Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]([CH:24]([CH3:26])[CH3:25])=[CH:19][C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH:24]([CH3:26])[CH3:25])[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: COC(=O)C=C(N)C(C)C
Solvent: CC#N
Product: COC(=O)c1c(C(F)(F)F)cc(-c2ccc(Cl)cc2)nc1C(C)C

Procedure:
150 mg (0.599 mmol) of 1-(4-chlorophenyl)-4,4,4-trifluorobutane-1,3-dione [Katsuyama et al., Synthesis, 1321-1324 (1997)] and 171 mg (1.20 mmol) of methyl 3-amino-4-methylpent-2-enoate [Holz et al., J. Org. Chem. 68., 1701-1707 (2003)] in 2 ml of acetonitrile were reacted at reflux temperature overnight. The volatile components were then removed on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10). This gave 34 mg (16% of theory) of the target compound.
Reaction SMILES: C([O:8][N:9]1[C:13](=[O:14])[CH2:12][C@@H:11]([NH:15][S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:10]1=[O:35])C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[OH:8][N:9]1[C:13](=[O:14])[CH2:12][C@@H:11]([NH:15][S:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)(=[O:17])=[O:18])[C:10]1=[O:35]
Reactant: O=C1C[C@@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1C[C@@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1O
Reaction time: 1 h

Procedure:
4-(4Trifluoromethyl-phenyl)-piperazine-1-sulfonic acid ((3R)-1-benzyloxy-2,5-dioxo-pyrrolidin-3-yl)-amid (76 mg; 0.15 mmol) was dissolved in EtOAc (5 ml)+MeOH (5 ml). A slurry of 10% Pd/C (35 mg) in MeOH (1 ml) was added under a stream of nitrogen. The mixture was hydrogenated at room temperature at 1 atm. pressure of H2 for 1 h. The reaction mixture was filtered through celite and the filtercake was washed with EtOAc and MeOH. Evaporation of solvent, the crude product was purified by flash chromatograohy through 10 g of Si-60-gel using a gradient of 100% Heptane to 100% (EtOAc+1% AcOH), gradient time=30 min, then isocratic system 100% (EtOAc+1% AcOH) for 15 min. flow=20 ml/min. The fractions containing the product was evaporated and the residue was trituated with Et2O and the resulting colourless solid was dried to give the title compound. Obtained 47 mg (74% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=O)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:13]([C:10]1[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]2=[N:8][CH:9]=1)=[O:15])[CH2:29][CH3:30]
Reactant: CCCN
Reactant: Cc1cccn2c(=O)c(C(=O)O)cnc12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cnc2c(C)cccn2c1=O
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
A mixture containing 9.2 g (0.045 mol) of 9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 7.05 ml (0.05 mol) of triethylamine in 280 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 3.7 ml (0.045 mol) of methyl chloroformate dissolved in 25 ml of chloroform is dropped to the above mixture at -21° C. during 10 minutes. After stirring for 5 minutes, 2.95 g (0.05 mol) of propylamine dissolved in 50 ml of chloroform are dropped to the above solution at a temperature between -21° C. and -19° C. during 45 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 7.8 g (70.7%) of the named compound as snow-white crystals after recrystallization from ethanol, m.p.: 138°-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[O:6]1[CH2:10][CH2:11][O:12][CH:5]1[C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1
Reactant: OCCO
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Brc1cccc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromobenzaldehyde (15.87 g, 85.78 mmol), 1,2-ethyleneglycol (8.01 g, 128.7 mmol) and p-toluenesulfonic acid hydrate (100 mg ) in benzene (200 ml) was refluxed at 110° C. under nitrogen for 3 hours, and the water formed in the reaction was collected through a Dean Stark trap. The resulting solution was cooled to room temperature, and washed with 10% sodium hydroxide (2×100 ml), water (4×100 ml) and brine (1×100 ml), and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave the title compound as an oily material (16.8 g, 86%).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[C@@H:14]([O:17][C@@H:18]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[CH3:19])[O:15][CH2:16][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([C@H:18]([O:17][C@H:14]2[O:15][CH2:16][C@@H:10]3[CH2:9][NH:8][CH2:12][C@H:11]3[C@@H:13]2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:19])[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=1
Reactant: [H][H]
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(Cc3ccccc3)C[C@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21

Procedure:
(3aS,6R,7R,7aR)-2-Benzyl-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-2-methylphenyl)octahydropyrano[3,4-c]pyrrole (example 1: 2.51 g, 4.32 mmol) was combined 0.5 g 20% Pd(OH)2/C and suspended in 100 mL ethanol in a Parr apparatus. The reaction vessel was shaken vigorously under 45 psi hydrogen for 7 hr. The reaction mixture was filtered through a pad of celite and rinsed copiously with methanol. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a combination of DCM/methanol/NH4OH=90:9:1. MS: (MH)+492.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>Cl[Pd]Cl.[Cu]I.C(NCC)C>[OH:35][CH2:31][CH2:32][C:33]#[C:34][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C#CCCO
Reactant: COC(=O)c1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccccc1C#CCCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
50 ml (0.36 M) of methyl 2-bromobenzoate, 930 mg (3.56 mM) of triphenylphosphine and 316 mg (1.78 mM) of PdCl2 are added to 1200 ml of diethylamine in a 2000 ml reactor. After stirring at room temperature for 5 minutes, 27 ml (0.36 M) of 3-butyn-1-ol and 680 mg (3.56 mM) of CuI (1) are added. The reaction medium is then stirred at 20° C. for 120 hours, the solvent is then evaporated off and the residue obtained is then purified by chromatography on silica, using dichloromethane as eluent. After evaporation, 46.7 g of a brown oil are thus obtained (64% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:18]#[N:19].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:18]#[N:19]
Reactant: [C-]#N
Reactant: COc1c(CBr)cccc1Oc1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1ccccc1
Yield: 95.1 %

Procedure:
A solution of phenyl 2-methoxy-3-bromomethylphenyl ether (8.5 g) in dimethyl sulfoxide (30 ml) and powdered sodium cyanide (1.45 g) were treated in a similar manner to that of Example 14-(4) to give oily 2-(2-methoxy-3-phenoxyphenyl)acetonitrile (6.6 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:2][C:3](=O)[CH2:4][CH2:5][CH3:6].[CH2:13]([SH:16])[CH2:14][SH:15].CS(O)(=O)=O>C(Cl)Cl>[CH2:4]([C:3]1([CH2:2][CH2:1][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[S:16][CH2:13][CH2:14][S:15]1)[CH2:5][CH3:6]
Reactant: CCCC(=O)CCn1ccnc1
Reactant: SCCS
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCCC1(CCn2ccnc2)SCCS1
Reaction time: 0.25 h

Procedure:
A solution 1-(hexan-3-on-1-yl)imidazole (1.00 g) was stirred with ethane-1,2-dithiol (1 ml) at room temperature and then 1 ml of methanesulfonic acid was added in portions with cooling. After 15 minutes, 20 ml of methylene chloride was added and the mixture stirred for 4 hours. The reaction mixture was poured into 300 ml of methylene chloride which solution was washed with 3×100 ml 5% sodium hydroxide, 1×100 ml water and the organic layer dried over magnesium sulfate. Removal of the solvent afforded an oil which was chromatographed on silica gel, eluting with hexane, 50% hexane/ethyl acetate and ethyl acetate to yield 1.2 g of 1-[2-(2-propyl-1,3-dithiolan-2-yl)ethyl]imidazole. The residue was taken up in a small volume of ether and treated with ethereal hydrogen chloride until precipitation was complete. The resulting precipitate was filtered off and recrystallized from methanol/ethyl acetate, to give 1-[2-(propyl-1,3-dithiolan-2-yl)ethyl]imidazole hydrochloride, m.p. 118° -121° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:8]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:7]=2[N:6]([CH3:16])[C:5](=[O:17])[O:4]1)[CH3:2].[BH4-].[Na+]>[Pd].CO>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]2[N:6]([CH3:16])[C:5](=[O:17])[O:4][C:3]([CH2:18][CH3:19])([CH2:1][CH3:2])[C:8]=2[CH:9]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a stirred suspension of 4,4-diethyl-1-methyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one (3.74 g, 14.15 mmol) and 5% palladium on carbon (0.20 g) in methanol (35 mL) at 0° C. was added sodium borohydride (10.70 g, 28.30 mmol) portionwise. After stirring 1 hr at 0° C., the reaction was quenched with ice and ammonium chloride solution (sat.) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over magnesium sulfate. Solvent was removed and trituration of the residue with ether gave 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a yellow solid (2.67 g, 81%). 1H NMR (DMSO-d6): δ 6.78 (d, J=8.6 Hz, 1H), 6.56 (m, 1H), 6.40 (d, J=2.4 Hz, 1H), 4.93 (s, 2H), 3.18 (s, 3H), 1.99 (m, 4H), 0.80 (t, J=7.3 Hz, 6H); MS (ESI) m/z 235 ([M+H]+); Anal. calcd for C13H18N2O2: C, 66.64; H, 7.74; N, 11.96. Found: C, 64.97; H, 7.67; N, 11.62.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[CH:2]1.[NH2:9][C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:40])=[C:24]([NH:26][C:27](=[O:39])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4([C:37]#[N:38])[CH2:36][CH2:35]4)[CH:29]=3)[CH:25]=1)[N:13]=2>N1C=CC=CC=1>[C:37]([C:34]1([C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([NH:26][C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][C:23]=2[CH3:40])[O:19][C:14]2[N:13]=[C:12]3[S:11][C:10]([NH:9][C:6]([C:4]4[N:3]=[CH:2][O:1][CH:5]=4)=[O:7])=[N:18][C:17]3=[CH:16][CH:15]=2)=[O:39])[CH2:36][CH2:35]1)#[N:38]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: O=C(Cl)c1cocn1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)c4cocn4)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
1,3-Oxazole-4-carbonyl chloride synthesized above was suspended in pyridine (2.0 mL) at 0° C., N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl)-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.452 mmol) produced in Example C29(iv) was added, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, 1% aqueous citric acid solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate/hexane to give the title compound (125 mg, 77%) as a colorless powder.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH2:5]([C:8]1[N:9]([CH2:21][CH2:22][CH2:23][C:24](=O)[CH3:25])[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=1)[CH2:6][CH3:7]>CO>[CH3:3][O:2][N:4]=[C:24]([CH2:23][CH2:22][CH2:21][N:9]1[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=[C:8]1[CH2:5][CH2:6][CH3:7])[CH3:25]
Reactant: CON
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC(C)=O
Agent: Cl
Solvent: CO
Product: CCCc1nc2cnc3cccnc3c2n1CCCC(C)=NOC
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
Methoxylamine hydrochloride (2.23 g, 26.7 mmol) was added to a solution of 5-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one (6.06 g of crude material prepared as described in Parts A and B of Example 22) in methanol (80 mL). The reaction mixture was stirred at room temperature for 48 hours and then concentrated under reduced pressure. The residue was dissolved dichloromethane (60 mL) and the pH was adjusted to 8 by the addition of saturated aqueous sodium bicarbonate (40 mL) and then solid sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (30 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to afford 6.33 g of 5-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one O-methyloxime a yellow oil.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1>O>[NH:2]([C:5]1[N:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=1)[NH2:3]
Reactant: NN
Reactant: N#Cc1ccc(Cl)nc1
Solvent: O
Product: N#Cc1ccc(NN)nc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
90.3 g (1.8 mol) of hydrazine hydrate are added to 25.0 g (180.4 mmol) of 6-chloronicotinonitrile, and the mixture is stirred at a bath temperature of 100° C. for 15 min. The reaction mixture is cooled to RT, diluted with water and stirred at RT for 30 min. The precipitate formed is filtered off, the filter residue is washed with water and the crystals are air-dried for 24 h and recrystallized once from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.[F:27][C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([NH:34][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)=[CH:26][CH:25]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: Nc1cccc(F)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)Nc3cccc(F)c3)cc2)cn1
Yield: 10 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using 3-fluorophenylamine instead of cyclopropylmethylamine, to the title compound (13 mg, 10%) which was obtained as an off-white solid. MS: m/e=438.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2(Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[H-].[Na+].[C:22](O)(=[O:24])[CH3:23]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH2:18][O:24][CH2:22][CH3:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc(C2(Br)CCCCC2)nc1CBr
Reactant: CC(=O)O
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOCc1nc(C2CCCCC2)oc1C(=O)OCC
Temperature: 65 °C
Reaction time: 1 h

Procedure:
1.25 g 2-(1-Bromo-cyclohexyl)-4-bromomethyl-oxazole-5-carboxylic acid ethyl ester was dissolved in 15 ml ethanol. 176 mg sodium hydride were added and the reaction mixture stirred at 65° C. for one hour. The cooled reaction mixture was neutralized by the addition of acetic acid (pH˜6). 50 mg palladium on charcoal (10%) were added and the reaction mixture was stirred under an atmosphere of hydrogen for one hour. The catalyst was filtered off through a pad of celite, the filtrate was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 370 mg 2-Cyclohexyl-4-ethoxymethyl-oxazole-5-carboxylic acid ethyl ester as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>O>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1cccc(Cl)c1
Solvent: O
Product: O=C(O)c1cccnc1Nc1cccc(Cl)c1
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A mixture of 2-chloro-3-pyridinecarboxylic acid (78.75 g, 0.500 mol), 3-chloroaniline (127.6 g, 1.00 mol), paratoluenesulfonic acid.H2O (8.5 g, 45 mmol), and H2O (500 mL) was refluxed 4 hrs. The solids dissolved, and after 1 hr, the solution gave a precipitate. The cooled mixture was filtered, and the collected yellow solid was washed with cold H2 0 and was dried (60° ) to give 2-[(3-chlorophenyl)amino]-3-pyridinecarboxylic acid (116.0 g, 93.3%), mp 197°-199° C. B. Stirring 2-[(3-chloro-phenyl)amino]-3-pyridinecarboxylic acid (30.8 g, 124 mmol) with SOCl2 (50 mL, 680 mmol) and DMF (0.5 mL) at 25° C. for 1 hr gave a solution which deposited a precipitate. Excess thionyl chloride was evaporated, the residue was mixed with benzene, and the solvent was evaporated to give crude, solid 2 -[(3-chlorophenyl)amino]-3-pyridinecarbonyl chloride which was used directly in the next step C. Collecting, washing with benzene and petroleum ether, and drying the precipitate gave 2-8 (3-chlorophenyl)amino]-3-pyridinecarbonyl chloride (32 g, 96%) as a yellow solid, mp 112°-115° C. C. A solution of N(C2H5)3 (1.3 mL, 9.3 mmol) and 1-(1-pyrrolidinyl)cyclohexene (1.41 g, 9.3 mmol) in toluene (5 mL) was added dropwise over 10 min. to a magnetically stirred, cooled (ice-acetone bath at -10° C.) suspension of crude acid chloride (prepared by the procedure of Step 26B above from 9.3 mmol of the corresponding acid) and toluene (40 mL). The solid dissolved, and the dark red reaction mixture was kept 2 hrs. between -5 to +5° C. and then warmed to room temperature over 0.5 hr. The reaction mixture was then heated in an oil bath for 4 hrs; the oil bath temperature was 80° C. The reaction mixture was allowed to cool and to stand at room temperature for 12 hrs., after which toluene was evaporated. The residue was dissolved in CH2Cl2 (100 mL) and the solution was washed with 100 mL portions of H2O, 1N HCl, 1M Na2CO3, and with H2O. Aqueous extracts were backextracted with CH2Cl2, and combined organic solutions were dried over Na2SO4, filtered, and evaporated. The residue was crystallized from acetonitrile to provide the desired product 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8]naphthyridin-5(7H)-one
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[C:21]3=[N:22][C:23](Cl)=[CH:24][C:25](=[O:26])[N:20]3[CH2:19][C@@:18]2([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:34]12[O:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][NH:36][CH2:35]2.C(N(CC)CC)C>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[C:21]3=[N:22][C:23]([N:36]4[CH2:35][CH:34]5[O:41][CH:38]([CH2:39][CH2:40]5)[CH2:37]4)=[CH:24][C:25](=[O:26])[N:20]3[CH2:19][C@@:18]2([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1CCc1ccc(OCc2ccccc2)cc1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(CC)CC
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CC4CCC(C3)O4)cc2=O)N1CCc1ccc(OCc2ccccc2)cc1

Procedure:
1.40 g (3.02 mmol) of (S)-1-[2-(4-benzyloxyphenyl)ethyl]-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, 903 mg (6.04 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride and 763 mg (7.54 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: 2/8 heptane/EtOAc), 1.2 g of (S)-1-[2-(4-benzyloxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [C:1]([C:3]1[C:10]([Cl:11])=[CH:9][C:6]([CH2:7]Br)=[CH:5][C:4]=1[Cl:12])#[N:2].C(C1C=CC(C[N:20]2[C:24]([CH:25]=[O:26])=[CH:23][N:22]=[CH:21]2)=CC=1F)#N>>[C:1]([C:3]1[C:10]([Cl:11])=[CH:9][C:6]([CH2:7][N:20]2[C:24]([CH:25]=[O:26])=[CH:23][N:22]=[CH:21]2)=[CH:5][C:4]=1[Cl:12])#[N:2]
Reactant: N#Cc1c(Cl)cc(CBr)cc1Cl
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Product: N#Cc1c(Cl)cc(Cn2cncc2C=O)cc1Cl

Procedure:
The titled product was prepared from the product of Step C using the same procedures as those described in Example 1, Steps D through G for the preparation of 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.O[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:21]([O:20][C:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: COC(=O)c1ccc(F)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1OCCCCNC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (21 mmol), tert-butyl 4-hydroxybutylcarbamate (21 mmol) and triphenyl phosphine (24 mmol) in THF (70 ml) was cooled to −10° C. Then, DIAD (43 mmol) was added. The mixture was stirred for 30 min at −10° C. under N2. The ice-bath was removed and the mixture was stirred overnight at 20° C. The solvent was removed under vacuum. The residue was washed with petroleum and diethyl ether. The white solid was filtered and it was confirmed to be triphenylphosphine oxide (PPh3═O). The filtrate was evaporated to dryness. The residue was purified with flash column (petroleum/ethyl acetate 100:0 to 5:1). Yield: 8.18 g (purity 90%, yield 98%).
Reaction SMILES: [CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C[SiH](C)c1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(OC(=O)c2ccc([SiH](C)C)cc2)cc1

Procedure:
A solution of 19.9 g (0.100 mol) of p-dimethylsilylbenzoyl chloride and 12.4 g (0.100 mol) of a p-methoxyphenol in 40 ml of dry toluene was boiled for 15 hours. The completeness of the reaction was checked by thin-layer chromatography. After the solvent had been stripped off in vacuo on a rotary evaporator, the crude product was recrystallized from n-hexane, to give p-methoxyphenyl 4-dimethylsilylbenzoate, melting point 67° C.