Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([CH2:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]1)#[CH:12]>C(N(CC)CC)C.COC(C)(C)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>[CH2:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]#[C:12][C:2]2[N:3]=[N:4][C:5]([CH2:8][CH2:9][CH3:10])=[CH:6][CH:7]=2)[CH2:18][CH2:17]1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCc1ccc(Br)nn1
Reactant: C#C[C@H]1CC[C@H](CCCCC)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCCCC[C@H]1CC[C@H](C#Cc2ccc(CCC)nn2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
8.0 g of 3-bromo-6-propylpyridazine (prepared according to Example 3) were dissolved in 50 ml of triethylamine in a sulphonation flask under nitrogen. The solution was cooled to 0° C., treated with 562 mg of bis-(triphenylphosphine)-palladium (II) dichloride and 76 mg of copper (I) iodide and then treated dropwise within 20 minutes with 7.5 g of trans-1-ethynyl-4-pentylcyclohexane. The mixture was subsequently stirred at 0° C. for several hours, then at room temperature overnight and finally at 50° C. for a further 3 hours. For the working-up, the dark coloured mixture was diluted with 100 ml of tert.butyl methyl ether and suction filtered through a paper filter (rinsing with tert.butyl methyl ether). The filtrate was concentrated on a rotary evaporator. The dark coloured crystalline residue was taken up in 150 ml of tert.butyl methyl ether and washed successively with 100 ml of 2% (wt./vol.) ammonium chloride solution and with 100 ml of water. Each of the aqueous phases were back-extracted with a small amount of tert.butyl methyl ether. The combined organic phases were dried over sodium sulphate and concentrated on a rotary evaporator. For the purification, the brown coloured crystals obtained were chromatographed on silica gel with hexane/ethyl acetate (vol. 2:1), there being obtained a fraction of the desired product 3-[2-(trans-4-pentylcyclohexyl)ethynyl]-6-propylpyridazine (5.2 g) and a mixed fraction consisting of 3-bromo-6-propylpyridazine and product (4.8 g). The pure fraction was recrystallized once from ethanol at -20° C. and once from hexane at -20° C. and finally dried well in a vacuum drying oven at 40° C. There were thus obtained 3.4 g (28.5%) of 3-[2-(trans-4-pentylcyclohexyl)ethynyl]-6-propylpyridazine in the form of white crystals of melting point (C-I) 118.5° C., boiling point 210°-220° C./0.08 Torr.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[F:7][C:8]([F:25])([F:24])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(I)CC>C1COCC1>[F:7][C:8]([F:24])([F:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][C:10]=1[CH:19]([CH2:1][CH2:2][CH3:3])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCC(C(=O)OC)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reaction time: 1 h
Yield: 87 %

Procedure:
Potassium t-butoxide (7.7 ml, 1M in THF, 7.7 mmol) was added to a solution of methyl 2-[2,5-bis(trifluoromethyl)phenyl]acetate (2 g, 7 mmol) in THF at 0° C. The resulting yellow solution was stirred for 40 min. n-Propyl iodide (1.7 g, 10.5 mmol) was added and the mixture stirred for 1 h. The mixture was poured onto HCl (2M) and extracted into EtOAc. The combined organic phases were washed with Na2S2O3 solution, brine, then dried (MgSO4) and concentrated in vacuo to give the product as a yellow oil (2 g, 87%). 1H NMR (400 MHz, CDCl3): δ 0.92 (3H, t, J 7.3), 1.23-1.29 (1H, m), 1.35-1.43 (1H, m), 1.67-1.81 (1H, m), 2.05-2.17 (1H, m), 3.69 (3H, s), 4.10 (1H, t, J 7.5), 7.62 (1H, s, J 8.2), 7.78 (1H, d, J 8.2), 7.90 (1H, s).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH2:4][CH2:5][OH:6].C(N(CC)C(C)C)(C)C.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])[C:29](O)=[O:30])#[N:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:3]([NH:2][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([O:35][CH:36]([CH3:38])[CH3:37])=[C:26]([C:24]#[N:25])[CH:27]=2)[CH2:4][CH2:5][OH:6])=[CH:13][CH:12]=1
Reactant: N[C@H](CCO)Cc1ccc(Br)cc1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(Br)cc2)cc1C#N
Reaction time: 0.05 h
Yield: 78.7 %

Procedure:
To a suspension of (3S)-3-Amino-4-(4-bromophenyl)-1-butanol hydrochloride (1.80 g, 6.42 mmol) in dry DMF (32 mL) was added N,N-diisopropylethyl amine (2.49 g, 19.3 mmol) and the resultant clear solution was stirred for 3 min. 3-Cyano-4-[(1-methylethyl)oxy]benzoic acid (1.45 g, 7.06 mmol) and HBTU (2.68 g, 7.06 mmol) were added and the reaction was stirred at rt under nitrogen. After 1.5 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (75% EtOAc/hexanes) to give 2.18 g (78%) of the title compound as a white solid. LC/MS (ES) m/e 431.2 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>C[O-].[Na+].CO>[OH:21][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(-c3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (63 mg, 0.21 mmol) and glycine (317 mg, 4.22 mmol) in 0.5 M sodium methoxide/methanol (8 mL) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. Water (20 mL) was added and the suspension was adjusted to pH=10 with 1N HCl (3 mL). The mixture was extracted twice with dichloromethane. And the remaining aqueous layer was acidified to pH=3 with 1N HCl (1.5 mL). The white precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (36 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.49 (br s, 1H), 8.91 (s, 1H), 8.18 (m, 2H), 7.63 (m, 2H), 4.03 (d, J=5.8 Hz, 2H); MS: (+) m/z 329.9 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17](S(C)(=O)=O)[N:16]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[NH2:34].Cl>C(O)C.C(OCC)C>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([NH:34][C:33]3[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:31]([O:30][CH3:29])[CH:32]=3)[N:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2Nc2nc(S(C)(=O)=O)ncc2C#N)cc1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(Nc2ncc(C#N)c(Nc3ccccc3C(=O)c3ccc(C)cc3)n2)cc(OC)c1OC
Temperature: 180 °C
Yield: 36.6 %

Procedure:
To a mixture of 4-{[2-(4-methylbenzoyl)phenyl]amino}-2-(methylsulfonyl) pyrimidine-5-carbonitrile (54 mg, 0.138 mmol) and 3,4,5-trimethoxyaniline (26 mg, 0.142 mmol) in absolute ethanol (3 ml) was added 1N HCl in diethyl ether (3 drops). The reaction was facilitated using microwave irradiation. The reaction was heated at 180° C. for 600 sec. using Personal Chemistry SmithSynthesizer. On cooling a crude yellow solid was collected by filtration. Pure sample was obtained after chromatography to give 4-{[2-(4-methylbenzoyl)phenyl]amino}-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-5-carbonitrile (25 mg, %) as a canary yellow solid. 1H NMR (DMSO-d6): δ 10.0 (s, 1H), 9.39 (br s, 1H), 8.39 (s, 1H), 8.04 (d, 1H, J=8.4 Hz), 7.58-7.48 (m, 4H), 7.28 (t, 1H, J=7.6 Hz), 7.22 (d, 2H, J=7.9 Hz), 6.91 (s, 1H), 3.65 (s, 3H), 3.61 (s, 6H), 2.35 (s, 3H); ES-MS m/z 496 (M+H).
Reaction SMILES: FC(F)(F)[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=1)C)=O.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:3][NH:5][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=1
Reactant: CN(C(=O)C(F)(F)F)c1ccc(C#CCCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNc1ccc(C#CCCCO)cc1

Procedure:
Intermediate 36 (0.221 g, 0.7752 mmol) was reacted with K2CO3 (0.7752 mmol, 0.107 g) in 12 mL of 2:1 MeOH:Water at room temperature overnight. The reaction was worked up quenching the reaction with 1× saturated NaHCO3, extracted 4×25 ml EtOAc then washed 1× water, 1× saturated NaCl, dried over Na2SO4, then concentrated. The product was purified 0-10% MeOH in DCM over 15 min on TEA silica 12 g. ES/MS calcd. for C12H15NO 189.1. Found m/z=190 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1.C(OC([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=2)[C:32](=[O:40])[NH:31]1)=O)(C)(C)C.CO>C(O)CCC>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[C:5]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][N:3]=[C:2]([NH:39][C:36]4[CH:37]=[C:38]5[C:33]([C:32](=[O:40])[NH:31][NH:30]5)=[CH:34][CH:35]=4)[N:7]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: Clc1ncc(-c2ccccc2)c(Nc2cc(C3CC3)n[nH]2)n1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Solvent: CO
Solvent: CCCCO
Product: O=c1[nH][nH]c2cc(Nc3ncc(-c4ccccc4)c(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Temperature: 95 °C
Reaction time: 12 h

Procedure:
To ((2-Chloro-5-phenyl-pyrimidin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (75 mg, 0.241 mmol), was added 6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (180 mg, 0.72 mmol) in n-butanol and the solution was heated to 95° C. in a sealed tube. After 12 hr, the solution was concentrated and the title compound was isolated by preparative HPLC as a white solid (5.2 mg, 5% yield) HNMR (500 MHz, MeOH d-6). □17.82–7.80 (2H, m), 7.59–7.50 (6H, m), 7.19–7.17 (1H, m), 6.08 (1H, s), 2.65 (1H, m), 0.91–0.89 (2H, m), 0.45 (2H, m); LCMS m/e: 1.9 min, 425.1 (M+H), 423.1 (M−H).
Reaction SMILES: [OH:1][CH:2]([CH:27]([OH:29])[CH3:28])[CH:3]=[CH:4][C:5]([O:7][CH:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH:10]([C:16]2([CH3:24])[CH:18]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[O:17]2)[CH:9]1[O:25][CH3:26])=[O:6].[C:30](OC(=O)C)(=[O:32])[CH3:31].N1C=CC=CC=1.[CH2:43]([O:45]CC)[CH3:44]>CN(C)C1C=CN=CC=1.ClCCl>[C:30]([O:1][CH:2]([CH:27]([O:29][C:43](=[O:45])[CH3:44])[CH3:28])[CH:3]=[CH:4][C:5]([O:7][CH:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH:10]([C:16]2([CH3:24])[CH:18]([CH2:19][CH:20]=[C:21]([CH3:22])[CH3:23])[O:17]2)[CH:9]1[O:25][CH3:26])=[O:6])(=[O:32])[CH3:31]
Reactant: CCOCC
Reactant: COC1C(OC(=O)C=CC(O)C(C)O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1C(OC(=O)C=CC(OC(C)=O)C(C)OC(C)=O)CCC2(CO2)C1C1(C)OC1CC=C(C)C

Procedure:
A mixture of 6-(4,5-dihydroxy-2-hexenoyloxy)-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (which is the same compound as "WF 2015A" and was prepared in the same manner as that described in European Patent Application Publication No. 0314401) (34 mg), acetic anhydride (34 μl), pyridine (30 μl), and 4-dimethylaminopyridine (1 mg) in dichloromethane (0.7 ml) was stirred overnight at ambient temperature. The mixture was diluted with diethyl ether and washed with brine (X3). The organic layer was dried and concentrated in vacuo to yield 6-(4,5-diacetoxy-2-hexenoyloxy)-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (41.7 mg) as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)Cl.CS(C)=O.[CH3:14][C@H:15]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:16][CH2:17][OH:18]>C(N(CC)CC)C>[CH3:14][C@H:15]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23])[CH2:16][CH:17]=[O:18]
Reactant: C[C@@H](CCO)CCO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@@H](CC=O)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 56.3 g. of oxalyl chloride in 300 ml. of dry methylene chloride cooled to -60° C. and under a nitrogen atmosphere was added dropwise 74.81 g. of dimethylsulfoxide in 100 ml. of dry methylene chloride. After 15 minutes 92.0 g. of 3-(S)-methyl-5-(t-butyldimethylsilyloxy)-1-pentanol in 250 ml. of the same solvent was added dropwise. After 30 minutes 206.1 g. of triethylamine was added to -60° C. followed by the removal of the cooling bath. The reaction was stirred at room temperature for 1.5 hours, and was then poured into water and extracted with methylene chloride. The extracts were washed with 2.5% hydrochloric, a saturated sodium bicarbonate solution, water and a brine solution, and then dried over magnesium sulfate. The solvent was removed and the residue dissolved in ether and rewashed and dried as before. Removal of the ether gave 90.9 g. of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C-:19]#[N:20].[Na+].O>CN(C=O)C.O>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:19]#[N:20])=[C:2]([Br:1])[CH:3]=1
Reactant: [C-]#N
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[3-bromo-4-(bromomethyl)phenyl]-1,3-benzoxazole (156 mg, 0.42 mmol), and sodium cyanide (41 mg, 0.84 mmol) in DMF:H2O (3:1, 16 mL) was stirred at rt for 18 h. Water (50 mL) was added to the reaction mixture and it was extracted with EtOAc (3×). The organics were combined, washed with brine (2×), dried over Na2SO4, and evaporated to dryness to give an orange oil. The crude oil was purified by flash chromatography eluting with a gradient of EtOAc:hexane (0 to 30 min: 0 to 20% EtOAc) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-bromophenyl]acetonitrile as a yellow solid (M.p. 190–191° C.). 1H NMR (CDCl3, 300 MHz) δ 8.50 (s, 1H), 8.22 (dd, 1H), 7.78 (m, 1H), 7.70 (d, 1H), 7.60 (m, 1H), 7.39 (m, 2H), 3.91 (s, 2H). MS (ESI) 313 (M)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].CC[O:31][C:32]([C:34]1C(C2C=CC=CC=2Cl)C(C(OC)=O)=C(C)[NH:36][C:35]=1[CH2:52][O:53]CCN)=[O:33].C(/C(O)=O)=C/C(O)=[O:60]>ClCCl>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[NH2:36][C@H:35]([C:52]([O-:53])=[O:60])[CH2:34][C:32]([O-:31])=[O:33]
Reactant: O=C(O)/C=C\C(=O)O
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: ClCCl
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
16 g of amlodipine and 12 g of amlodipine maleate were melted in a 300 ml flask. The melted substance was cooled to room temperature and dissolved in 300 ml of dichloromethane. The mixture was extracted with 300 ml of a 1M NaOH solution. The organic layer was discarded and the aqueous layer acidified with 55 ml of a 6 M HCl solution. The mixture was extracted with 300 ml of dichloromethane. The layers were separated and the organic layer dried over Na2SO4. The mixture was evaporated to dryness and the remaining solid recrystallised from ethanol. The obtained solid was dried in a vacuum oven at 40° C. leaving 4.7 g of an off white product.
Reaction SMILES: ClC1C2N(C)O[C@H]3N[C@H](C([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36](=[O:38])[CH3:37])=O)C[C@@]3(O)C=2C=CC=1.C(N(CC)CC)C>CO>[C:36]([O:35][C@@H:20]1[C:21]([CH3:34])=[CH:22][C@H:23]2[C@@:28]([OH:29])([C@@H:27]([CH3:30])[CH2:26][CH2:25][C@H:24]2[C:31]([CH3:33])=[CH2:32])[C@H:19]1[OH:18])(=[O:38])[CH3:37]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C(C)[C@@H]1CC[C@H](C)[C@]2(O)[C@@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b -hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate, (Preparation 1, 100 g) and triethylamine (10 ml) in methanol (1000 ml) was stirred at room temperature for 3 hours. The reaction mixture was evaporated and the residue was crystallised from ethyl acetate/hexane to give a pure sample of the terpene, (1S,2R,4aR,5R,8S,8aS)-1,8a-dihydroxy-5-isopropenyl-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydro-2-naphthalenyl acetate (Preparation 126). The remaining solution was concentrated and purified by flash column chromatography on silica-gel eluting with ethyl acetate:dichloromethane:hexane (2:1:7) to give further terpene moiety (1S,2R,4aR,5R,8S,8aS)-1,8a-dihydroxy-5-isopropenyl-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydro-2-naphthalenyl acetate as a white solid (Preparation 126, 43 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([NH:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:14])=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(-c2ccco2)c2ncn(CC(=O)O)c2n1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2ncn(CC(=O)NCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A suspension of 2-amino-6-(2-furyl)-9H-purine-9-acetic acid (129 mg, 0.5 mmol) in DMF (2 mL) was treated with carbonyl diimidazole (81 mg, 0.5 mmol), stirred at room temperature for 1 h, treated with benzylamine (55 μL, 0.5 mmol), stirred at room temperature for 2 h, diluted with water, filtered and dried to give the title compound (115 mg, 66%) as a white solid.
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:8]([F:9])=[CH:7][C:6]([N:10]2[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])=[CH:5][C:4]=1[F:21].[O:24]1[CH2:29][CH2:28][O:27][CH2:26]C1>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>[CH3:26][O:27][C:28]1[C:29](=[O:24])[CH:5]=[CH:4][C:3]([C:3]2[C:8]([F:9])=[CH:7][C:6]([N:10]3[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]3=[O:20])=[CH:5][C:4]=2[F:21])=[CH:8][CH:7]=1
Reactant: CC(=O)NCC1CN(c2cc(F)c([Sn](C)(C)C)c(F)c2)C(=O)O1
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(-c2c(F)cc(N3CC(CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 110 °C
Yield: 9 %

Procedure:
The (±)-N-[[3-[4-(trimethylstannyl)-3,5-difluorophenyl ]-2-oxo-5oxazolidinyl]methyl]acetamide (80 mg, 0.185 mmol) was dissolved in 1,4-dioxane (5 mL) and then treated with the 5-bromo-2-methoxytropolone (49.5 mg, .230 mmol). After degassing the solution 3 times with N2, the bis(triphenylphosphine)palladium(II) chloride (28 mg, .040 mmol) was added. The solution was degassed (3x) again, after which the reaction was heated to reflux (110° C.) for 5 h. At this point, the reaction was incomplete; more catalyst (28 mg, 0.040 mmol) was added and, after degassing (3×), the solution was again heated to reflux for 5 h. At this time, the reaction was still incomplete; the above process was repeated a third time with more fresh catalyst (28 mg). Finally, the solvent was removed in vacuo and the residual oil was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with aqueous KF (75 mL) and brine (50 mL). After drying over anhydrous Na2SO4, the organic layer was filtered and concentrated under reduced pressure to yield a foamy solid. This solid was purified first by preparative TLC (5% MeOH/CHCl3), and then by radial chromatography (eluting with a gradient of 0-5% MeOH in 10% CH3CN/CHCl3) to give 7 mg (9%) of the title compound as a solid with a HRMS (M+) calculated for C20H18F2N2O5 404.1184, found 404.1183.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[Mg]Br>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)c([Mg]Br)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: Cc1ccc(C)c(C2(O)CCN(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-Benzyl-4-piperidinone (946 mg, 5 mmol) was added to 5 mL anhydrous THF and cooled to 0° C. under nitrogen. 10 mL of 2,5-dimethylphenylmagnesium bromide (0.5 M solution in THF) was added drop-wise. The reaction was stirred at 0° C. for 10 minutes, then allowed to warm to room temperature and stirred for 1 h. The reaction was concentrated, and brought back up in methanol/H2O/acetic acid (1:1:0.5). The solution was filtered and purified by reverse-phase HPLC (2-99% CH3CN/0.085% TFA) to yield 1-benzyl-4-(2,5-dimethyl-phenyl)-piperidin-4-ol 3a. MS (ESI) m/z (M+H+) 296.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Oc1ccccc1F
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(Oc2ccccc2F)cc1[N+](=O)[O-]
Temperature: 160 °C
Reaction time: 48 h
Yield: 383.5 %

Procedure:
To 4-fluoro-2-nitrotoluene (25 g, 0.016 mol), 2-fluorophenol (15.8 mL, 0.017 mol) in NMP (350 mL) was added potassium carbonate (22.27 g, 0.016 mol) and the mixture was stirred at 160° C. for 48 h. After cooling at room temperature, water (350 mL) was added and the solution was extracted into ethyl acetate (2×150 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated and the residue was purified by flash chromatography eluting with Hex:EtOAc 95:5 to yield 15.17 g of 4-(2-fluoro-phenoxy)-2-nitrotoluene: MS: 248 (M+H).