Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:24])[N:5]2[C:10]3[CH:11]=[CH:12][N:13](S(C4C=CC(C)=CC=4)(=O)=O)[C:9]=3[N:8]=[CH:7][C:6]=12.C([O:27][C:28]([CH2:30][N:31]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32]1)=[O:29])C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:24][C:4]1[N:5]2[C:10]3[CH:11]=[CH:12][NH:13][C:9]=3[N:8]=[CH:7][C:6]2=[C:2]([C:34]2[CH:33]=[N:32][N:31]([CH2:30][C:28]([OH:29])=[O:27])[CH:35]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C)n23)cc1
Reactant: CCOC(=O)Cn1cc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-c2cnn(CC(=O)O)c2)c2cnc3[nH]ccc3n12
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-1-methyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.356 g, 0.878 mmol) (Preparation #AB.1), 1-(ethoxycarbonylmethyl)-1H-pyrazole-4-boronic acid, pinacol ester (0.295 g, 1.05 mmol), and Cs2CO3 (0.1716 g, 2.20 mmol) were combined in 1,4-dioxane (7.0 mL) and water (1.8 mL). The mixture was degassed by bubbling N2 directly into the mixture. After about 10 min, PdCl2(PPh3)2 (0.043 g, 0.061 mmol) was added and degassing continued for about 5 more min. The mixture was heated at about 85° C. for about 16 h. Aqueous NaOH (1 N, 3 mL) was added and heating continued for about 2 h. The mixture was allowed to cool to rt and aqueous HCl (1 N, 10 mL) was added. The mixture was concentrated in vacuo to give 2-(4-(1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)-1H-pyrazol-1-yl)acetic acid: LCMS (Table 2, Method b) Rt=1.37 min.; MS m/z: 297 (M+H)+
Reaction SMILES: O[CH:2]([P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.S(Br)([Br:23])=O>C(Cl)Cl>[Br:23][CH:2]([P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Br)Br
Reactant: COP(=O)(OC)C(O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COP(=O)(OC)C(Br)c1ccccc1
Reaction time: 8 h
Yield: 88.2 %

Procedure:
In a round bottom flask 4 (1 g, 4.63 mmol, 1 eq) was dissolved in dry DCM (10 mL) and dry pyridine (0.47 mL, 5.78 mmol, 1.25 eq) was added. Thionyl bromide (0.45 mL, 5.78 mmol, 1.25 eq) was then added to the round bottom flask under inert atmosphere. The round bottom flask was sealed with a septum, cooled in an ice bath and slowly allowed to come to room temperature overnight. The solvent was then evaporated and the crude product was dissolved in ethyl acetate. The organic layer was washed with 1 M HCl, saturated NaHCO3, water, brine, then dried over Na2SO4 and filtered. The solvent was evaporated and the crude product was purified on a silica plug 1:4 (hexanes:ethyl acetate) followed by 3:7 (hexanes:ethyl acetate) to give 5 as a viscous oil (1.14 g, 88%). The product was dried under high vacuum over P2O5. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=7.8 Hz, 2H), 7.34 (d, J=7.5 Hz, 3H), 7.26 (s, 1H), 4.88 (d, J=13.1 Hz, 1H), 3.85 (d, J=10.8 Hz, 3H), 3.60 (d, J=10.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 134.56 (d, JC-P=3.3 Hz), 129.70 (d, JC-P=6.7 Hz), 129.40 (d, JC-P=2.2 Hz), 129.04 (d, JC-P=1.3 Hz), 54.87 (dd, JC-P=22.1, 7.0 Hz), 41.11 (d, JC-P=159.9 Hz). 31P NMR (162 MHz, CDCl3) δ 20.55 (s). ESIMS calculated for C9H12BrO3PNa [M+Na]+300.96, found: 300.96.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][NH:10][C:11]([NH:13][NH2:14])=[O:12]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:9][NH:10][C:11]([NH:13][N:14]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:12])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: NNC(=O)NN
Solvent: CO
Product: O=C(NN=Cc1cccnc1)NN=Cc1cccnc1
Reaction time: 1 h

Procedure:
32.2 g of pyridine-3-carbaldehyde are added in the course of approx. 10 minutes, at room temperature, to a suspension of 13.5 g of carbohydrazide in 200 ml of methanol, the temperature rising to more than 35°. The reaction mixture is further stirred for 1 hour and then cooled to 5°. The crystals that precipitate are filtered off with suction and dried in vacuo at 70°. 40 g of the title compound having a melting point of 202-204° are thus obtained.
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:12][C:13]([F:20])([F:19])[C:14](=[CH2:18])[C:15]([OH:17])=[O:16]>>[F:12][C:13]([F:20])([F:19])[C:14](=[CH2:18])[C:15]([O:17][CH:2]([O:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)[CH:1]([CH3:10])[CH3:8])=[O:16]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: C=C(C(=O)O)C(F)(F)F
Product: C=C(C(=O)OC(OC12CC3CC(CC(C3)C1)C2)C(C)C)C(F)(F)F
Yield: 63 %

Procedure:
By following the same procedures as in Examples 1-1-1 to 1-1-3 aside from using 1-adamantanol instead of 2-adamantanol and 2-(trifluoromethyl)acrylic acid instead of methacrylic acid, 1-(1-adamantyloxy)-2-methylpropyl 2-(trifluoromethyl)acrylate was produced (four step yield 63%).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH2:20]Br.O>C1COCC1>[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH2:20][CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: COc1cc(Br)c(CBr)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)c(CCC#N)cc1OC
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.3 mL of acetonitrile (5.8 mmoles, 1.8 eq.) in 15 mL of THF there are added, at −60° C., 1.77 mL of n-butyllithium (2M in cyclohexane, 3.5 mmoles, 1.1 eq.). The solution is stirred for 15 minutes at −60° C. and then 1 g of 1-bromo-2-(bromomethyl)-4,5-dimethoxybenzene (3.2 mmoles) dissolved in 5 mL of THF is added. The reaction mixture is stirred for 1 hour and then hydrolysed using 10 mL of water and extracted twice with ethyl acetate. The organic phases are combined and evaporated under reduced pressure. The crude reaction product is purified by chromatography on silica gel (eluant: methylcyclohexane/ethyl acetate (70/30)). After evaporating off the solvent under reduced pressure, 505 mg of an orange oil which crystallises in the form of a beige solid are obtained.
Reaction SMILES: [CH3:1][C:2](=[CH:17][C:18](=[O:20])[CH3:19])[C:3](=[O:16])[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]>[Ni].C(OCC)(=O)C>[CH3:1][CH:2]([CH2:17][C:18](=[O:20])[CH3:19])[C:3](=[O:16])[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: CC(=O)C=C(C)C(=O)CN1C(=O)c2ccccc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(=O)CC(C)C(=O)CN1C(=O)c2ccccc2C1=O
Reaction time: 0.2 h
Yield: 97.6 %

Procedure:
3-Methyl-1-phthalimidohex-3-ene-2,5-dione (423 mg, 1.56 millimoles) was catalytically hydrogenated with 300 mg of Raney nickel (containing ethanol) in 45 ml ethyl acetate using a catalytic reduction apparatus. In 12 minutes, hydrogen was absorbed in an amount stoichiometrically required to hydrogenate the carbon-carbon double bond of the above compound. The catalyst was separated by suction filtration with a care taken not to bring it into contact with the air. The solvent was evaporated from the filtrate under reduced pressure to afford 416 mg of 3-methyl-1-phthalimidohexane-2,5-dione as white crystals in a yield of 98%. Recrystallization from methanol afforded colorless prisms having a melting point of 101.5° to 102.5° C. The spectral data and the results of elemental analysis of the product were as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[N:13][CH:12]=1.Br[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[N:22]3[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]3=[N:20][CH:19]=2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[N:13][CH:12]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccnnc2)c1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccnnc4)c3)cnc2n1

Procedure:
4-Fluoro-3-(pyridazin-4-yl)phenylboronic acid (300 mg, 1.38 mmol) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (100 mg, 0.39 mmol) using the method of Example 20. Purification by chromatography (silica gel, 3% MeOH/CH2Cl2) then dissolving in toluene and washing with water followed by recrystallisation from hot toluene with isohexane gave the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.73 (6H, s), 3.23 (1H, s), 7.41 (1H, dd, J 10, 9 Hz), 7.75-7.78 (1H, m), 8.08-8.13 (1H, m), 8.28 (1H, s), 8.31 (1H, dd, J 7, 2 Hz), 8.83 (1H, s), 9.32 (1H, dd, J 5, 1 Hz), 9.50-9.52 (1H, m); MS (ES+) m/z 351 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:3][C:2]=1[NH:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)#[N:9]
Reactant: Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)ccc2C#N)c1
Reaction time: 3 h

Procedure:
A mixture of tert-butyl (1S,2R)-2-(3-bromo-4-cyanophenylamino)cyclohexylcarbamate (98 mg, 0.25 mmol), m-toluidine (54 uL, 0.50 mmol), BINAP (31 mg, 0.050 mmol), Pd(OAc)2 (12 mg, 0.053 mmol) and Cs2CO3 (160 mg, 0.49 mmol) in toluene (3 mL) was degassed with Ar, then was stirred at 100 C for 3 h. EtOAc and water were added. The organic phase was separated, washed with 1N HCl, then with brine, dried over Na2SO4, concentrated in vacuo to give tert-butyl (1S,2R)-2-(4-cyano-3-(m-tolylamino)phenylamino)cyclohexylcarbamate as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]([OH:22])[N:6]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:7]2=[O:12].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.[I:42]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([I:42])=[C:8]2[C:4]=1[CH:5]([OH:22])[N:6]([C:13]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:21])[C:7]2=[O:12]
Reactant: II
Reactant: COc1cccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 77 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.55 g, 11.9 mmol) was dissolved in THF (140 mL), and the solution was treated with TMEDA (4.00 mL, 26.2 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 26.4 mL, 26.2 mmol) and iodine (3.62 g, 14.3 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=9/1, 7/3) to obtain 4-methoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (3.88 g, yield 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)=[O:8].[OH-].[Na+].O.C(O)C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)=[O:8]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc(F)ccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)O)cc1
Yield: 86.4 %

Procedure:
A mixture of 0.60 g of ethyl 4-[(5-fluoro-2-methylbenzoyl)amino]benzoate 0.60 ml of 10N NaOH, 25 ml of water and 50 ml of absolute ethyl alcohol is heated on a steam bath for 1 hour, cooled and acidified with acetic acid. The resulting solid is filtered and dried in vacuo at 60°-80° C. to give 0.47 g of the desired product as a solid, m.p. 272°-275° C.
Reaction SMILES: I[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].CCCCC>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(I)c(N)n1
Reactant: COc1ccc(Cl)c(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCCC
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(-c2ccc(N)nc2N)c1
Temperature: 80 °C
Yield: 109 %

Procedure:
To a suspension of 3-iodopyridine-2,6-diamine (Preparation 44, 2 g, 8.51 mmol) in 1,4-dioxane (10 ml) and water (5 ml) was added 2-chloro-5-methoxyphenyl boronic acid (0.793 g, 4.25 mmol), cesium carbonate (2.77 g, 8.51 mmol) and palladium tetrakis(triphenylphosphine) (0.123 g, 0.0125 mmol). The reaction was purged with nitrogen and heated at 80° C. for 20 minutes. Three further portions of palladium tetrakis(triphenylphosphine) (0.123 g, 0.0125 mmol) and 2-chloro-5-methoxyphenyl boronic acid (0.793 g, 4.25 mmol) were added at 20 minute intervals. The reaction was heated at 80° C. for 18 hours before concentrating in vacuo. The residue was taken up in ethyl acetate (20 ml) and washed with a saturated aqueous solution of brine (20 ml) before drying over Na2SO4 and concentrating in vacuo. The residue was purified by silica gel column chromatography, eluting with 50:50 to 100:0 ethyl acetate:pentane to afford the title compound as a brown foam (1.157 g, 55% yield).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:18]=[O:19])=[CH:13][CH:12]=2)[N:8]=1)=[O:2].[Cl:20]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:20][C:6]1[S:5][C:4]([NH:3][CH:1]=[O:2])=[N:8][C:7]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH:18]=[O:19])=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=CNc1ccc(SCc2csc(NC=O)n2)cc1
Solvent: CC(=O)O
Product: O=CNc1ccc(SCc2nc(NC=O)sc2Cl)cc1
Temperature: 50 °C
Yield: 61.2 %

Procedure:
To a solution of 2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole (2.9 g) in acetic acid (30 ml) was portionwise added N-chlorosuccinimide at 50° C. with stirring. The mixture was heated at 50° C. with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1), washed with water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 5-chloro-2-formylamino 4(4-formylaminophenylthiomethyl)thiazole (2.0 g yield: 61.2%).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C@@H:6]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[N:15]=1)=[O:9])C.[OH-].[Na+]>CCO>[F:30][C:26]1[CH:25]=[C:24]([C@@H:6]([NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:15]=2)=[O:9])[CH2:5][C:4]([OH:31])=[O:3])[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C[C@H](NC(=O)NCCCc1ccc2c(n1)NCCC2)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@H](NC(=O)NCCCc1ccc2c(n1)NCCC2)c1cccc(F)c1
Reaction time: 2 h

Procedure:
To a solution of 11-9 (0.4037 mmol) in EtOH (3 mL) was added 1N NaOH (0.600 ml, 0.600 mmol). After stirring for 2 h, the solvents were evaporated and the residue was chromatographed (silica gel, 20:10:1:1 to 10:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 11-10 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5](Br)[CH:4]=1.C([Li])CCC.C[O:22][C:23]([CH:25]1[CH2:31][CH2:30][C:29]2([C:33]3([CH3:38])[O:37][CH2:36][CH2:35][O:34]3)[CH2:32][CH:26]1[C:27](=[O:39])[O:28]2)=O>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([C:23]([CH:25]2[CH2:31][CH2:30][C:29]3([C:33]4([CH3:38])[O:37][CH2:36][CH2:35][O:34]4)[CH2:32][CH:26]2[C:27](=[O:39])[O:28]3)=[O:22])[CH:4]=1
Reactant: COC(=O)C1CCC2(C3(C)OCCO3)CC1C(=O)O2
Reactant: COc1cc(Br)c(OC)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)C2CCC3(C4(C)OCCO4)CC2C(=O)O3)c(OC)c2ccccc12
Yield: 65 %

Procedure:
Following the method described in Example 4, a solution of 3.2 g of 1,4-dimethoxy-3-bromo-naphthalene in anhydrous tetrahydrofuran was treated at -78° C. with n-butyllithium and then added to a solution in anhydrous tetrahydrofuran of 2.7 g of the compound prepared in Example 3. After silica gel column purification 2.8 g of the title compound was obtained (65% yield) m/z 426 (M+.): IR (film): 1780 cm-1 (C=O, five membered ring lactone), 1670 cm-1 (C=O, benzylic ketone); PMR (CDCl3): inter alia: δ 1.4 (s, CH3), 3.85 (s, two OCH3), 3.9 (s, --O--CH2 --CH2 --O--), 6.9 (s, aromatic H) and 7.4-8.4 (m, four aromatic H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[CH-]=O.[CH-]=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Co].[Co+2]>[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH2:7][CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Cc1ccccc1
Agent: [Co+2]
Agent: [Co]
Agent: [C-]#[O+]
Product: C1=CC=CCCCCCCC=C1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
The catalyst, 75 mg of tris-(dibenzyl sulfide)-tris-chloro-rhodium and 2.4 g of dicobalt octacarbonyl, and 500 g of toluene are introduced into a fine-steel autoclave. The autoclave is repeatedly purged with a 1:1 gas mixture of carbon monoxide and hydrogen with which a pressure of up to 100 bars is established. The autoclave is heated with stirring to 170° C. and the pressure is increased to 200 bars using the same gas mixture, the pressure subsequently being kept constant by the introduction of more CO/H2 when the pressure falls. After 1 hour, the temperature is reduced to 110° C. and a solution of 500 g of cyclododeca-1,5,9-triene in 1,000 g of toluene is pumped into the autoclave over a period of 3 hours. After another 90 minutes, the reaction mixture is cooled and the autoclave is vented and purged with nitrogen. The reaction solution is filtered. The solvent is distilled off at 1,600 Pa. The reaction product is distilled in a thin layer evaporator at 13 Pa and at a jacket temperature of around 220° C. The composition of the distillate is determined by gas chromatography (column: 1 m Carbowax 6000 on Teflon; heating rate: 15° C./min; 130° to 260° C.). The sample is diluted with tetrahydrofuran.
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#N)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].C(O)=[O:19]>>[NH2:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=[O:19])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15]
Reactant: N#Cc1cc(C(F)(F)F)c(N)c(C(F)(F)F)c1
Reactant: O=CO
Product: Nc1c(C(F)(F)F)cc(C=O)cc1C(F)(F)F

Procedure:
A solution of 5 g (19.67 mmol) 4-amino-3,5-bis-trifluoromethyl-benzonitrile in 30 mL formic acid was shaken in 10 equal portions in pressurised containers for 20 h at 110° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][C:46]=1[O:47]CC1C=CC=CC=1)[CH2:12][NH:13][C:14](=[O:43])[CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35]CC2C=CC=CC=2)[CH:22]=1)=[O:18])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][C:46]=1[OH:47])[CH2:12][NH:13][C:14](=[O:43])[CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:35])[CH:22]=1)=[O:18]
Reactant: O=C(CCC(=O)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCC(=O)NCc1ccc(O)c(O)c1)NCc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Succinic acid bis(3,4-dibenzyloxybenzylamide) (300 mg, 0.42 mmol) was dissolved in THF (50 ml) in a pressure bottle and warmed to 35 C to ensure dissolution of the solid. Palladium on carbon (50 mg 10% Pd/C) was added, and the vessel was pressurized with hydrogen (to 3 atm). The reaction was agitated for 1 hour at room temperature, whereupon TLC revealed reaction had gone to completion. The catalyst was removed by
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>>[Si:37]([O:13][C:11]1[CH:10]=[CH:9][C:8]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:20]=3)[CH2:15]2)=[C:7]([NH:6][CH2:5][C:4]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:2]([F:1])[CH:3]=2)[CH:12]=1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: Oc1ccc2c(c1)CCC(c1ccc(O)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Yield: 85.3 %

Procedure:
Synthesized from 6-{2-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzylamino]-4-hydroxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol (240 mg) and tert-butyldimethylsilyl chloride (220 mg) according to an analogous synthetic method to Example 201 described below, the title compound (300 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([O:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: COC(=O)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccccc1Oc1ccnc(Cl)c1
Yield: 70.4 %

Procedure:
Using the method of Example 3, Step A, methyl 2-hydroxybenzoate (2.88 mg, 18.9 mmol), 60% sodium hydride in mineral oil (757 mg, 18.9 mmol), and 2-chloro-4-nitropyridine (3.00 g, 18.9 mmol) were reacted to provide methyl 2-(2-chloropyridin-4-yloxy)benzoate (3.51 g, 70% yield) as an oil. 1H NMR (CDCl3) δ 8.22 (d, 1H), 8.05 (d, 1H), 7.63 (t, 1H), 7.40 (t, 1H), 7.16 (d, 1H), 6.72-6.74 (m, 1H), 3.77 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10](Br)=[CH:9][C:8](C(C2C=CC(CC)=CC=2)=O)=[C:7](Cl)[CH:6]=1)C=C.[CH2:23]([O:26][C:27]1[C:28]([Cl:40])=[C:29]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:30](N(OC)C)=[O:31])[CH:24]=[CH2:25]>>[CH2:23]([O:26][C:27]1[C:28]([Cl:40])=[C:29]([C:30]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:1])=[CH:6][CH:7]=2)=[O:31])[CH:36]=[C:37]([Br:39])[CH:38]=1)[CH:24]=[CH2:25]
Reactant: C=CCOc1cc(Br)cc(C(=O)N(C)OC)c1Cl
Reactant: C=CCOc1cc(Cl)c(C(=O)c2ccc(CC)cc2)cc1Br
Product: C=CCOc1cc(Br)cc(C(=O)c2ccc(OC)cc2)c1Cl

Procedure:
Similar procedure with preparation of 31 proceeded except for using compound 182 to obtain the compound 183.
Reaction SMILES: [CH2:1]([P:17]([OH:19])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:20]O>O>[CH2:1]([P:17](=[O:20])([OH:19])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCP(O)O
Reactant: OO
Solvent: O
Product: CCCCCCCCCCCCCCCCP(=O)(O)O
Reaction time: 6 h
Yield: 97 %

Procedure:
29.0 g (0.1 mol) of hexadecylphosphonous acid (produced as in example 7) are suspended in 150 ml of water and at about 30° C. 30% strength hydrogen peroxide solution is passed through the suspension at a flow rate of 1 mol equivalent per hour. After the reaction has ended after 6 hours, the reaction solution is filtered and the residue is dried under reduced pressure to obtain 29.7 g (97% of theory) of hexadecylphosphonic acid as a colorless solid.