Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.Cl.[F:4][C:5]1[CH:6]=[C:7]([S:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]([NH2:24])=[O:23])=[CH:17][CH2:16][CH2:15]3)[CH:8]=[CH:9][CH:10]=1.[H][H]>CO>[F:4][C:5]1[CH:6]=[C:7]([S:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([C:22]([NH2:24])=[O:23])[CH2:17][CH2:16][CH2:15]3)[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)C1=CCCc2cc(Sc3cccc(F)c3)ccc21
Reactant: [H][H]
Agent: Cl
Agent: O=O
Solvent: CO
Product: NC(=O)[C@@H]1CCCc2cc(Sc3cccc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm) a catalyst solution was prepared in the glass insert of a 6 ml autoclave by reacting a solution of 6.45 mg (0.00668 mmol) of [Ru(trifluoroacetate)2((S)-pTol-MeOBIPHEP)] (S/C 25) in 0.5 ml of methanol with 0.5 ml of methanol containing 0.020 mmol of HCl and stirring for 2 h at room temperature. After addition of 50 mg (0.167 mmol) of 6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acid amide, the asymmetric hydrogenation was run for 18 hours at 40° C. under 40 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave, the methanol solution was filtered through a silicagel pad and evaporated in vacuo to give (R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid amide in quantitative yield and with an enantiomeric ratio of 98.8:1.2. The conversion was >=99.9%.
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N>C(O)(=O)C.O.[Rh]>[CH:1]1([C:7]23[CH2:14][CH2:13][N:10]([CH2:9][CH2:8]2)[CH2:11][CH2:12]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc(C23CCN(CC2)CC3)cc1
Agent: [Rh]
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: C1CCC(C23CCN(CC2)CC3)CC1
Reaction time: 120 h
Yield: 91.1 %

Procedure:
4-Phenylquinuclidine (5 g) (see J. Org. Chem., 22, 1484, (1957)) was dissolved in glacial acetic acid (25 ml), 5% w/w rhodium-on-alumina (2 g) was added and the mixture hydrogenated for 5 days at 345 kPa (50 psi). The mixture was filtered through a short column of Arbacel (trade mark) filter aid and the pad washed with methanol. The filtrate was collected and the solvent removed under reduced pressure to give a residue which was dissolved in water. The pH was adjusted to >10 by addition of 0.88 aqueous ammonia solution. The aqueous mixture was extracted with ethyl acetate (×3) and the organic layers combined, washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give 4-cyclohexylquinuclidine (4.7 g) as a pale pink solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]2)(=O)=O)=CC=1>COCCOC>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][N:18]([CH:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]2)[C:17](=[O:21])[CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(OCc3ccccc3)cc2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
Potassium tert-butoxide (5.05 g) was added at room temperature to a DME (70 mL) solution of 4-(benzyloxy)pyridin-2(1H)-one (7.55 g). The reaction mixture was stirred at room temperature for 10 minutes. Then, potassium carbonate (10.4 g) and tert-butyl 4-(((4-methylphenyl)sulfonyl)oxy)piperidine-1-carboxylate (20.0 g) were added thereto, and the mixture was stirred at 100 C for 1 day in a nitrogen atmosphere. Then, DME (30 mL) was added thereto, and the mixture was further stirred during the weekend at 100 C. Saturated saline was added to the reaction mixture, followed by extraction with ethyl acetate twice. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.40 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=2[N+:22]([O-])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:22][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:11]=1[CH2:10][NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1ccc(CNc2cccc(C#N)c2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(CNc2cccc(C#N)c2)c(N)c1
Yield: 108.6 %

Procedure:
Ethyl 4-[(3-cyanophenylamino)methyl]-3-nitrobenzoate (5.79 g) was dissolved in 50 ml of ethanol, then 50 ml of purified water, 0.96 g of ammonium chloride and 4.97 g of iron powder were added and the mixture was refluxed under heating for 40 minutes. The reaction solution was filtered through Celite and concentrated in vacuo. Ethyl acetate was added to the resulting residue. The mixture was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, concentrated in vacuo and dried to give 5.71 g of ethyl 3-amino-4-[(3-cyanophenylamino)methyl]benzoate.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:24]=[C:25]([Cl:27])[N:26]=2)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:13])[CH2:5][CH2:4]1.[Cl:28][C:29]1[C:33]([Cl:34])=[C:32]([CH3:35])[NH:31][C:30]=1[C:36](NC1CCN(C2C=CC=C(Cl)N=2)CC1)=[O:37]>>[Cl:27][C:25]1[CH:24]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:36]([C:30]3[NH:31][C:32]([CH3:35])=[C:33]([Cl:34])[C:29]=3[Cl:28])=[O:37])[CH2:8][CH2:7]2)[N:26]=1)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:13]
Reactant: NC1CCN(c2cc(C(=O)NCCCN3CCOCC3)cc(Cl)n2)CC1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cccc(Cl)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NCCCN4CCOCC4)cc(Cl)n3)CC2)c(Cl)c1Cl

Procedure:
The title compound was synthesised by an analogous method to Example 99 starting from 2-(4-aminopiperidin-1-yl)-6-chloro-N-(3-morpholin-4-ylpropyl)isonicotinamide hydrochloride salt (Intermediate 219) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27]Cl)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:17][C:16]2[C:15]3[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=3)[O:9][C:8](=[O:19])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][CH2:21]1
Reactant: ClCCN1CCOCC1
Reactant: O=c1oc2cc(O)ccc2c(O)c1-c1ccccc1
Product: O=c1oc2cc(O)ccc2c(OCCN2CCOCC2)c1-c1ccccc1
Yield: 77.6 %

Procedure:
Following the method of Example 30, 30.5 g. (0.12 mol) of 3-phenyl-4,7-dihydroxy-coumarin are treated with 19.5 g. (0.13 mol) of 2-morpholino-1-chloroethane. 34 g. of an oil are obtained, which cannot be crystallised. Yield 77.6% (theoretical yield 44.7 g.).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7](I)=[C:6]([CH2:11][CH3:12])[N:5]=[C:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].[F:19][C:20]([F:25])([F:24])C([O-])=O.[Na+].CN1CCCC1=O>CCOCC.[Cu]I>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([C:20]([F:25])([F:24])[F:19])=[C:6]([CH2:11][CH3:12])[N:5]=[C:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: CCc1nc(-c2ccccc2)n(CC)c(=O)c1I
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCc1nc(-c2ccccc2)n(CC)c(=O)c1C(F)(F)F
Temperature: 175 °C
Yield: 47.3 %

Procedure:
A mixture of 1.00 g (2.5 mmol) of 3,6-diethyl-5-iodo-2-phenyl-4(3H)-pyrimidinone, 1.08 g (5.7 mmol) of copper (I) iodide, 1.54 g (11.3 mmol) of sodium trifluoroacetate and 8 mL of anhydrous N-methylpyrrolidinone was heated at 175° C. for 2 h. The mixture was cooled, diluted with 175 mL of ether, washed with four 50 mL portions of water and dried over MgSO4. Removal of the solvent on the rotovap afforded 0.92 g of crude product as a brown oil. This material was purified by flash chromatography on a 25 g column of silica gel eluting with 100 mL portions of 0, 10, 20, 30, 40, 50 and 75% ether in hexanes to afford 0.35 g of 3,6-diethyl-2-phenyl-5-trifluoromethyl-4(3H)-pyrimidinone (compound 185) as a white solid. 1H-NMR (CDCl3) 1.25(3H,t), 1.30(3H,t), 2.8(2H,q), 4.0(2H, q), 7.5(5H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][N:12]=1)=[O:6].N1CCCCC1.O>C1(C)C=CC=CC=1>[C:13]1([C:10]2[S:9][C:8]3=[N:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:12]3[N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CCCCl)Nc1nnc(-c2ccccc2)s1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C1CCCN2N=C(c3ccccc3)SC2=N1

Procedure:
A mixture of 4-chloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)butanamide (1.1 g, 0.004 mol) and piperidine (0.7 g, 0.8 ml, 0.008 mol) in toluene (50 ml) was heated under reflux for 3 h. The reaction mixture was cooled, poured into water and stirred. Toluene was separated dried and evaporated to give a crude product which was purified by repeated silica gel and neutral alumina column chromatography eluting with EtOAc/hexane (50:50 v/v) and CHCl3/hexane (80:20 v/v); mp 189-92° C., m/e 245, 90% (consistent with molecular formula C12H11N3OS, calcd. 245.06) 1H NMR CDCl3): δ 2.33-2.36 (m, 2H, —CH2), 2.75 (t, J=7.5 Hz, 2H, —CH2), 4.28-4.31 (t, J=7.5 Hz, 2H, —CH2), 7.46-7.52 (m, 3H, ArH), 7.94-8.10 (m, 2H, ArH). 13C NMR: δ 18.3, 31.3, 47.9, 127.4, 129.1, 130.5, 130.6, 157.4, 163.9, 173.6.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH:19]1([CH2:24][C:25](O)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([CH2:24][C:25]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)CC1CCCC1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(CC1CCCC1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-cyclopentylacetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.00 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 3.81-3.84 (m, 4H), 3.05-3.14 (m, 4H), 2.29 (d, J=7.5 Hz, 2H), 2.13-2.23 (m, 1H), 1.75-1.84 (m, 2H), 1.49-1.66 (m, 4H), 1.21-1.29 (m, 2H); MS (ESI−) M/Z 355 (M−H)−.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH2:6]([C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:1][CH:3]2[O:5][CH2:4]2)=[CH:19][CH:20]=1)=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Cc1ccccc1)c1ccc(OCC2CO2)cc1

Procedure:
A 100 ml 3-neck round-bottom flask equipped with a magnetic stir bar, thermometer and reflux condenser was charged with 11.0 g epichlorohydrin, 5.0 g 4-hydroxyphenyl benzyl ketone, and 0.1 ml H2O. The reactants were stirred on a hotplate. NaOH was then added, ~0.2 g per addition, up to a total of 0.95 g NaOH. The rate of NaOH addition was controlled to keep the reaction temperature below 100° C. At the end of the exothermic reaction, excess epichlorohydrin was removed by vacuum distillation with the flask temperature kept below 150° C. The residue was air-dried, then recrystallized twice from ethanol and redried. The yield was 2.8 g (44%), m.p. 81.0°-82.4° C. A 1H-NMR spectrum of this compound, with peak assignments, is provided in FIG. 1.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4](=O)[O:3]1.[NH2:20][OH:21]>C(OCC)(=O)C>[OH:21][N:20]1[C:2](=[O:1])[C@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4]1=[O:3]
Reactant: NO
Reactant: CC(C)C(=O)O[C@@H]1C(=O)OC(=O)[C@H]1OC(=O)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)C(=O)O[C@H]1C(=O)N(O)C(=O)[C@@H]1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of compound (30) (5.98 g, 22 mmol) in ethyl acetate (50 mL) at 0° C. was added a 50% aqueous solution of hydroxylamine (1.75 g, 26.4 mmol). The resulting mixture was stirred at room temperature for 3 h and washed successively with aqueous citric acid solution and brine, then dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was suspended in toluene and the reaction mixture heated under reflux for 5 h, with the azeotropically liberated water being collected in a Dean-Stark apparatus. Toluene was removed in vacuo to afford the title compound (28) (6.3 g, quantitative yield). 1H-NMR (400 MHz, CDCl3): δ 1.22 (d, J=6.8 Hz, 12H), 2.69 (hept, J=6.8 Hz, 2H), 5.48 (s, 2H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[CH2:10])[CH2:5][CH:4]1[CH:11]=[CH2:12])=[CH2:2].[CH3:13][O:14][SiH:15]([O:18][CH3:19])[O:16][CH3:17]>[Pt]>[CH3:13][O:14][Si:15]([O:18][CH3:19])([O:16][CH3:17])[CH2:2][CH2:1][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][Si:15]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:13])[CH2:5][CH:4]1[CH2:11][CH2:12][Si:15]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:13]
Reactant: CO[SiH](OC)OC
Reactant: C=CC1CCC(C=C)C(C=C)C1
Agent: [Pt]
Product: CO[Si](CCC1CCC(CC[Si](OC)(OC)OC)C(CC[Si](OC)(OC)OC)C1)(OC)OC
Temperature: 90 °C

Procedure:
Into a 500 ml round-bottom flask, equipped with an addition funnel, thermometer, condenser and a magnetic stirrer, were charged 1,2,4-trivinylcyclohexane (50 grams, 0.31 mole, from Acros Organics) and platinum catalyst (10 ppm of H2PtCl6 solution from Sigma-Aldrich). The mixture was heated to 90° C. and dry air was bubbled into the reaction mixture. Trimethoxysilane (124 grams, 1.02 mole, from Momentive), was added to the flask using an addition funnel over a 70-minute period at such a rate as to maintain the reaction temperature at approximately 90° C. The reaction was recatalyzed with platinum catalysts (10 ppm of platinum-divinyltetramethyldisiloxane complex, containing 1.9% Pt, Karstedt's catalyst; see U.S. Pat. No. 377,452) and promoted with dried air sparge. The reaction was monitored using gas chromatography. After the reaction was complete, excess trimethoxysilane was removed by vacuum distillation. The final product is a clear yellow liquid.
Reaction SMILES: [C:1](=[O:19])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]3[CH2:39][CH2:38][NH:37][CH2:36]3)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C>ClCCCl.O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]3[CH2:39][CH2:38][N:37]([C:1]([O:2][CH2:3][C:4]4[N:5]=[CH:6][S:7][CH:8]=4)=[O:19])[CH2:36]3)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(-c2ccc(OCC3CCNC3)cc2)cc1
Reactant: O=C(OCc1cscn1)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O
Product: O=C(OCc1cscn1)N1CCC(COc2ccc(-c3ccc(F)cc3)cc2)C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
0.30 g (1.07 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate, 0.34 g (1.28 mmol) of 3-(4′-fluorobiphenyl-4-yloxymethyl)pyrrolidine, 0.20 g (1.61 mmol) of N,N-diisopropylethylamine and 0.01 g (0.11 mmol) of dimethylaminopyridine are dissolved in 10 ml of 1,2-dichloroethane. The mixture is stirred at 70° C. for 4 hours. After returning to ambient temperature, water is added to the reaction medium. After extraction of the aqueous phase with dichloromethane, the organic phases are successively washed three times with a 1M aqueous sodium hydroxide solution and then twice with a saturated aqueous ammonium chloride solution. After having dried the organic phases over sodium sulphate, they are filtered and the filtrate is evaporated to dryness. After purification by chromatography on a column of silica gel, elution being carried out with dichloromethane and methanol (98/2), 0.16 g of the expected product is obtained in the form of a powder.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][C:4]=1[CH3:39].Br.CC(O)=O>CCOC(C)=O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:27][CH:26]=3)=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][C:4]=1[CH3:39]
Reactant: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OCCN4CCCC4)cc3)c2cc1C
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2cc1O
Temperature: 25 °C
Yield: 51.3 %

Procedure:
A solution of 7-methoxy-6-methyl-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-3-(4-trifluoromethyl-phenyl)-chromen-2-one (50 mg, 0.093 mmol) in 1:1 48% HBr:AcOH (3 μL) was heated at 130° C. for 7 h. The mixture was cooled to room temperature and poured into AcOEt/1 M NaOH. The layers were separated and the organic phase was washed with H2O (2×) and brine and dried (MgSO4). The solvent was removed in vacuo. The residue was purified using reverse phase HPLC, followed by extraction with AcOEt/NaHCO3 to provide the desired compound as a yellow solid (25 mg, 52%). 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.21 (d, J=0.75 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 6.72 (s, 1H), 6.62 (d, J=8.8 Hz, 2H), 4.14 (t, J=5.5 Hz, 2H), 3.92 (s, 2H), 3.13 (t, J=5.5 Hz, 2H), 2.97–2.85 (br s, 4H), 2.13 (s, 3H), 2.00–1.89 (m, 4H); MS (ESI) m/z 523.9 (M)+; HPLC tR 5.07 min.
Reaction SMILES: C([Li])CCC.[C:6]1([P:12](=[O:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:31]1(=[O:37])[O:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CCCCCC.O1CCCC1>[OH:37][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([CH:13]([P:12](=[O:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:36]
Reactant: CCCCCCCCCCCP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC(C(=O)CCCCO)P(=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.6M n-Butyl lithium solution in hexane (56 ml) was added to a stirred solution of the phosphine oxide (31.0 g) in dry tetrahydrofuran (400 ml) at -40° to -45° C. under nitrogen. The deep orange solution was stirred for 10 minutes at -40° to -50° C., then a solution of valerolactone (9.0 g) in dry tetrahydrofuran was added. The pale solution was allowed to warm to room temperature, poured on to ice and extracted with ether. The extract was dried and evaporated and the residue was crystallised from ether-petroleum spirit to give 1-(5-hydroxypentanoyl)undecyl-diphenylphosphine oxide, m.p. 70° C.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:12][C:13](=[O:38])[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2(O)[NH:34][C:33]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[N:31]=4)[N:26]=[CH:25][C:24]=3[O:23][CH2:22]2)[CH2:17][CH2:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([BH3-])#N.[Na+]>ClCCl.CO>[CH2:5]([O:12][C:13](=[O:38])[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]2[NH:34][C:33]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[N:31]=4)[N:26]=[CH:25][C:24]=3[O:23][CH2:22]2)[CH2:17][CH2:16]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc2ncc3c(c2n1)NC(O)([C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1)CO3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1)CO3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic acid (10 μL, 0.17 mmol, 5.4 eq) is added at room temperature to a stirred solution of [trans-4-(3-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid benzyl ester (15 mg, 0.03 mmol, 1.0 eq) in dichloromethane (3 mL) and methanol (3 mL), followed by sodium cyanoborohydride (10 mg, 0.16 mmol, 5.0 eq). After 30 minutes stirring at room temperature, the reaction mixture is extracted with ethyl acetate (3×10 mL) and a saturated ammonium chloride aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 10:1, v/v) to afford [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid benzyl ester as a white solid (11 mg, 76% yield).
Reaction SMILES: [OH-].[Li+].IC1C=C(C=CC=1)C[O:8][C:9](=[O:29])[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([I:18])[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([I:27])[CH:22]=2)=[C:14]([I:28])[CH:13]=1.Cl.CO>C1COCC1>[I:18][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][C:9]([OH:29])=[O:8])[CH:13]=[C:14]([I:28])[C:15]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([I:27])[CH:22]=1
Reactant: O=C(CCc1cc(I)c(OCc2cccc(I)c2)c(I)c1)OCc1cccc(I)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1cc(I)c(OCc2cccc(I)c2)c(I)c1
Reaction time: 14 h
Yield: 94.6 %

Procedure:
A 1.2 M solution of lithium hydroxide (275 ,L, 0.33 mmol) was added to a solution of 3-[3,5-diiodo-4-(3-iodo-benzyloxy)-phenyl]-propionic acid 3-iodo-benzyl ester (as prepared in Example 2, 213 mg, 0.25 mmol) in 2 mL THF. The biphasic solution was stirred for 14 hours, then 6 mL 0.5 M HCl was added and an oil formed. Methanol (0.5 mL) was added and the oil formed a solid, which was removed by filtration, yielding the title compound as an off-white powder (150 mg, 95%). 1H NMR (400 MHz, DMSO-d6): δ 12.15 (s, 1H), 7.96 (s, 1H), 7.76-7.75 (m, 3H), 7.62 (d, J=7.6 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 4.87 (s, 2H), 2.75 (t, J=7.2 Hz, 2H), 2.54 (t, J=7.4 Hz). HPLC (40-90), 17.23 min. LRMS (EI−) calc'd for [C16H13I3O3+CF3COO] 746.8, found 746.8.