to a solution of 8-nitro-quinolin-5-ol 563 (566 mg, 2.98 mmol) in DMF (5 ml) and the mixture was heated at 90° C. for 6 h. After cooling, the mixture was diluted with water (25 ml) and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine (25 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound (572 mg, 69%) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].BrC1C=CC=C2C=1C1(COC3C=C4C(=CC1=3)CCO4)C(=O)N2CC1OC(C(F)(F)F)=CC=1.[F:56][C:57]1[N:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1.N1C=C(B(O)O)C=NC=1>>[F:56][C:57]1[N:62]=[CH:61][C:60]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]2)[C:5](=[O:12])[N:6]3[CH3:11])=[CH:59][CH:58]=1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: OB(O)c1ccc(F)nc1
Agent: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: OB(O)c1cncnc1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(-c3ccc(F)nc3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 4.14, and making non-critical variations using 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (6-fluoropyridin-3-yl)boronic acid to replace pyrimidine-5-boronic acid, the title compound was obtained (100%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.75-7.65 (m, 1H), 7.42-7.30 (m, 1H), 7.19-7.05 (m, 1H), 7.00-6.90 (m, 1H), 6.90-6.80 (m, 1H), 6.78-6.64 (m, 1H), 6.24-6.12 (m, 2H), 5.92-5.79 (m, 2H), 4.74-4.63 (m, 1H), 4.40-4.29 (m, 1H), 3.34-3.26 (m, 3H); MS (ES+) m/z 391.4 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH2:41]([NH2:44])[CH:42]=[CH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:41]([NH:44][C:38]([C:35]1[CH:36]=[CH:37][N:33]([S:30]([C:28]2[CH:27]=[CH:26][C:17]3[N:18]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])=[N:15][C:16]=3[CH:29]=2)(=[O:32])=[O:31])[CH:34]=1)=[O:39])[CH:42]=[CH2:43]
Reactant: C=CCN
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCNC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 33, step A, using DIPEA (0.1 mL, 74 mg, 0.57 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (0.078 mmol) (see the step B in example 33 for preparation), allylamine (0.1 mL, 76 mg, 1.33 mmol) and HATU (100 mg, 0.31 mmol) in DMF (5 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to 32 mg (85%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.57 (m, 4 H), 1.60 (s, 9 H), 2.20-2.41 (m, 1 H), 3.24-3.38 (m, 2 H), 3.84-3.97 (m, 4 H), 4.43 (d, J=7.42 Hz, 2 H), 5.03-5.10 (m, 1 H), 5.10-5.19 (m, 1 H), 5.75-5.94 (m, 1 H), 6.67 (dd, J=3.32, 1.76 Hz, 1 H), 7.30 (dd, J=3.42, 2.25 Hz, 1 H), 7.79-7.85 (m, 1 H), 7.93 (d, J=9.0 Hz, 1H), 7.970 (dd, dd=9.0, 1.8 Hz, 1 H), 8.27 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=484.7; Anal. Calcd for C25H32N4O4S+0.90 TFA+0.20H2O (590.85): C, 54.48; H, 5.68; N, 9.48. Found: C, 54.53; H, 5.69; N, 9.57.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C@@H]12N(C3C=NC4C(=CC=CC=4)N=3)C[C@@H]1CCNC2.[CH3:37][O:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[C:40]=1[C:41](Cl)=[O:42].C1(C2C=CC=CC=2)C(C(Cl)=O)=CC=CC=1>>[CH3:49][O:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:39]([O:38][CH3:37])[C:40]=1[C:41]([N:3]1[CH2:4][CH2:5][CH:6]2[CH:1]([N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7]2)[CH2:2]1)=[O:42]
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Agent: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Product: COc1cccc(OC)c1C(=O)N1CCC2CN(c3cnc4ccccc4n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Example 5, substituting the trifluoro acetic acid salt of 2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline (Intermediate 2) for (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline and 2,6-dimethoxy benzoyl chloride for biphenyl-2-carbonyl chloride. MS (ESI) mass calcd. for C23H24N4O3, 404.46; m/z found, 405.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.25 (s, 0.25H), 7.98 (s, 0.75H), 7.90-7.80 (m, 1H), 7.60-7.47 (m, 1H), 7.44-7.30 (m, 2H), 7.23 (t, J=8.4, 0.25H), 7.13 (t, J=8.4, 0.75H), 6.58-6.44 (m, 1.25H), 6.03 (d, J=8.4, 0.75H), 4.90-4.56 (m, 1H), 4.32-3.84 (m, 3H), 3.81 (s, 6H), 3.78-3.56 (m, 1H), 3.50-3.30 (m, 1H), 3.17-2.91 (m, 1H), 2.41-1.53 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]([CH3:18])C(O)=O)=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[O:20]1CCC[CH2:21]1>>[Cl:1][C:2]1[C:3]([CH2:14][CH2:18][CH2:21][OH:20])=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1c(Cl)cccc1-c1ccccc1
Reactant: C1CCOC1
Solvent: O
Product: OCCCc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a dry argon atmosphere, borane-tetrahydrofuran complex (230 ml of a 1.5M solution in tetrahydrofuran) was added dropwise to a stirred solution of (3-chloro[1,1'-biphenyl]-2-yl)propanoic acid (40.0 g, 0.15 mole) in tetrahydrofuran (250 ml). The reaction mixture was stirred at room temperature for approximately 18 hours. Water (30 ml) was then added to the reaction mixture during a 0.5 hour period. The solvent was removed from the mixture under reduced pressure to yield an oil. The oil was partitioned between methylene chloride and dilute aqueous sodium hydroxide. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to yield 3-(3-chloro[1,1'-biphenyl]-2-yl)-1-propanol as an oil.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[N:4]=1)=O.[CH:10]([C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[C:14]=1[NH2:15])([CH3:12])[CH3:11].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:9][C:5]1[NH:4][C:3](=[N:15][C:14]2[C:16]([CH:20]([CH3:21])[CH3:22])=[CH:17][CH:18]=[CH:19][C:13]=2[CH:10]([CH3:12])[CH3:11])[CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1N=c1cccc(Br)[nH]1
Temperature: 70 °C

Procedure:
A dry, 500 mL 3-neck round bottom flask is charged with a solution of 2-formyl-6-bromopyridine (72.1 g, 383 mmol) and 2,6-diisopropylaniline (72.5 g, 383 mmol) in 500 mL of anhydrous toluene containing 0.3 nm pore size molecular sieves (6 g) and 80 mg of p-TsOH. The reactor is equipped with a condenser, an over head mechanical stirrer and a thermocouple well. The mixture is heated to 70° C. under N2 for 12 h. After filtration and removal of the volatiles under reduced pressure, a brown oil is isolated. Yield was 109 g, 81.9 percent.
Reaction SMILES: [CH:1]1C=[CH:3][C:4]([C:23]([OH:25])=[O:24])=[C:5](C2C3C=CC(O)=CC=3OC3C=2C=CC(C=3)=O)[CH:6]=1.N1C=NN=N1.C(N(C(C)C)P(OCC)[O:36]CC)(C)C.[CH2:45]([Cl:47])Cl.C(Cl)(Cl)Cl>C1COCC1>[Cl:47][C:45]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:1]=1)[C:23]([O:25][OH:36])=[O:24]
Reactant: ClCCl
Reactant: CCOP(OCC)N(C(C)C)C(C)C
Reactant: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Agent: c1nnn[nH]1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(OO)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
This example illustrates a method of preparing an embodiment of the compound of formula II, namely, fluorescein diphosphate tetraethyl ester. 2.5 g of fluorescein (7.5 mmol) is suspended in THF (60 mL) and anhydrous CH2CI2 (mL). 3.1 g of 1H-tetrazole 3.1 g.(44 mmol) is added and stirred at room temperature for ˜1.5 hours or until the reaction mixture becomes a transparent dark yellowish solution. The resulting solution is cooled to 0° C. and 5.0 g of diethyl N. N-diisopropylphosphoramidite (23 mmol) is added dropwise over a period of 3-4 minutes to yield a very light yellow solution. The cooling bath is removed and the reaction stirred at room temperature until TLC shows no starting material remains (˜5 minutes). The reaction is cooled back to 0° C. Rf (fluorescein diphosphite, tetraethyl ester)=0.7-0.75, a quenching spot that becomes fluorescent yellow upon heating; hexanes/EtOAc (3:2) A solution of 3-chloroperoxybenzoic acid (MCPBA) (5.5 g, 32 mmol) in CH2Cl2/CHCl3 (9:1, 50 mL) is prepared, and washed with saturated NaCl (1×50 mL), followed by drying over Na2SO4. The dried solution is added to the 0° C. reaction mixture to yield a cloudy yellowish solution. The cooling bath is removed and the reaction stirred at room temperature until TLC indicates completion (˜10 minutes). The solvent is removed from the reaction mixture in vacuo and the resulting yellow gum is dissolved in EtOAc (˜100 mL). The solution is washed with 10-20% sodium thiosulfate/H2O (1×100 mL), saturated NaHCO3 (1×100 mL), and saturated NaCl (1×100 mL), and dried over Na2SO2. The solvent is removed in vacuo. At this point, TLC in hexanes/EtOAc (3:2) shows two spots: Rf-0.65-0.7, a quenching spot that becomes fluorescent upon heating; and Rf-0.95-1.0, a quenching spot that does not fluoresce upon heating. 50 mL of methanol are added to the gum to precipitate the high-Rf material. The solid is removed by filtration, and methanol is removed from the filtrate in vacuo. The resulting product is purified by column chromatography under the following conditions:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-])=O.[CH:11]([Mg]Br)=[CH2:12].[Cl-].[NH4+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>>[CH:17]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[NH:1][CH:12]=[CH:11]2)([C:21]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)[C:18]1[CH:19]=[CH:18][CH:17]=[CH:21][CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C=C[Mg]Br
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: c1ccc(C(Oc2cccc3cc[nH]c23)c2ccccc2)cc1
Temperature: -40 °C

Procedure:
To a stirred solution of the protected nitrophenol (3.05 g, 10 mmol) (Example 34a part i) in dry THF (100 ml) at -40° C. under nitrogen was added 1M vinyl magnesium bromide in the THF (35 ml) over 5 minutes. After stirring for a further three quarters of an hour at -40° C., the reaction mixture was poured into aqueous ammonium chloride and extracted into diethyl ether. The combined organic extracts were dried, filtered and evaporated in vacuo. The product was purified by column chromatography on silica, eluting with 12.5% ethyl acetate in hexane, to give a pale yellow solid.