Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][C:8](Cl)=[N:9][CH:10]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][C:19](=[N:22][O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>CS(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][C:8]([N:16]2[CH2:17][CH2:18][C:19](=[N:22][O:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[CH2:20][CH2:21]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)nc1C(F)(F)F
Temperature: 110 °C
Reaction time: 18 h

Procedure:
2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (0.2 g, 0.78 mmol), 2d (0.2 g, 0.71 mmol), and diisopropylethylamine (0.2 mL, 1.2 mmol) were combined in 2 mL of DMSO and stirred at 110° C. for 18 h. The mixture was cooled to room temperature, diluted with aqueous NaHCO3 (5 mL) and extracted with EtOAc (5 mL). The organic layer was concentrated under vacuum to afford the crude 57a.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[O:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[O:20]1[CH2:21][CH:22]=[C:23]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH2:24][CH2:25]1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(C3=CCOCC3)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.4 g, 4.76 mmol) in dioxane (6 mL) was added 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.0 g, 4.76 mmol), Pd(dppf)Cl2DCM (408 mg, 0.5 mmol) and sat. NaHCO3 solution (2 mL). The mixture was stirred at 100° C. for 2 h under nitrogen. The mixture was cooled to rt and diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=4:1) to give 930 mg (86%) of the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.13-2.16 (2H, m), 2.53 (2H, s), 2.65 (2H, t, J=6.4 Hz), 2.96 (2H, t, J=6.0 Hz), 3.94 (2H, t, J=5.6 Hz), 4.34 (2H, s), 6.26 (1H, s), 7.25 (1H, d, J=5.6 Hz), 7.33 (1H, d, J=8.4 Hz), 7.99 (1H, d, J=8.0 Hz). [M+H] Calc'd for C15H16O2, 229. Found, 229.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH:5]=O.O.[NH2:16]N>C(O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:3]=[N:2][NH:16][CH:5]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C=C(C=O)c1ccc(F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2cn[nH]c2)cc1

Procedure:
To a solution of 3-(dimethylamino)-2-(4-fluorophenyl)acrylaldehyde (3.0 g) in ethanol (30 mL) was added hydrazine monohydrate (0.90 mL), followed by heating and refluxing for 3 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure until the amount of the reaction liquid was reduced to about a half. Water (20 mL) was added thereto, and the resulting solid was collected by filtration and dried under reduced pressure to obtain 4-(4-fluorophenyl)-1H-pyrazole (2.44 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH+:3]1[O-:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1
Solvent: ClCCl
Product: CC1(C)CS(=O)(=O)CC(C)(C)[NH+]1[O-]
Temperature: 25 °C

Procedure:
5.7 g (0.03 mole) of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is dissolved in 100 ml of methylene chloride. To this solution there is then added dropwise at 20°C in ca. 90 minutes a solution of 11.2 g of m-chloroperoxybenzoic acid in 100ml of methylene chloride. The reaction is slightly exothermic. Stirring is subsequently maintained for 15 hours at room temperature, and the precipitated m-chlorobenzoic acid filtered off. The reddish coloured methylene chloride solution is extracted twice with 50 ml of 2N sodium hydroxide solution each time, and then with 50 ml of 2N hydrochloric acid, and subsequently dried over sodium sulphate. After the solvent has been distilled off, the residue is crystallised from ethanol to obtain 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-1,4,4-trioxide (8) of the formula ##SPC12##
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1>[C:9]([C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1nc(Br)cs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1csc(C=O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 3.7 %

Procedure:
A solution of 4-bromo-2-thiazolecarboxaldehyde (14.8 g), 1-dodecyne (14.1 g), and triethylamine (23.5 g) in dry tetrahydrofuran (85 m) was chilled to 5° C. and degassed under nitrogen. bis(Triphenylphosphine)palladium (II) chloride (0.54 g) and copper (I) iodide (0.07 g) were added to the mixture, which was degassed, and stirred, under nitrogen, at room temperature for 2.5 hrs. The reaction mixture was heated at 40° C. for 7 hrs, during which time additional amounts of 1-dodecyne (3.9 g), bis(triphenylphosphine)palladium (II) chloride (0.11 g), and copper(I)iodide (0.02 g) were added. The mixture was cooled to room temperature, the precipitate was collected, and the filter cake was washed with ethyl acetate. The filtrate was diluted with ethyl acetate (300 ml). Water was added in portions, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with heptane to heptane: 1% ethyl acetate. A portion (1.05 g) of the residue was rechromatographed, eluting with hexane:(0.3 to 1%) ethyl acetate. The appropriate fractions were collected and evaporated to yield 0.79 g (76.5% yield) of product, mp 25.5°-26° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12]Br.[C:15]([O:19][C:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH:23]1[CH2:31][NH:32][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:34])=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[C:15]([O:19][C:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][N:32]([CH2:12][C:5]1[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14])[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:34])=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(NCC1Nc2ccccc2N1C(=O)OC(C)(C)C)c1ccccn1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C(C)c1ccccn1

Procedure:
Using General Procedure A: Reaction of 2-bromomethyl-5-cyano-benzoic acid methyl ester and 2-[(1-pyridin-2-yl-ethylamino)-methyl]-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester in CH3CN with DIPEA, KI, and DMAP gave 2-{[(4-cyano-2-methoxycarbonyl-benzyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a light yellow solid. 1H NMR (CDCl3) δ 1.56-1.59 (m, 3H), 1.71 (s, 9H), 3.86 (s, 3H), 4.23 (s, 1H), 4.28-4.30 (m, 2H), 4.40-4.47 (m, 2H), 7.10-7.16 (m, 1H), 7.24-7.32 (m, 3H), 7.42-7.46 (m, 1H), 7.51-7.66 (m, 2H), 7.71-7.76 (m, 1H), 7.82 (d, 1H, J=1.7 Hz), 7.92 (d, 1H, J=8.0 Hz), 8.53 (d, 1H, J=4.8 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1.ClCCl.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1)[CH3:23]
Reactant: CCO
Reactant: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Solvent: ClCCl
Product: CCOc1nc(-c2ccccc2O)nc2ccccc12
Temperature: 180 °C

Procedure:
2-(4-Chloro-quinazolin-2-yl)-phenol (50 mg, 0.196 mmol) was placed in a microwave tube charged with a stir bar and dissolved 0.5 ml dry dichloromethane, followed by the addition of 2 ml dry ethanol. Tube was sealed with a cap and heated at 160 to 200° C. for one hour in CEM microwave. Solvent was removed under reduced pressure, reconstituted organic in DMSO and purified by Gilson HPLC. The desired compound was concentrated to a white solid as the TFA salt. LC/MS (10-99%) M/Z 267.2, retention time 2.57 minutes.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:29]1([CH2:36][CH2:37][C:38]2[S:42][C:41]([C:43]([O-])=O)=[CH:40][CH:39]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[Li+]>>[N:29]1([CH2:36][CH2:37][C:38]2[S:42][C:41]([CH2:43][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:40][CH:39]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C([O-])c1ccc(CCN2CCCCCC2)s1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: [Li+]
Product: CCN(Cc1ccc(CCN2CCCCCC2)s1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 71.1 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and lithium 5-(2-azepan-1-ylethyl)thiophene-2-carboxylate (60 mg) according to an analogous synthetic method to Example 152 and purified by LC-MS, the title compound (29 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:16][CH2:17][CH3:18])=[C:5]([CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[O:11][CH3:12])C=O.CC1C=CC(S(O)(=O)=O)=CC=1.CO[CH:32]([O:35][CH3:36])[O:33][CH3:34].[OH-].[K+]>CO>[CH3:12][O:11][C:10]1[C:3]([O:2][CH3:1])=[C:4]([CH2:16][CH2:17][CH3:18])[C:5]([CH:32]([O:33][CH3:34])[O:35][CH3:36])=[CH:8][C:9]=1[N+:13]([O-:15])=[O:14]
Reactant: CCCc1c(C=O)cc([N+](=O)[O-])c(OC)c1OC
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(OC)OC)cc([N+](=O)[O-])c(OC)c1OC

Procedure:
A solution of the aldehyde from step (d) (14 g) tosic acid (0.2 g) and trimethylorthoformate (6.7 ml) in dry methanol (100 ml) was heated under reflux for 30 mins. A solution of potassium hydroxide in methanol (5 ml) was added to the reaction mixture and the solution evaporated to dryness. The residue was dissolved in ether, washed with water, dried, filtered and evaporated to leave a solid which crystallised from pentane as pale yellow prisms (11.6 g); mp 52.1°-54.0°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:17]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:18]
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.61 mmol) of the compound of Example 15A were dissolved in 2.0 ml of DMF, and the mixture was degassed with argon. After addition of 79 mg (0.67 mmol) of zinc cyanide and 42 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium(0), the reaction was stirred in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 120° C. for 30 min. After cooling, solid components were filtered off and the filtrate was separated into its components by preparative HPLC (Method 15). Concentration of the product fractions and drying of the residue under high vacuum gave 115 mg (88% pure, 61% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]1([CH2:29][C:30]([N:32]=[C:33]=[S:34])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:21]=[CH:20][C:19]([NH:22][C:33]([NH:32][C:30](=[O:31])[CH2:29][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[S:34])=[CH:18][CH:17]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cn3)c2cc1OC
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cn3)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 298.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine (85 mg, 0.0285 mmol, 1.0 eq.), and Phenyl-acetyl isothiocyanate (256 mg, 1.44 mmol, 5.0 eq.) dissolved in EtOAc/MeOH 50:50 (2 mL). The reaction mixture was stirred at room temperature for 12 hours, and the solvent was evaporated via rotary evaporation. Purification was done on Biotage with solvent system 95% EtOAc, 4% TEA and 1% MeOH. The combined pure fractions were concentrated and dried under vacuum overnight to yield 1-[6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-3-phenylacetyl-thiourea as a light yellow solid (40.4 mg, 29.7%). 1H NMR (400 MHz, CDCl3): 8.65 (d, 1H), 8.33 (d, 1H), 8.27 (dd, 1H), 7.35 (m, 7H), 7.15 (d, 1H), 6.92 (d, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 3.76 (s, 2H); MS (EI) for C25H22N4O4S: 475 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:38]([N:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][NH2:53])[CH2:47][CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:53][CH2:52][CH2:51][N:48]2[CH2:49][CH2:50][N:45]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:46][CH2:47]2)=[O:15])[CH:3]=1
Reactant: NCCN1CCN(Cc2ccccc2)CC1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C(=O)NCCN2CCN(Cc3ccccc3)CC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, 2-(4-benzylpiperazino)ethan-1-amine (41.3 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulforxide/methanol and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (t, 3H) 2.19-2.51 (m, 9H) 3.14-3.20 (m, 1H) 3.35 (t, 2H) 3.42-3.49 (m, 2H) 4.41-4.49 (m, 2H) 6.97-7.11 (m, 1H) 7.19-7.44 (m, 5H); MS (ESI) positive ion 409 (M+H).
Reaction SMILES: [C:1]1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH2:15]([NH:19][CH:20]([C:23]1[CH:28]=[CH:27][C:26](OCC)=[CH:25][CH:24]=1)[CH2:21][NH2:22])CCC>>[CH3:15][NH:19][CH:20]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:1])[CH:28]=1)[CH2:21][NH2:22]
Reactant: CCCCNC(CN)c1ccc(OCC)cc1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: CNC(CN)c1cccc(C)c1

Procedure:
m.p. dihydrochloride 202°-205° C; β-n-butylamino-β-(4-ethoxyphenyl)-ethylamine;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17](O)(=[O:28])[CH2:18][NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:16][C:17]([CH2:18][NH:19][C:20](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1Cl
Reactant: O=C(O)CNC(=O)c1ccccc1
Product: O=C(CNC(=O)c1ccccc1)NC(c1ccccc1)c1ccc(Cl)cc1Cl

Procedure:
Prepared in analogy to example 1.1 from rac-C-(2,4-dichloro-phenyl)-C-phenyl-methylamine (example 4.2) and hippuric acid.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[Br:6][C:7]1[CH:8]=[CH:9][C:10](I)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]>Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:4][CH3:5])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: CC[Zn]CC
Reactant: COC(=O)c1cc(Br)ccc1I
Agent: Cl
Product: CCc1ccc(Br)cc1C(=O)OC
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 176.1 %

Procedure:
Add diethyl zinc (3050 mL, 3.05 mol, 1 M hexane) over 3 hours to a 5° C. solution of methyl 5-bromo-2-iodobenzoate (1876 g, 5.50 mol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (40 g, 0.05 mol). Heat the mixture to 60-65° C. over 2 hours and stir for an additional 2 hours, then cool to 10-15° C. and pour into ice cold aqueous 1 M HCl (10 L). Separate the phases, extract the aqueous layer with methyl-tert-butyl ether (2×10 L), combine the organic phases, wash with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and evaporate under reduced pressure. Dissolve in ethyl acetate (400 mL) and add petroleum ether (8 L), then let stand at 15-20° C. for 16 hours and filter through a pad of silica gel, wash with ethyl acetate/petroleum ether (1:20, 8 L) and evaporate the filtrate under reduced pressure to provide the title compound as a pale yellow oil (1306 g, 96%). ES/MS m/e: (79Br/81Br) 243/245 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH:12]=[C:13]([CH3:21])[CH2:14][O:15][CH2:16][P:17](=[O:20])([OH:19])[OH:18])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2.[C:26]1(O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:26]1([O:20][P:17]([CH2:16][O:15][CH2:14][C:13]([CH3:21])=[CH:12][CH2:11][C:10]2[C:2]([OH:1])=[C:3]3[C:7](=[C:8]([CH3:24])[C:9]=2[O:22][CH3:23])[CH2:6][O:5][C:4]3=[O:25])(=[O:19])[OH:18])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(O)O)C(=O)OC2
Reactant: Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(O)Oc1ccccc1)C(=O)OC2
Temperature: 25 °C
Yield: 31.7 %

Procedure:
To a solution of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid (49 mg, 0.13 mmol) in DMF (0.4 mL) and phenol (62 mg, 0.65 mmol) was added dicyclohexyl carbodiimide (107 mg, 0.52 mmol) and DMAP (8 mg, 0.065 mmol) in DMF (0.6 mL), slowly at 0° C. The reaction was allowed to warm to room temperature and heated to 140° C. for 10 hours. After cooling to room temperature the mixture was filtered and extracted with aqueous 1N NaOH solution. The aqueous layer was acidified with aqueous 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by RP HPLC to provide 18.5 mg of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid monophenyl ester, as a pale yellow solid and 4.1 mg of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diphenyl ester (minor product) also as a pale yellow solid. Major product: 1H NMR (300 MHz, CD3OD) δ 1.82 (s, 3H), 2.16 (s, 3H), 3.46 (d, 2H, J=7 Hz), 3.70 (d, 2H, J=8 Hz), 3.77 (s, 3H), 3.96 (s, 2H), 5.25 (s, 2H), 5.52 (t, 1H, J=8 Hz), 7.10-7.21 (m, 3H), 7.30 (t, 2H, J=8 Hz) ppm; 31P (121.4 MHz, CD3OD) δ 17.3 ppm; MS (m/z) 449.0 [M+H]+, 471.2 [M+Na]+. Minor product: 1H NMR (300 MHz, CD3OD) δ 1.82 (s, 3H), 2.15 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.98-4.06 (m, 4H), 5.25 (s, 2H), 5.50-5.61 (m, 1H), 7.10-7.25 (m, 6H), 7.30-7.41 (m, 4H) ppm; 31P (121.4 MHz, CD3OD) δ 16.3 ppm; MS (m/z) 525.2 [M+H]+, 547.2 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:27][CH2:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COc1cccc(CCN)c1
Solvent: CCN(CC)CC
Product: COc1cccc(CCNc2nc(Cl)nc3c2ncn3C2CCCC2)c1

Procedure:
2-Chloro-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-(3-methoxyphenyl)ethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH3:15])([CH3:14])[C:7](=O)[CH2:6][CH2:5]2.[NH:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])N>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:8]([CH3:15])([CH3:14])[C:7]3[NH:17][C:19]4[C:26]([C:6]=3[CH2:5][C:4]=2[CH:3]=1)=[CH:25][CH:24]=[C:21]([C:22]#[N:23])[CH:20]=4
Reactant: COc1cc2c(cc1Cl)CCC(=O)C2(C)C
Reactant: N#Cc1cccc(NN)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Cl)Cc1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
6-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound I1-1, 4.45 g, 16.5 mmol) and 3-hydrazinobenzonitrile (2.63 g, 1.2 eq.) were dissolved in TFA (91 mL), and stirred at 90° C. for 3 hours. According to the concentration under reduced pressure, TFA was removed and the residues were added with saturated aqueous solution of NaHCO3, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with ethyl acetate. After stirring at room temperature, the precipitated solid was separated by filtration. The filtrate was concentrated under reduced pressure to obtain the target compound as a mixture with 11-3 (red powder, 6.46 g).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:25])=O>>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][Cl:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(CO)cc1OCCCCCC
Reactant: O=S(Cl)Cl
Product: CCCCCCOc1ccc(CCl)cc1OCCCCCC
Temperature: 25 °C

Procedure:
Thionyl chloride (140 ml.) and 3,4-dihexoxybenzyl alcohol (14.0 g.) are combined and stirred at room temperature for one-half hour, at which time gas evolution ceases. The mixture is refluxed for one-half hour and then distilled to remove thionyl chloride (about 100 ml.). The residue is poured into ice-water (250 g. of each) and the aqueous solution extracted with chloroform (3× 100 ml.). The chloroform extracts are combined, washed successively with saturated sodium bicarbonate solution (2× 100 ml.) and water (3× 100 ml.). It is then dried (Na2SO4) and concentrated to give 3,4-dihexoxybenzyl chloride as a brown oil (11.7 g.).