Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]3[CH:23]=[CH:24][N:25]=[C:18]3[CH2:17][O:16][C:15]=2[C:14]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:11])=[O:10].[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[Sn](CCCC)(CCCC)CCCC)[CH3:31].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.CS(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]3[CH:23]=[CH:24][N:25]=[C:18]3[CH2:17][O:16][C:15]=2[C:14]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:11])=[O:10])[CH3:31]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1nccn1-2
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1nccn1-2
Temperature: 95 °C
Yield: 24.8 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate (Intermediate 25, 0.598 g), N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.997 g), tris-(dibenzylideneacetone)dipalladium (0) (0.057 g) and tri-tert-butylphosphonium tetrafluoroborate (0.036 g) in dioxane (15 mL) and DMSO (1.5 mL) was de-gassed and purged with nitrogen then heated to 95° C. under an atmosphere of nitrogen for 2 hours. Further amounts of tris-(dibenzylideneacetone)dipalladium (0) (0.057 g) and tri-tert-butylphosphonium tetrafluoroborate (0.036 g) were added and the mixture stirred and heated at 95° C. for 2 hours. Further amounts of N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.997 g), tris-(dibenzylideneacetone)dipalladium (0) (0.057 g) and tri-tert-butylphosphonium tetrafluoroborate (0.036 g) were added and the mixture was stirred and heated at 95° C. for 30 minutes. After cooling, the mixture was diluted with ethyl acetate and washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-30% to give methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-5-oxa-3,9b-diaza-cyclopenta[a]naphthalene-6-carboxylate (0.158 g) as a light brown foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH:14]4[CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][N:13]4[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:29]([N:36]1[C:44]([CH3:45])=[C:43]2[C:38]([CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=[CH:42]2)=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CN(C=O)C.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>[CH2:29]([N:36]1[C:44]([CH3:45])=[C:43]2[C:38]([CH:39]=[C:40]([C:8]3[CH:9]=[C:10]([CH:11]4[O:16][CH2:15][CH:14]5[CH2:17][NH:18][CH2:19][CH2:20][N:13]5[CH2:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:41]=[CH:42]2)=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2nn1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN2CC(c3cc(Br)c4c(N)ncnn34)OCC2C1
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: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2ccc(-c3cc(C4CN5CCNCC5CO4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a stirred solution of tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (300 mg, 0.66 mmol) and tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.099 mmol) in degassed 1,4-dioxane (5 mL) and DMF (5 mL) were added 2-benzyl-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (345 mg, 0.99 mmol), K2CO3 (274 mg, 1.99 mmol), and H2O (1.0 mL). The reaction was degassed and heated (100° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (250 mL) and saturated aqueous K2CO3 solution (200 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The crude residue was dissolved in dichloromethane (20 mL) and treated with trifluoroacetic acid (5 mL). The solution was allowed to stir for 30 minutes and concentrated. The mixture was partitioned between ethyl acetate (75 mL) and H2O (50 mL). The layers were separated and the organic phase was washed with 1N HCl (50 mL). The combined aqueous phase was transferred to a stirring mixture of ethyl acetate and pH 14 brine and allowed to stir for 30 minutes, keeping the pH above 12 with additional NaOH pellets as needed. The layers were partitioned and aqueous layer was extracted 2× with ethyl acetate (75 mL ea.). The combined organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 135 mg (42%) of the desired product. 1H NMR (300 MHz, DMSO-d6) 7.91 (s, 1 H), 7.78 (d, 1 H), 7.52 (s, 1 H), 7.34-7.19 (m, 5 H), 7.21 (dd, 1H), 6.72 (s, 1H), 5.63 (s, 2H), 5.12 (dd, 1H), 3.73 (dd, 1H), 3.30-3.23 (m, 1H), 2.92 (dd, 1H), 2.75-2.64 (m, 4H), 2.61 (s, 3H), 2.41 (t, 1H), 2.25-2.06 (m, 4H); LC-MS [M+H]+=495, RT=2.17 min.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(-c2ccccc2)cc1
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(F)cc1

Procedure:
Chlorosulfonic acid (8.7 mL, 0.13 mole) was added dropwise to stirred cold (0° C.) 4-fluorobiphenyl (10.2 g, 59 mmol). After 30 minutes at 0° C. the reaction mixture was poured onto ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water, brine, dried over magnesium sulfate, and concentrated to afford a white solid. The desired 4′-fluorobiphenylsulfonyl chloride (4.3 g), was separated from 4′-fluorobiphenylsulfonic acid by crystallization of the latter from ethyl acetate and crystallization of the remaining material from hexanes.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[NH:8][N:7]=2)=[CH:2]1.P(Cl)(Cl)([Cl:19])=O>ClC(Cl)C>[Cl:19][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(-c2ccsc2)c2ccccc12
Solvent: CC(Cl)Cl
Product: Clc1nnc(-c2ccsc2)c2ccccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
500 mg of 4-(3-thienyl)-1-phthalazinone and 3 ml of phosphorus oxychloride were dissolved in 6 ml of dichloroethane, and the solution was stirred at 100° C. for 4 hours. The reaction solution was distilled off, and a 1-N aqueous NaOH solution was added thereto under cooling with ice. The solution was extracted with chloroform and dried over magnesium sulfide. The solvent was then distilled off, thereby obtaining 515 mg of 1-chloro-4-(3-thienyl)phthalazine.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1B1OC(C)(C)C(C)(C)O1)[C:17]([O:19]C)=[O:18]>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:23]1[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[CH3:13])[CH:11]=[CH:10]2
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Product: Cc1cc(C(=O)O)ccc1-c1ccc2cc(O)ccc2n1

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol and methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. 1H NMR (DMSO-d6, 400 MHz): δ 10.45 (brs, 1H), 8.61-8.46 (m, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 2.42 (s, 3H). MS (ESI): m/z 279.9 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:13])[NH:7][C:8](SC)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[N:14]1([CH2:20][C:21]2[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=2)[O:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([C:5]1[C:6](=[O:13])[NH:7][C:8]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:23]2[CH:29]=[CH:30][CH:31]=[C:21]([CH2:20][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:22]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(SC)[nH]c1=O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Product: CCCCc1cnc(NCCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O
Yield: 82.5 %

Procedure:
A mixture of 5-butyl-2-(methylthio)-4(3H)-pyrimidinone (0.85 g) and 3-[3-[(1-piperidinyl)methyl]phenoxy]propanamine (1.1 g) was heated at 98°-100° for 6 hours and 140° for 2 hours. The residue was chromatographed (silica/methanol) to give an oil which solidified yielding the title compound (1.41 g) m.p. 105°-105.5°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:8](=[O:16])[NH:7][C:6]1=[O:17].Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[C:25]1([CH2:29][CH2:28][NH:27][CH2:26]1)[CH2:24][CH2:23]2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN1C(=O)CCC1>[ClH:1].[F:19][C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[C:25]1([CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[CH:10]=[C:9]([C:11]4[S:12][CH:13]=[CH:14][CH:15]=4)[C:8](=[O:16])[NH:7][C:6]3=[O:17])[CH2:26]1)[CH2:24][CH2:23]2
Reactant: Fc1ccc2c(c1)CCC21CCNC1
Reactant: O=c1[nH]c(=O)n(CCCCl)cc1-c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c(=O)n(CCCN2CCC3(CCc4cc(F)ccc43)C2)cc1-c1cccs1
Temperature: 70 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A mixture of 1-(3-chloropropyl)-5-(thiophen-2-yl)pyrimidine-2,4(1H,3H)-dione (Prep24, 50 mg, 0.18 mmol), 5-fluoro-2,3-dihydrospiro[indene-1,3′-pyrrolidine]hydrochloride salt (Prep14, 52 mg, 0.27 mmol), potassium carbonate (112 mg, 0.81 mmol), sodium iodide (112 mg, 0.75 mmol) and NMP (1 ml) was stirred at 70° C. overnight. The mixture was diluted with water and extracted with ethyl acetate. The EA phase was evaporated and the crude purified by preparative TLC to give the free base of the title compound (60 mg). the compound was purified by preparative HPLC and treated with a 1N solution of HCl-ether to give the title compound (6 mg, y=7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:11]2[CH:20]=[CH:19][C:18]3[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=3[CH:12]=2)\[CH3:10])=[CH:4][CH:3]=1.[P:25]([O:32][CH2:33][CH3:34])([O:29]CC)[O:26][CH2:27][CH3:28].C(Br)C>[Ni](Br)Br>[CH3:21][C:17]1([CH3:22])[CH2:16][CH2:15][C:14]([CH3:23])([CH3:24])[C:13]2[CH:12]=[C:11](/[C:9](/[CH3:10])=[CH:8]/[C:5]3[CH:4]=[CH:3][C:2]([P:25]([O:26][CH2:27][CH3:28])(=[O:29])[O:32][CH2:33][CH3:34])=[CH:7][CH:6]=3)[CH:20]=[CH:19][C:18]1=2
Reactant: C/C(=C\c1ccc(Br)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOP(OCC)OCC
Agent: Br[Ni]Br
Solvent: CCBr
Product: CCOP(=O)(OCC)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
20 g (52 millimoles) of (E)-1-(4-bromophenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propene and 0.86 g (7.5 mol %) of anhydrous nickel(II) bromide were heated to about 160° C. under nitrogen in a distillation apparatus equipped with a dropping funnel. 104 g (60 millimoles) of triethyl phosphite were then added dropwise in such a way that the rate of dropwise addition corresponded to the rate at which the ethyl bromide distilled off. Stirring was continued for 0.5 hour, after which the mixture was cooled, a little toluene was added and the mixture was evaporated down. The residue was filtered with ethyl acetate over silica gel. 14.2 g (62%) of the title compound of melting point 72.5°-73.5° C. (from heptane) were obtained in this manner. Preparation of 1-(bromophenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propene
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14](Cl)[CH:13]=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1.[Na].[CH3:22][OH:23]>>[CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([O:23][CH3:22])[CH:13]=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(Nc2cc(Cl)ccc2[N+](=O)[O-])cc1
Reactant: CO
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc(N(C)C)cc2)c1

Procedure:
24.9 g of N,N-dimethyl-N′-(5-chloro-2-nitrophenyl)benzene-1,4-diamine was added to a solution that consists of 8 g of sodium in 200 ml of methanol, and the mixture was heated in an autoclave for 9 hours to 120° C. After cooling, crystalline product was suctioned out.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11].O=O>ClCCCl.C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[CH3:3][C:4]1[C:5](=[O:1])[C:6]([CH3:10])=[CH:7][C:8](=[C:8]2[CH:7]=[C:6]([CH3:10])[C:5](=[O:11])[C:4]([CH3:3])=[CH:9]2)[CH:9]=1
Reactant: [OH-]
Reactant: Cc1cccc(C)c1O
Agent: [Co+2]
Agent: O=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1=CC(=C2C=C(C)C(=O)C(C)=C2)C=C(C)C1=O
Temperature: 30 °C

Procedure:
The reaction was carried out in the same manner as in Comparative Example 1 without employing sodium hydroxide. More specifically, after 122 gm (1.0 mole) of 2,6-dimethylphenol had been dissolved in 2200 gm of 1,2-dichloroethane and 32.5 gm (0.1 mole) of "Salcomine" had been added to the solution, oxygen was passed into the mixture at 30°C. The temperature of the reaction system was raised gradually, but it was maintained at 30°C by cooling. During the above procedure there was formed 3,3',5,5'-tetramethyldiphenoquinone. After 5 hours had passed, the reaction mixture was filtered, and the filtrate was poured into 20 liters of methanol containing 2 liters of hydrochloric acid but precipitation of a polymer was not observed. The amount of diphenoquinone obtained was 12.3 gm, the yield being 10.1%.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.CCOC(C)=O>[Br:9][CH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: Cc1sccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccsc1CBr
Yield: 46.3 %

Procedure:
2-Methyl-thiophene-3-carbonitrile [see Beaton, et al.; Tetrahedron Lett. 39, 10, 1998, 1227-1230] (1.36 g, 11 mmol), N-bromosuccinimide (2.56 g, 14.4 mmol), and a catalytic amount of benzoyl peroxide were stirred in benzene (30 mL) at 80° C. for 2h. The solution was diluted with EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (10% EtOAc/hexanes) gave 1.03 g (46%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.39 (d, 1H, J=5.6 Hz), 7.17 (d, 1H, J=5.6 Hz), 4.79 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH:37]1[CH2:42][CH2:41][O:40][C:39]([CH3:44])([CH3:43])[CH2:38]1)(=O)=O.[Br-].[Li+]>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH:37]2[CH2:42][CH2:41][O:40][C:39]([CH3:44])([CH3:43])[CH2:38]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(COS(C)(=O)=O)CCO1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCOC(C)(C)C3)c2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 36.2 %

Procedure:
A mixture of N2-Butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. under nitrogen with stirring for 1 h. (2,2-Dimethyltetrahydro-2H-pyran-4-yl)methyl methanesulfonate (152 mg) was added and stirring was continued for 5 h at 50° C. The reaction was cooled to room temperature and stirred for 16 h. Lithium bromide (50 mg) was added and heating was continued for 5 h at 50° C., then 8 h at 90° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give crude material (210 mg). This was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to give the title compound (75 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1I.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.[Cu]Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Br:15])=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: Brc1ccccc1I
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1ccc(Oc2ccccc2Br)cc1C
Temperature: 120 °C
Yield: 30.3 %

Procedure:
A mixture of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (2.0 g, 10.3 mmol), 1-bromo-2-iodobenzene (8.74 g, 30.9 mmol), cesium carbonate (4.03 g, 12.4 mmol), copper (I) chloride (0.51 g, 5.15 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (0.47 g, 2.55 mmol) in 1-methyl-2-pyrrolidinone (20 mL) is heated to 120° C. for 10 hours under N2. The reaction is cooled and quenched with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 1.09 g (30%) of the title compound. Rf=0.34 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][C:2]1[CH:1]=[C:6]([O:7][CH2:11][CH:10]=[CH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(C)c1
Reaction time: 18 h
Yield: 94.5 %

Procedure:
m-Cresol 10.4 ml (100 mmole), 10.8 ml (125 mmole) allyl bromide, and 16.56 g (120 mmole) of potassium carbonate were stirred in 50 ml of acetone and refluxed, with stirring, under nitrogen, for 18 hours. The reaction was cooled, the insoluble inorganics were filtered off and the filtrate was stripped to give 14.0 g (95%) of subtitled product, which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[C@@H:11]1([NH:21][CH2:1][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: N#Cc1cccc(C=O)c1
Product: N#Cc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-Formylbenzonitrile and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]1[C:18](=[O:19])[C:9]2=[CH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[CH:17]=[C:8]2[CH2:7]1.[Br:20]Br.O>ClCCl>[Br:20][C:17]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]2[C:18](=[O:19])[CH:6]([CH3:5])[CH2:7][C:8]=12
Reactant: BrBr
Reactant: CC1Cc2cc3c(cc2C1=O)CCCC3
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1Cc2c(cc3c(c2Br)CCCC3)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 43.0 g (322 mmol) of AlCl3 in 50 ml of dichloromethane, a solution of 26.4 g (132 mmol) of 2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-1-one in 25 ml of dichloromethane was added dropwise, while vigorously stirring, over 10 min at 0° C. Then, 6.8 ml (21.1 g, 132 mmol) of bromine was added dropwise over 1 h at this temperature. The resulting mixture was stirred overnight at this temperature and then added to 400 ml of cold water. The organic layer was separated, and the aqueous layer was extracted with 3×150 ml of methyl-tert-butyl ether. The combined organic fractions were washed with aqueous Na2CO3, dried over K2CO3, and evaporated to dryness. Fractional distillation gave the title product, b.p. 165-175° C./1 mm Hg. Yield 19.3 g (53%) of yellowish oil.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.Cl.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:11][C@@H:12]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:26]=1)[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14]
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Yield: 99.5 %

Procedure:
100 g (0.206 mol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionate (1.1) from Example 1 were dissolved in 1 liter of methanol, the solution was treated with methanolic hydrogen chloride solution and with 10 g of 20% palladium hydroxide/carbon and hydrogen was passed in for 6 hours. Then the catalyst was filtered off, the solution was evaporated and the residue was treated with tert-butylether. The precipitate formed was filtered off. 72 g (90%) of an amorphous powder were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:19]([C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:34]=1[OH:35])[C:26]([O:28][CH2:29][CH2:30][NH2:31])=[O:27])([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:19]([C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:34]=1[OH:35])[C:26]([O:28][CH2:29][CH2:30][NH:31][C:8](=[O:9])[C:7]1[CH:11]=[C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:13]([OH:14])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)=[O:27])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(C(=O)OCCN)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)NCCOC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
To a stirred solution of 25 grams (0.1 mole) of 3,5-di-t-butyl-4-hydroxybenzoic acid and 29.3 grams (0.1 mole) of N-(3,5-di-t-butyl-4'hydroxybenzoyloxyethyl)amine in 100 milliliters of drytetrahydrofuran was added dropwise a solution of 20.6 grams (0.1 mole) of dicyclohexylcarbodiimide in 75 milliliters of dry tetrahydrofuran. The mixture was stirred for several hours and the white solid (dicyclohexyl urea) was filtered off and discarded. Evaporation of the filtrate gave a product which was recrystallized from 1:1 benzene-hexane to give N-(3',5'di-t-butyl-4'-hydroxybenzoyloxyethyl)-3,5-di-t-butyl-4-hydroxybenzamide; melting point 185°-187° C. When tested by the procedure of Example 2, the sample containing this compound lasted 1,000 hours, about 3.3 times as long as the control.