Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)(O)[C:4]=2[CH:3]=1.[I-].[K+].O.[PH2](=O)[O-].[Na+].[PH2](=O)O>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:6]3[C:11]([C:12]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: OC1(c2ccc(F)cc2)c2ccccc2C(O)(c2ccc(F)cc2)c2cc(Br)ccc21
Agent: O=[PH2]O
Agent: O=[PH2][O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-c2c3ccccc3c(-c3ccc(F)cc3)c3cc(Br)ccc23)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
8.32 g (17.3 mmol) of 2-bromo-9,10-bis(4-fluorophenyl)-9,10-dihydro-9,10-anthracenediol, 5.17 g (31.1 mmol) of potassium iodide, 9.90 g (93.4 mmol) of sodium phosphinate monohydrate, and 50 mL of glacial acetic acid were put into a 200 mL three-neck flask, and the mixture was refluxed at 120° C. for 4 hours. Then, 20 mL of a 50% phosphinic acid was added into the reaction mixture, and the mixture was stirred for 1 hour at 120° C. After the reaction, the reaction mixture was washed with water, and the aqueous layer was extracted with ethyl acetate. This extracted solution was combined with the organic layer, and then dried with magnesium sulfate. After drying, the mixture was subjected to suction filtration, and the filtrate was concentrated. The obtained residue was dissolved in toluene, and filtered through Florisil, celite, and then alumina, and the filtrate was concentrated. The obtained residue was recrystallized with chloroform and hexane, giving 7.2 g of 2-bromo-9,10-bis(4-fluorophenyl)anthracene as light yellow powder in 74% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@@:11]1([CH3:23])[N:19]=[C:18]([NH2:20])[C:14]2([CH2:17][CH2:16][CH2:15]2)[S:13](=[O:22])(=[O:21])[CH2:12]1.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@@:11]2([CH3:23])[N:19]=[C:18]([NH2:20])[C:14]3([CH2:17][CH2:16][CH2:15]3)[S:13](=[O:21])(=[O:22])[CH2:12]2)[CH:4]=1
Reactant: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Temperature: 23 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of (R)-7-(2-fluoro-5-nitro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (470 mg, 1.38 mmol, Eq: 1.00) in ethanol (10 ml) was added at 23° C. under inert atmosphere triethylamine (139 mg, 192 μl, 1.38 mmol, Eq: 1.00) and after inertisation Pd/C 10% (62.9 mg, 59.1 μmol, Eq: 0.1). The suspension was set under hydrogen (balloon) and stirred at 23° C. for 1 hour. The catalyst was filtered off, washed three times with ethanol and evaporated to give the crude (R)-7-(5-amino-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (345 mg, 1.11 mmol, 80.5% yield) as a light brown solid. MS (ISP): m/z=312.5 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([OH:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(N)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(N)ccc1-c1ccc(C(=O)O)cc1
Yield: 105.6 %

Procedure:
4-Bromo-3-methylaniline (7.40 g, 40 mmol) and 4-carboxybenzeneboronic acid (7.90 g, 48 mmol) were stirred in 1,2-dimethoxyethane (DME) (150 ml). Anhydrous sodium carbonate (19.0 g, 179 mmol) was dissolved in water (150 ml) and added to the above. The mixture was then purged with a stream of Ar for 15 min. Tetrakis (triphenylphosphine)palladium (O) (0.25 g, 0.2 mmol) was added, and the mixture was stirred at reflux for 20 h under Ar. DME was removed by evaporation under reduced pressure, and the clear residue was acidified (5M HCl) to yield a thick grey suspension. The solid was filtered off, washed with water and dried in vacuo at 60° C., to give the title compound (9.60 g, quantitative).
Reaction SMILES: [C:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[CH:12](C1(O)CC1)(C)C>>[CH:6]([C:1]1([O:7][S:8](=[O:10])(=[O:11])[NH2:9])[CH2:2][CH2:3]1)([CH3:5])[CH3:12]
Reactant: NS(=O)(=O)Oc1ccccc1
Reactant: CC(C)C1(O)CC1
Product: CC(C)C1(OS(N)(=O)=O)CC1

Procedure:
Sulfamic acid 1-isopropyl-cyclopropyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-isopropylcyclopropanol (synthesized by methods reported in Synthesis 1991, 234.) to obtain sulfamic acid 1-isopropyl-cyclopropyl ester.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]#N)=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].S(=O)(=O)(O)[OH:35]>O1CCCC1>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([CH:18]=[O:35])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1
Reactant: N#Cc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A 0.01 mole sample of 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carbonitrile in tetrahydrofuran at -40° C. is reacted with diisobutyl aluminum hydride. To the mixture is added saturated aqueous ammonium chloride followed by dilute sulfuric acid. The mixture is extracted wth methylene chloride and the extract washed with water and dried (MgSO4). The solvent is removed under reduced pressure to give the product of the example.
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1.[CH3:31][NH:32][CH3:33].O>C(O)C>[CH3:31][N:32]([CH3:33])[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Solvent: O
Solvent: CCO
Product: CN(C)C1CCN(C(=O)OC(C)(C)C)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 8-bromo-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (Intermediate H) (500 mg, 1.072 mmol) in ethanol (10 ml) was added 40% dimethylamine in water (0.407 ml, 3.22 mmol) and the mixture was left to stir under an atmosphere of nitrogen overnight. The solvent was concentrated in vacuo. The crude product was purified by chromatography on silica eluting with EtOAc in iso-hexane to affore the title compound;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[C:28]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][Zn+])=[CH:32][CH:31]=1)#[N:29]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][C:30]([C:28]#[N:29])=[CH:31][CH:32]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: N#Cc1ccc(C[Zn+])cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccc(C#N)cc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-cyano-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9): tR=0.74 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH3:28])[N:20]=1>>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[N:20]=3)[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: Cn1nc(CCl)c2ccccc21
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Product: Cn1nc(CN2c3nc(Cl)cc(=O)n3CC[C@H]2C(F)(F)F)c2ccccc21

Procedure:
180 mg (0.71 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 145.39 mg (0.78 mmol) of 3-chloromethyl-1-methyl-1H-indazole were used in the reaction. After purification by chromatography on silica gel (eluent: 80/20 DCM/MeOH), 250 mg of (8S)-2-chloro-9-(1-methyl-1H-indazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.O.[C:12](Cl)(=O)[CH2:13][CH2:14]C>C(Cl)Cl.N1C=CC=CC=1.C(O)C>[O:9]=[C:4]([CH2:12][CH2:13][CH3:14])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CCCC(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
176 g of 2,2-dimethyl-4,6-dioxo-1,3-dioxane (Meldrum's acid) are dissolved in 550 ml of methylene chloride and 188 ml of pyridine. The mixture is cooled to 5° C. with a bath of water and ice and 133 ml of butyryl chloride are added dropwise. When the addition is complete, the mixture is stirred for three hours at room temperature. The solution is washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated under vacuum to give an oil. This oil is dissolved in 700 ml of ethanol and the mixture is refluxed for six hours. The ethanol is evaporated off under vacuum and the residue obtained is distilled to give 145.4 g of ethyl 3-oxohexanoate in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[C:17]([F:29])=[C:18]([CH:24]=[C:25]([F:28])[C:26]=1F)[C:19]([O:21][CH2:22][CH3:23])=[O:20].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:26]2[C:25]([F:28])=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([F:29])[C:16]=2[CH3:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(F)c(F)c(C)c1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc(F)c(N2C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C2)c(C)c1F
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A solution of (3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidine (1.80 g, 8.97 mmol), ethyl 3-methyl-2,4,5-trifluorobenzoate (2.18 g, 10.0 mmol), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (2.24 mL, 15 mmol) in dimethyl sulfoxide (20 mL) was stirred under a nitrogen atmosphere at an external temperature of 60° C. for 70 hours. The temperature of the mixture was cooled to room temperature. The resultant mixture was poured to a 10% aqueous citric acid solution, followed by extraction with ethyl acetate (200 mL×3), washing by water (200 mL), saturated aqueous sodium hydrogencarbonate (150 mL), and saturated brine (150 mL), and dried over anhydrous sodium magnesium. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=6:1), to thereby yield the title compound as colorless crystals (2.51 g, 70.2%).
Reaction SMILES: [CH2:1](N1C(=O)C2N(C)C=NC=2N(C)C1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[Mg].II.C(Br)CCCCCCCCC=C.C1[O:44]C1.[Cl-].[NH4+].Cl>O1CCCC1>[CH2:1]([OH:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: C1CO1
Agent: C=CCCCCCCCCCBr
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCCO
Reaction time: 0.5 h
Yield: 61 %

Procedure:
This example illustrates the synthesis of 1-(12-Tridecenyl)-3,7-dimethylxanthine (CT2555). To a suspension of magnesium (4.12 g, 172 mmol) and a crystal of iodine in tetrahydrofuran (40 ml) was added 10-undecenyl bromide (8.00 g, 34.3 mmol) in tetrahydrofuran (30 ml) over 30 min and the reaction stirred for a further 30 min after the addition was complete. The solution was added via a canula over 5 min to a solution of ethylene oxide (2.65 g, 60.0 mmol) in tetrahydrofuran (30 ml) and stirred at 25° C. for 16 hr. Saturated ammonium chloride (100 ml) and 1M hydrogen chloride (200 ml) were added and extracted with diethyl ether (2×200 ml). The combined organic extracts were dried (magnesium sulfate) and evaporated to give a residue which was distilled at 1.5 mm Hg to afford 12-tridecenyl alcohol as a clear liquid (4.11 g, 61%, b.p. 98°- 101° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[OH:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[F:11]
Reactant: COc1ccc(O)c(N)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: COc1ccc(O)c(NC(=O)c2cc([N+](=O)[O-])ccc2F)c1

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-methoxyphenol (557 mg, 4.0 mmol) and 2-fluoro-5-nitrobenzoyl chloride (814 mg, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[C:4]([Br:13])[CH:3]=1.[NH4+].[OH-].[CH3:16][N:17](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Br:13][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=1)[C:16]#[N:17]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)Cc1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [NH4+]
Product: CS(=O)(=O)Cc1cc(Br)cc(C#N)c1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
A mixture of 1.37 g (4.17 mmol) of 1,3-dibromo-5-(methylsulfonylmethyl)benzene, 297 mg (2.53 mmol) of Zn(CN)2, and 298 mg (0.258 mmol) of Pd(PPh3)4 in 10 mL of DMF (degassed) was heated at 80° C. After 2.5 h, a 10% NH4OH aqueous solution was added, and the aqueous layer was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (50-60) % EtOAc/hexanes provided 228 mg of 3-bromo-5-(methylsulfonylmethyl)benzonitrile as a colorless solid in 20% yield.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:24])([F:23])[C@:9]([NH:13][C@H:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][OH:16])([CH3:12])[C:10]#[N:11].O.C([O-])([O-])=O.[K+].[K+]>C(OCC)C>[NH2:11][CH2:10][C@@:9]([NH:13][C@H:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:15][OH:16])([CH3:12])[C:8]([F:23])([F:24])[F:7]
Reactant: C[C@@](C#N)(N[C@@H](CO)c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: C[C@@](CN)(N[C@@H](CO)c1ccccc1)C(F)(F)F
Temperature: 4 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
In a three-neck flask under argon, are added in small portions, 1.6 g of lithium aluminium hydride, on a solution cooled to 4° C., 2.5 g of (2S)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenyl-ethylamino)-2-methyl-propionitrile in 250 mL of anhydrous ethyl ether. Strong gas evolvement is observed with a rise of the temperature to 8° C. At the end of the addition, the temperature is left to rise up to room temperature and then the reaction mixture is left with stirring for 18 h. The obtained mixture is cooled to 4° C. before adding dropwise and very slowly, 2 mL of water. Strong gas evolvement is observed with a rise of the temperature up to 12° C. To the resulting mixture maintained at 4° C., are added dropwise and very slowly, 2 mL of 15% potash and then, still dropwise and very slowly, 4 mL of water. The white precipitate formed is filtered and the obtained filtrate dried on magnesium sulfate and then concentrated under reduced pressure in order to obtain 2.2 g of (2R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methyl-ethylamino)-2-phenyl-ethanol including the following characteristics:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]1[CH:46]=[CH:45][C:13]2[N:14]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](OC4C=CC=CC=4)=[O:35])=[CH:29][C:28]=3[O:43][CH3:44])(=[O:26])=[O:25])[C:15](=[O:23])[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:12]=2[CH:11]=1)[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]1[CH:46]=[CH:45][C:13]2[N:14]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:35])=[CH:29][C:28]=3[O:43][CH3:44])(=[O:25])=[O:26])[C:15](=[O:23])[N:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:12]=2[CH:11]=1)[CH3:8]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1OC
Reactant: C1CCNCC1
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)N2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2 ml of piperidine were added to a solution of 500 mg of the compound obtained in Example 16 step A) in 25 ml of DCM. The reaction mixture was then stirred for 18 hours at room temperature. It was concentrated to dryness and the resulting product was passed over silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.36 g of the expected product in the form of white crystals. M.p. =232° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:12]=2[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:28])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:12]=2[C:13]([Cl:28])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nc(-c3ccccc3)ccc2C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Product: COc1ccc(-c2nc(-c3ccccc3)ccc2C(=O)Cl)cc1OC
Yield: 100 %

Procedure:
A mixture of 2-(3,4-dimethoxyphenyl)-6-phenylnicotinic acid (compound no. 303; 1.8 g; 0.0054 mole) and thionyl chloride (20 ml) is heated to boiling point under reflux for 1 h. The medium is concentrated under reduced pressure. A yellow syrup (1.9 g; yield=100%) is obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13]Cl)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].O>C(O)C>[C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CCl)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1CCC2(CC1)OCC(CNC1CCCCC1)O2
Temperature: 180 °C
Yield: 98 %

Procedure:
6.5 g (0.0250 mol) of 8-t-butyl-2-chloromethyl-1,4-dioxaspiro[4.5]decane and 4.6 g (0.0450 mol) of cyclohexylamine are dissolved in 50 of 95% ethanol in the presence of 5.65 g (0.040 mol) of K2CO3 and 0.42 g (0.0025 mol) of KI in an autoclave. The mixture is heated to 180° C. for 8 hours with stirring. After returning to room temperature, the reaction medium is poured into 500 ml of water and extracted with 200 ml of CH2Cl2. The organic phase is dried over magnesium sulphate and concentrated under vacuum. The brown oil is used directly in the following step (yield: 98%; NMR analysis).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]1[CH2:11][C:12]([OH:14])=O.[Br:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH2:21])[S:19][CH:20]=1>>[Br:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH:21][C:12](=[O:14])[CH2:11][N:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][CH:10]=[C:4]23)[S:19][CH:20]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cn1c(=O)ccn2nccc12
Product: O=C(Cn1c(=O)ccn2nccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetic acid (39 mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min)=2.451, method [7], MS(ESI) 420.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J=2.6 Hz, 1H), 6.97 (s, 1H), 6.25 (d, J=7.9 Hz, 1H), 5.94 (d, J=2.6 Hz, 1H), 4.98 (s, 2H).
Reaction SMILES: I[C:2]1[C:9]([O:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1B(O)O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>C1(C)C=CC=CC=1.C(OCC)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.C(O)C>[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[C:2]1[C:9]([O:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(B(O)O)c(OCc2ccccc2)c1
Reactant: CCCOc1cccc(CO)c1I
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: OBO
Solvent: CCO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCOc1cccc(CO)c1-c1ccc(OC)cc1OCc1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 2-iodo-3-propyloxybenzyl alcohol (1.02 g, 3.48 mmol), 2-benzyloxy-4-methoxyphenyl boronic acid (999 mg, 3.83 mmol), Pd(PPh3)4 (200 mg, 0.173 mmol) and 2 M sodium carbonate solution (3.5 ml, 7.96 mmol) was refluxed in toluene (20 ml/ethanol (5 ml) under argon. After 5 hours a further 70 mg of boronic acid was added and refluxing was continued for a further 1 hour. The mixture was cooled, diluted with diethyl ether (200 ml) and washed successively with brine, 5% aqueous sodium hydroxide solution , water and brine and then dried (MgSO4) and concentrated. Purification by chromatography on silica gel gave the title compound as a colourless gum. Yield 1.072 g (81%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[NH:12][CH:13]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:5][CH:4]=1.Br>CC(O)=O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[NH:12][CH:13]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCc2nc(-c3cccs3)c[nH]2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(CCc2nc(-c3cccs3)c[nH]2)cc1
Yield: 26.8 %

Procedure:
A mixture of XIX (2.9 g, 0.01 mole), glacial HOAc (10 mL) and 48% HBr (35 mL) was stirred at reflux for 3 hours. The hot solution was decanted from the separated tar and chilled at 5°-10° C. overnight. The precipitated hydrobromide salt was collected, washed with Et2O, dissolved in H2O (100 mL), and the solution was made basic with saturated NaHCO3 solution. The solid was collected, chromatographed on silica gel, and the product eluted with 95CHCl3 --5CH3OH--0.5H2O to yield 0.725 g (27%) of XX; m.p. 165.5°-167° C. (50% CH3OH).