Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[K+]>ClCCl>[CH2:24]([O:31][C:32]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[CH2:10][CH2:9]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(CN2CCC(N3CCc4ccccc4C3)CC2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(N2CCc3ccccc3C2)CC1

Procedure:
2-(1-Benzyl-piperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline (280 mg, 0.90 mmol), benzyloxycarbonyl chloride (310 mg, 1.8 mmol) and potassium bicarbonate (230 mg, 2.3 mmol) were stirred at room temperature for 23 hours in dichloromethane (5 ml). The reaction solution was mixed with dichloromethane, washed with water and saturated brine and the dried with anhydrous sodium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 300 mg (0.86 mmol, 96% in yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.ClC1C=CC=CC=1.[S:19](=[O:23])(=[O:22])([OH:21])N>CN1CCCC1=O>[NH2:1][C:2]1[C:7]([S:19]([OH:23])(=[O:22])=[O:21])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: NS(=O)(=O)O
Solvent: CN1CCCC1=O
Solvent: Clc1ccccc1
Product: Cc1cc(N)c(S(=O)(=O)O)cc1[N+](=O)[O-]

Procedure:
18.3 g of 1-amino-3-methyl-4-nitrobenzene, 120 ml of chlorobenzene, 24 g of sulphamic acid and 12 ml of 1-methylpyrrolid-2-one are warmed to 120°C whilst stirring. The reaction mixture is stirred for 8 hours at this temperature. After cooling, the reaction mixture is filtered and the residue is washed with trichloroethylene and recrystallised from 200 ml of water. The crystals which have precipitated are filtered off, suspended in 100 ml of trichloroethylene, stirred for one hour at 75°C, separated from the organic solvent by filtration and dried at 80°C. 25 g (84% of theory) of yellow crystals, which according to thin layer chromatography are a single substance, of 1-amino-3-methyl-4-nitro-benzene-6 -sulphonic acid in the form of its ammonium salt [melting point 290° C (decomposition)]are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C-]#N.[K+]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([CH:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[OH:7])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Agent: [C-]#N
Agent: [K+]
Product: Cc1ccc(C(=O)C(O)c2ccc(C)cc2)cc1

Procedure:
250 g (2.08 mol) of p-methylbenzaldehyde were condensed with the aid of 30 g (0.46 mol) of KCN to give 4,4′-dimethylbenzoin according to a standard method (Organikum 18th edition (1990) 457). The crude product was used without further purification (yield, crude: found: C, 80.0%, H, 6.4%. calculated: 79.97%, H, 6.71%). The IR spectrum of 4,4′-dimethylbenzoin is shown in FIG. 8.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:18])=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[O:7][CH2:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>CN(C=O)C.O>[NH2:1][C:2]([C:4]1[C:5]([F:18])=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[O:7][CH2:8][CH:9]=[CH:10][C:11]([O:13][CH2:25][CH2:26][CH2:27][CH3:28])=[O:12])=[O:3]
Reactant: CCCCBr
Reactant: NC(=O)c1c(F)ccc(OCC=CC(=O)O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)C=CCOc1ccc(F)c(C(N)=O)c1F
Temperature: 50 °C
Yield: 57 %

Procedure:
4-[3-(Aminocarbonyl)-2,4-difluorophenoxy]-2-butenoic acid, mixture of isomers (3:2) E:Z, (526 mg, 2 mmol, 1 equiv.) was dissolved in dry DMF (5 ml). K2CO3 (850 mg, 6 mmol, 3 equiv.) and n-butylbromide (0.23 ml, 2.1 mmol, 1.05 equiv.) were added and the reaction mixture was heated for 70 h at 50° C. and for 1.5 h at r.t. After cooling at r.t., the mixture was diluted with H2O (50 ml) and extracted with EtOAc (3×40 ml). The combined organic extracts were washed with H2O (6×30 ml), dried (MgSO4) and evaporated to dryness under reduced pressure. The oily residue was purified by column chromatography on silica, eluted with CH2Cl2 and MeOH/CH2Cl2 (1%), to give 364 mg, 57% yield, mp<40° C. HPLC-MS (method 1): m/z 314 [M+H]+, Rt=3.88 min. By 1H-NMR analysis it was determined to be a mixture of isomers in a ratio (5:7) E:Z. When the same reaction was performed on the acid (3:40) E:Z mixture of isomers, the product obtained was determined to be a mixture of isomers in a ratio (1:4) E:Z.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[K+]>C(OCC)(=O)C>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOc1ccc(-c2ccccc2)cc1
Reaction time: 6 h

Procedure:
4-Hydroxy-1,1'-biphenyl (61.3 g, 0.36 mol) and decyl bromide (218 g, 0.72 mol) were heated at 80° C. To this solution, a 50% potassium hydroxide aqueous solution (57 g) was added dropwise at 80° C. and then stirring was continued for 6 h at the same temperature. After cooling, the mixture was diluted with ethyl acetate, the organic layer was separated, washed with H2O and dried over MgSO4. The solvent was removed under reduced pressure and the resultant residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to give the title compound as a white crystals; yield: 70 g (62.6%); mp 70.0°-73.0° C.
Reaction SMILES: C(O[CH:5]1[S:25][C@H:24]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[NH:35]1[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]1=[O:37].C(#N)C.C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>>[CH2:8]([O:7][C@H:6]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:24]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:25][CH:5]1[N:35]1[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]1=[O:37])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC1S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: Nc1cc[nH]c(=O)n1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1ccn(C2S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-O-acetyl 2,3,5-tri-O-benzyl-4-thio-D-arabinofuranose (478 mg, 1 mmol) and cytosine (111.0 mg, 1 mmol) in anhydrosis acetonitrile (25 mmol) were added consecutively hexamethyldisilazane (HMDS, 162 mg, 1 mmol) and chlorotrimethylsilane (TMSCl, 434 mg, 4 mmol), and the mixture was stirred at room temperature for 0.5 hours. This solution was cooled to −78° C. Trimethylsilyltrifluoromethane sulfonate (267 mg, 1.2 mmol) was added and the resulting solution was stirred at −78° C. for another 2.5 h, after which time the reaction was essentially complete. The mixture was warmed to room temperature, concentrated to a small volume (5 mL), diluted with methylene chloride (50 mL) and then washed with water (20 mL) followed by saturated sodium bicarbonate and water. The organic layer was dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography over silica gel (50 g. elution with CHCl3/MeOH 98:2) to afford 7 (412 mg 77.5%) as a colorless syrup TLC (95:5 CHCl3/MeOH) Rf 0.65; MS z/e 536 (M+Li)+.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[O:1]([CH:8]([CH3:12])[C:9]([O:11][CH2:18][CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)Oc1ccccc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Phenoxypropionic acid (6.64 g, 0.04 mol) is mixed with excess ethanol (10 ml) and concentrated sulfuric acid (0.5 ml) is added. The reaction mixture is refluxed for 3 hours, cooled to room temperature and concentrated. The residue is washed with 1N NaOH and brine, dried (Na2SO4), and concentrated to yield 7.32 g (94.3% yield) of the ester which can be used directly for the subsequent reaction without further purification. 1H nmr (CDCl3) δ: 7.22-7.29 (overlap 2H, phenyl H), 6.88-6.966 (overlap 3H, phenyl H), 4.10-4.20 (overlap 4H, 2CH2O), 2.73 (t, 2H. J=6.4 Hz, CH2), 1.23 (t, 3H, J=7.1 Hz, CH3); 13C nmr (CDCl3) δ: 170.7, 158.7, 129.4(2C), 120.9 114.6(2C), 63.4, 60.5, 34.5, 14.1.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22]CC4C=CC=CC=4)=[C:16]([Br:30])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=21.Cl>C(O)(=O)C.O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[C:16]([Br:30])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=21
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1O
Temperature: 25 °C

Procedure:
2-Amino-4-(4-benzyloxy-3-bromo-5-methoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (2) (2 g, 3.89 mmol) was taken in 20 ml acetic acid and charged with 10M hydrochloric acid (10 ml) under vigorous stirring at room temperature, and stirred further at room temperature until the reaction was complete. The reaction mixture was then diluted with 50 ml water, stirred for 3 h at room temperature, thus formed solids were separated by filtration, washed with water and then dried under high vacuum (1.61 g, 3.8 mmol, 97.8%).
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([OH:22])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][C:64]([P:67](=[O:74])([O:71]CC)[O:68]CC)([F:66])[F:65]>>[NH2:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:22])[NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][C:64]([P:67](=[O:68])([OH:74])[OH:71])([F:65])[F:66]
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCC
Agent: Cl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCC(F)(F)P(=O)(O)O)OCCCCCCCCCCCC

Procedure:
The title product was prepared from (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2,3-bis(dodecyloxy)propyl)thio)propanoic acid (1 eq, from example 20, step 5) and diethyl 3-(2-(2-aminoethoxy)ethoxy)-1,1-difluoropropylphosphonate hydrochloride (1.2 eq) by following the procedure described for example 19, step 4-6. 1H NMR (CDCl3): δ 9.15 (br s, 1H), 4.16 (br s, 1H), 3.48-3.77 (m, 9H), 3.34-3.48 (m, 4H), 3.07-3.17 (m, 2H), 2.93-3.07 (m, 2H), 2.67-2.82 (m, 2H), 2.25-2.41 (m, 2H), 1.62-1.71 (m, 2H), 1.45-1.60 (m, 4H), 1.04-1.35 (m, 36H), 0.87 (t, 6H). LRMS [M+H]=777.5.
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[C-]#N.[Na+].[CH3:24][N:25](C=O)C>C(OCC)(=O)C>[CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][C:24]#[N:25])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: ClCc1ccc(Cc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#CCc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-benzylbenzyl chloride (198.34 g) in dimethylchloride (DMF) (50 ml) was added in turn sodium hydrogen carbonate (76.88 g) and sodium cyanide (56.07 g). In that case, the solution was cooled as occasion demands, since heat is slightly generated. After stirring at room temperature for 17 hours, DMF (100 ml) was further added. After stirring at room temperature for 67 hours, ethyl acetate (300 ml) was added, and the precipitate was filtered, washed with ethyl acetate (300 ml). The filtrate and the washings were combined, washed with saturated aqueouse sodium chloride solution (20 ml×4), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound (189.69 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][NH:17][C:16](=[O:19])[N:15]1[CH3:20])=[O:13].Br[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(=O)([O-])O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][N:17]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=2)[C:16](=[O:19])[N:15]1[CH3:20])=[O:13]
Reactant: CN1C(=O)NCC1C(=O)NCc1ccc(F)c(F)c1Cl
Reactant: Cc1cc(Br)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(N2CC(C(=O)NCc3ccc(F)c(F)c3Cl)N(C)C2=O)ccn1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A solution of N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (152 mg, 0.5 mmol) (prepared as described in Example 28) and 4-bromo-2-methylpyridine (86 mg, 0.5 mmol) in 1,4-dioxane (3 ml) was treated with cesium carbonate (244 mg, 0.75 mmol), Xantphos™ (21.7 mg, 0.038 mmol) and tris(dibenzylideneacetone)dipalladium(0) (11.5 mg, 0.013 mmol) and the mixture was heated under reflux under argon for 3 hours. After cooling to room temperature, the reaction mixture was diluted with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane. The resulting residue was triturated with ether, the solid was collected and dried to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-1-(2-methyl-4-pyridinyl)-2-oxo-4-imidazolidinecarboxamide (123 mg, 62%). LC/MS [M+H]+=395, retention time=1.68 minutes.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][C:9](N)=[O:10]>[Ni]>[C:9](=[O:10])([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[NH2:8]
Reactant: CCCCCCO
Reactant: NC(N)=O
Agent: [Ni]
Product: CCCCCCOC(N)=O
Temperature: 130 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
A mixture of 918 parts of hexyl alcohol, 300 parts of urea and 14 parts of a cation exchanger which is commercially available under the registered name Amberlite 200 and, having been treated in accordance with Example (1 a), contains nickel, is heated to 130° C. whilst stirring. The temperature is then raised to 150° C. in the course of 6 hours and maintained thereat for a further 4 hours. After filtering off the exchanger, excess hexyl alcohol is distilled off under reduced pressure. 680 parts of hexyl carbamate (94% of theory) are obtained. Melting point= 56°-57° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:23]=[CH:24][CH:25]=1>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH:23]=[CH:24][CH:25]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(N)c1
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 65.1 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 930 mg of 2-methylpropan-2-yl [2-(3-aminophenyl)ethyl]carbamate in place of the 2,4-difluoroaniline. 285 mg of 2-methylpropan-2-yl {2-[3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)phenyl]ethyl}carbamate are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:18]([CH2:26][CH3:27])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=O)C.CC[O-].[Na+].C(O)(=O)C.O>C(O)C>[CH2:24]([O:23][C:21]([CH:20]1[CH2:19][N:18]([CH2:26][CH3:27])[C:7]2[N:8]=[C:9]3[CH:10]=[C:11]([F:17])[C:12]([F:16])=[CH:13][C:14]3=[CH:15][C:6]=2[C:4]1=[O:3])=[O:22])[CH3:25]
Reactant: CCOC(=O)CCN(CC)c1nc2cc(F)c(F)cc2cc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CN(CC)c2nc3cc(F)c(F)cc3cc2C1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A solution of 68 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-ethyl N-(β-ethoxycarbonylethyl)amino]quinoline in 200 cm3 of absolute ethanol is introduced in the course of 60 minutes into a solution of 16.1 g of sodium ethylate brought to reflux in 600 cm3 of absolute ethanol. The suspension obtained, still refluxing, is stirred for a further 60 minutes. 20 cm3 of glacial acetic acid are then introduced in the course of 30 minutes. The reaction mixture is stirred for a further 15 minutes and, with the mixture still refluxing, 400 cm3 of water are then introduced in the course of 45 minutes. The suspension obtained is cooled to approximately 20° C. The precipitate obtained is drained at approximately 20° C. and washed with twice 200 cm3 of water. The wet product is dried under reduced pressure (20 kPa) at approximately 50° C. 52.4 g of 3-ethoxycarbonyl-7,8-difluoro-1-ethyl-4-oxo-1,2,3,4-tetrahydro-benzo[b][1,8]naphthyridine are isolated in the form of a golden-yellow solid, melting point 152° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:9]([NH:11][CH:12]2[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][CH:13]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.CO.[BH4-].[Na+]>COCCOC>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[C:9]([NH:11][CH:12]2[CH2:17][CH:16]([OH:18])[CH2:15][CH2:14][CH:13]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:10])[CH2:2][CH2:3]1
Reactant: COc1ccc(C2CCC(=O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COc1ccc(C2CCC(O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Yield: 87.8 %

Procedure:
7.2 g of (±)-3,4-bis-cyclopropylmethoxy-N-[(1RS,2RS)-2-(3,4-dimethoxyphenyl)-5-oxo-cyclohexyl]benzamide (compound C1) are dissolved in 550 ml of 1,2-dimethoxyethane and 34 ml of methanol and treated portionwise with 600 mg of sodium borohydride at room temperature. The reaction mixture is concentrated, the residue redissolved in ethyl acetate and extracted with water. The organic layer is dried using sodium sulfate, concentrated and the residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 6/3/1. 6.35 g of the title compound are obtained.
Reaction SMILES: F[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[C:6]([CH3:12])[CH:5]=[CH:4][C:3]=1[O:13][CH2:14][O:15][CH3:16].[CH:17]1([C:20]#[N:21])[CH2:19][CH2:18]1.C[Si](N([K])[Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:11][O:10][CH2:9][O:8][C:7]1[C:6]([CH3:12])=[CH:5][CH:4]=[C:3]([O:13][CH2:14][O:15][CH3:16])[C:2]=1[C:17]1([C:20]#[N:21])[CH2:19][CH2:18]1
Reactant: COCOc1ccc(C)c(OCOC)c1F
Reactant: N#CC1CC1
Agent: C[Si](C)(C)N([K])[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COCOc1ccc(C)c(OCOC)c1C1(C#N)CC1
Temperature: 105 °C
Yield: 42.7 %

Procedure:
2-fluoro-1,3-bis(methoxymethoxy)-4-methyl-benzene (Intermediate 34, 17.5 g, 76.011 mmol) and cyclopropanecarbonitrile (22.625 g, 337.23 mmol) were warmed under stirring to 105° C. A solution of [bis(trimethylsilyl)amino]potassium 0.5M in Toluene (275 ml) was slowly added for 1 hour to the previous solution. The reaction mixture was stirred for 6 hour at the same temperature. After cooling the solid was filtered off and the filtrate was partitioned between Brine (200 ml) and ethyl acetate (300 ml). The aqueous layer was re-extracted with ethyl acetate (200 ml) and combined organic layers were dried (Na2SO4), filtered and evaporated (the temperature during the concentration was ˜60° C. for removing the excess of cyclopropane carbonitrile). The residue was triturated with isopropanol (25 ml) and the solid collected and dried to afford the title compound (9.0 g) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20](=[O:22])[CH3:21])=[CH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:20](=[O:22])[CH3:21])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)NC1=CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: CC(C)O
Product: CC(=O)N[C@@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 7.5 h
Yield: 83.1 %

Procedure:
The enamide 3 (24 g, 72 mmol) was slurried in degassed isopropanol (200 mL). The resulting slurry was transferred to the appropriate reactor. Prior to the addition of the catalyst solution, the content of the reactor was purged with nitrogen. A solution of (R,R)-MeBPE(COD)RhBF4 catalyst (20.1 mg, 0.036 mmol, 0.05 mol %) in isopropanol (IPA) (100 mL) was added to the reactor. The content was cooled to 0° C. and purged with nitrogen three times. The reactor was then purged with hydrogen and pressurized to 90 psig. The reaction was aged with agitation at 0° C. for 7.5 h and conversion was monitored by the hydrogen uptake. The content was then warmed to RT and hydrogen was vented. After purging with nitrogen, the contents were drained. The reaction mixture was heated to 50° C. and filtered through a pad of Celite. The clear orange solution was concentrated to ˜50% volume (150 mL) and diluted with toluene (5.9 g, 5 wt %). The suspension was heated to 65° C. and water (14.7 mL) was added dropwise to form a cloudy solution. The slurry was slowly cooled to −10° C. and aged for 30 minutes. The solid was filtered and washed with cold IPA (2×45 mL). The cake was dried under vacuum at 45° C. overnight to afford 20.0 g (83% yield) of trans acetamide 4 (>99% de).