Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
(7-Fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (0.50 g, 2.41 mmol) (for a preparation see Example 88(a)) was combined with 1,1-dimethylethyl 4-piperidinylcarbamate (0.48 g, 2.41 mmol) in 1:1 MeOH/DCM (20 mL). Excess Na2SO4 was added as a drying agent and the solution was stirred at ambient temperature for 16 h. NaBH(OAc)3 (1.53 g, 7.23 mmol) was added and the reaction was stirred an additional 2 h. The solution was concentrated onto silica gel under vacuum and the crude residue purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as a yellow solid (0.678 g, 72%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1)#[N:2].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=O)[C:17](O)=[O:18]>>[C:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:9][C:17](=[O:18])[C:16]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[N:10]2)#[N:2]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: N#Cc1ccc(N)c(N)c1
Product: N#Cc1ccc2[nH]c(=O)c(-c3cccs3)nc2c1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-cyano-benzene-1,2-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-cyano-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH:25]1[CH2:30]CCCO1.BrC(O)C>>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:30][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:10]
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Agent: CC(O)Br
Product: COc1ccc(C(=O)C(CCOC2CCCCO2)c2ccccc2)cc1

Procedure:
The compound is prepared from 22.6 g of 4-methoxydesoxybenzoin and 20.9 g of tetrahydropyran-2-yl ether-protected bromoethanol according to the procedure described in Example 1(a).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CO>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([CH:3]2[CH2:2][O:4]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(C2CO2)cc1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
2-Bromo-1-(4-nitrophenyl)ethanone (1.9 g, 7.9 mmol) was stirred in methanol (30 mL) and the suspension cooled in an ice bath. Sodium borohydride (0.33 g, 8.7 mmol) was added in one portion and after five minutes the ice bath was removed and the mixture stirred at room temperature. After three hours potassium carbonate (1.1 g, 7.9 mmol) was added, and the mixture stirred at room temperature for a further 16 hours. The methanol was evaporated, water (50 mL) was added, and the mixture extracted with DCM (3×100 mL). The combined DCM phases were washed with brine, dried (sodium sulfate) and evaporated to give the title compound (I83) (1.296 g, 99% yield) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.25-8.18 (m, 2H), 7.50-7.41 (m, 2H), 3.96 (dd, J=4.1, 2.5 Hz, 1H), 3.23 (dd, J=5.5, 4.1 Hz, 1H), 2.78 (dd, J=5.5, 2.5 Hz, 1H). LCMS Method C: rt 5.42 min.
Reaction SMILES: [C:1]([O-:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].Cl>O>[C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C([O-])[C@H](O)c1ccccc1
Agent: Cl
Solvent: O
Product: O=C(O)[C@@H](O)c1ccccc1
Temperature: 1 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
The L-mandelate (S,R,R salt 2, 274 g, 1.03 mol) was dissolved in water (400 ml) and brought to pH 1.5 by adding concentrated hydrochloric acid. The mixture was cooled to 1° C. and seeded by adding a few crystals of S-mandelic acid. The mixture was stirred at 0° C. for a further 2 hours and the precipitated crystal slurry was filtered with suction. The filter residue was washed with ice-water (100 ml) and dried at 50° C. under reduced pressure. 86 g (57%) of L-mandelic acid were obtained, which were optically pure according to analysis.
Reaction SMILES: [C:1]([N:3]=[CH:4]OCC)#[N:2].[NH2:8][CH:9]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.C(OCC)(=O)C>C(O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:9]([NH:8][CH:4]=[N:3][C:1]#[N:2])[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:33][CH:32]=1
Reactant: Cn1c(=O)cc(-c2ccccc2)c2cc(C(N)c3ccc(Cl)cc3)ccc21
Reactant: CCOC=NC#N
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cn1c(=O)cc(-c2ccccc2)c2cc(C(NC=NC#N)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
Ethyl N-cyano-methanimidate (3.6 g) was added dropwise at room temperature to a solution of intermediate (5-b) (10.6 g) in ethanol (90 ml) and the mixture was stirred at room temperature for 48 hours. Water and ethyl acetate were added, the organic layer was decanted, washed with water, dried (MgSO4), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and evaporated, yielding 10.5 g (88%) of (±)-N-[[[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)methyl]amino]methylene]cyanamide (interm. 5-c).
Reaction SMILES: CB1OB(C)OB(C)O1.Br[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[CH:18]=2)[O:13][C:12]=1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.[C:37](=O)([O-])[O-].[Na+].[Na+].[N+](=C[Si](C)(C)C)=[N-]>CN(C=O)C.O.CCOC(C)=O.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>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:12]2[O:13][C:14]3=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=4)[C:23]([O:25][CH3:26])=[O:24])[CH:18]=[C:19]3[C:11]=2[CH3:37])=[CH:31][CH:32]=1
Reactant: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C)c3c2)c1
Reaction time: 1 h
Yield: 53.4 %

Procedure:
2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.236 mL, 1.69 mmol) was added to a stirring solution of methyl 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoate (360 mg, 0.845 mmol), sodium carbonate (269 mg, 2.53 mmol), Pd(Ph3P)4 (98 mg, 0.084 mmol) in DMF (10 mL) and Water (1.0 mL). It was subjected to MW irradiation (180° C.) for 30 min. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was diluted with MeOH and treated with (Diazomethyl)trimethylsilane (467 μL, 0.934 mmol) to re-esterfy the acid which had formed. It was allowed to stir for 1 hour and then concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product methyl 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)benzoate (163 mg, 0.451 mmol, 53% yield) consistent by LCMS. LC-MS retention time: 1.79 min; m/z (MH+): 362. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:53][O:54][C:55](=[O:69])[C:56]1[CH:61]=[C:60]([N:62]([S:64]([CH3:67])(=[O:66])=[O:65])[CH3:63])[N:59]=[C:58](Cl)[CH:57]=1.[CH:70]1([NH2:73])[CH2:72][CH2:71]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:53][O:54][C:55](=[O:69])[C:56]1[CH:61]=[C:60]([N:62]([S:64]([CH3:67])(=[O:66])=[O:65])[CH3:63])[N:59]=[C:58]([NH:73][CH:70]2[CH2:72][CH2:71]2)[CH:57]=1
Reactant: NC1CC1
Reactant: COC(=O)c1cc(Cl)nc(N(C)S(C)(=O)=O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NC2CC2)nc(N(C)S(C)(=O)=O)c1
Temperature: 90 °C
Yield: 69.8 %

Procedure:
Add palladium acetate (29 mg, 0.13 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (81 mg, 0.13 mmol), cesium carbonate (531 mg, 1.63 mmol), toluene (10 mL), and 2-chloro-6-(methanesulfonyl-methylamino)-isonicotinic acid methyl ester (347 mg, 1.25 mmol) to a sealed tube. After degassing the reaction vessel with nitrogen, add cyclopropylamine (0.114 mL, 1.63 mmol) to the reaction mixture. Heat the reaction vessel at 90° C. overnight. Cool to room temperature and filter the solids through a filtering agent. Wash with ethyl acetate. Concentrate the combined filtrates and purify (silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes) to give the title compound (261 mg 70%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:37]1([C:43]2[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=2[C:45](Cl)=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:45](=[O:46])[C:44]3[CH:48]=[CH:49][CH:50]=[CH:51][C:43]=3[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5]1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Product: O=C(Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1)c1ccccc1-c1ccccc1

Procedure:
Compound 4 as prepared in Example 25 (0.6 g, 1.5 mM) was treated with N,O-bis(trimethylsilyl)acetamide (0.65 g, 3.0 ml) then with 2-phenylbenzoyl chloride (0.39 g,1.8 mM) as described in Example 22 to yield the title product as a white solid. m.p. 1H NMR (300 MHz, CDCl3) δ7.92 (d, J=7.4 Hz, 1H); 7.60-7.04 (m, 17H); 3.76 (m, 2H); 2.89 (m, 1H); 2.08 (m, 1H); 1.90 (m, 1H); 1.64 (m, 4H). m/z (MH+)545
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH:7]=[CH:6][C:5]2=[O:19]>C(O)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:9]3=[C:4]([C:5](=[O:19])[CH:6]=[CH:7][N:8]3[C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]2=3)[CH:3]=1
Reactant: O=c1ccn(-c2ccc(Cl)cc2)c2ccc(Cl)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1ccn2c3ccc(Cl)cc3c3cc(Cl)cc1c32
Yield: 2 %

Procedure:
6-chloro-1-(4-chlorophenyl)-4(1H)-quinolinone (2 g) obtained in step 4 was dissolved in acetic acid (150 ml) and to the solution were added a boron tribromide-acetic acid complex (44 ml) and palladium diacetate (6.28 g). The mixture was heated under reflux for 1 hour in an argon atmosphere and allowed to cool. The insoluble content was removed by filtration and the solution was extracted with water and ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=1:2) to obtain the title compound (40 mg, 2%).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[CH:15]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: COc1cccc(C(=O)O)c1
Agent: N
Product: COc1cccc(C(=O)NC2C3CC4CC2CN(C4)C3)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-methoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 2.30 (d, J=14 Hz, 6H), 2.40 (s, 2H), 3.49 (s, 2H), 3.60 (s, 3H), 3.79-3.89 (m, 4H), 4.38 (s, 1H), 7.13 (d, J=3 Hz, 1H), 7.33-7.44 (m, 3H); MS (APCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1SC)=[O:5].[CH3:17][N:18]([CH3:20])[NH2:19]>COCCOCCOC.O>[CH3:17][N:18]([CH3:20])[N:19]1[C:2]2[C:3](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:4](=[O:5])[N:6]2[CH2:10][CH2:9][N:8]=[C:7]12
Reactant: CN(C)N
Reactant: CSC1=NCCN1C(=O)c1ccccc1F
Solvent: O
Solvent: COCCOCCOC
Product: CN(C)N1C2=NCCN2C(=O)c2ccccc21
Yield: 77 %

Procedure:
A solution of 2.40 g (10.1 mmoles) of the product of Example 1 and 3 ml of 1,1-dimethylhydrazine in 6 ml of diglyme was heated at 165° C. for 3 hours in a sealed glass tube. Upon cooling, the solution was diluted with water and the resulting solid was collected and air-dried to give 1.80 g of 2,10-dihydro-10-(dimethylamino)imidazo[2,1-b]quinazolin-5(3H)-one. Melting point 197°-198° C. Total yield 77%.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]([CH3:37])[S:35][CH:36]=2)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])C1C=CC=CC=1>C(O)C.[Pd]>[F:27][C:24]([F:25])([F:26])[C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:28]=[C:29]([C:32]3[N:33]=[C:34]([CH3:37])[S:35][CH:36]=3)[CH:30]=[CH:31][C:9]=2[OH:8])[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=1
Reactant: Cc1nc(-c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)cs1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(-c2ccc(O)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)cs1
Reaction time: 3.5 h
Yield: 77.2 %

Procedure:
2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol-4-yl)benzamide (160 mg, 0.3 mmol) and 10% Pd—C(240 mg) were dissolved in ethanol (10 ml) and stirred for 3.5 hours under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (103.4 mg, 79.2%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=3[C:22]#N)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)=[O:36]>O=[Pt]=O>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:21]=3[CH:22]=[O:36])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C#N
Reactant: O=CO
Agent: O=[Pt]=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzonitrile (242.1 mg, 0.488 mmol) in 88% aqueous formic acid (5.86 mL) was added PtO2 (57 mg, 0.251 mmol). The reaction was heated to 60° C. After 2 hours, additional PtO2 (57 mg, 0.251 mmol) was added. After 2 more hours, a third portion of PtO2 (57 mg, 0.251 mmol) was added. Heating of the reaction at 60° C. was continued for 18 more hours, and then the reaction was cooled to room temperature. The catalyst was removed by filtration through celite with THF (50 mL). The filtrate was diluted with EtOAc (100 mL) and washed with H2O (2×50 mL), 1:1 saturated NaHCO3/brine (2×50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography (5 to 35% EtOAc/hexanes) afforded 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzaldehyde. Rf=0.23 (25% EtOAc/hexanes). LCMS=500.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 10.26 (s, 1H), 7.79-8.02 (m, 6H), 5.74 (d, J=8.1 Hz, 1H), 5.08 (d, J=16.5 Hz, 1H), 4.91 (d, J=16.7 Hz, 1H), 4.18 (m, 1H), 0.81 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:30])([C:24]1[N:28]=[C:27]([CH3:29])[O:26][N:25]=1)[NH2:23]>>[CH3:21][C:22]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24]1[N:28]=[C:27]([CH3:29])[O:26][N:25]=1)[CH3:30]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=408.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:5]1([CH2:18][O:19]CC2C=CC=CC=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:3][OH:4]>[Pd].C(O)C>[OH:19][CH2:18][C:5]1([CH:2]([OH:1])[CH2:3][OH:4])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2ccccc2)(C(O)CO)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CO)(C(O)CO)CC1
Reaction time: 72 h
Yield: 77 %

Procedure:
A slurry of palladium on carbon (10%, 100 mg) in ethanol (10 mL) was added to a solution of (RS)-1,1-dimethylethyl 4-(1,2-dihydroxyethyl)-4-(phenylmethoxymethyl)-1-piperidinecarboxylate (Description 97, 1.05 g, 2.9 mmol) in ethanol (30 mL) and the mixture was shaken under hydrogen (50 psi) for 72 hours. The mixture was filtered through Celite™ and the solvent was evaporated under reduced pressure to give the title compound as a pale oil (615 mg, 77%). m/z (ES+) 276 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:16][CH:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCCCCCCCCC(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCCCCCCCCn1c2ccccc2c2ccccc21

Procedure:
10 g (0.25 mol) sodium hydride (60%) was added in several portions into a solution of 30.6 g (0.20 mol) carbazole in 200 mL THF. Then the mixture was transferred into a funnel from which it was added dropwisely into a solution of 180 g (0.6 mol) dibromodecane in 500 mL THF at 70° C. and the mixture was refluxed for 48 h. After cooling, it was filtered. The filtrate was distilled in order to remove remaining dibromodecane. The residue was diluted with water and extracted with CH2Cl2. The organics was washed with brine and dried over anhydrous MgSO4 overnight. After removed the solvent by rotary evaporator, it was purified by silica chromography to give 31.6 g (41%, yield, mp 38˜40° C.) white solid product. 1H NMR (500 MHz, CDCl3), δ (ppm): 8.14 (2H, d), 7.51 (2H, d), 7.44 (2H, d), 7.26 (2H, d), 4.30 (2H, t), 3.41 (2H, t), 1.27˜1.90 (16H, m).
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:49]=[CH:50][CH:51]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]3[CH2:48][CH2:47]3)=[O:45])[N:42]=2)[N:39]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:29][C:30]2[CH:51]=[CH:50][CH:49]=[C:32]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]5[CH2:47][CH2:48]5)=[O:45])[N:42]=4)[N:39]=3)[CH:31]=2)=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCCCC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c3)c2)CCCCC1
Yield: 77.9 %

Procedure:
Using 3-(1-cyanocyclohexyl)benzoic acid (100 mg, 0.45 mmol), oxalyl chloride (48 μL, 0.56 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (120 mg, 0.37 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (150 mg, 78%) was obtained as a white powder.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Br[C:26]1[CH:31]=[N:30][C:29]([CH:32]2[CH2:34][CH2:33]2)=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[CH:31]=[N:30][C:29]([CH:32]4[CH2:34][CH2:33]4)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Brc1cnc(C2CC2)cn1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2cnc(C3CC3)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-bromo-5-cyclopropyl-pyrazine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.46 min; Mass spectrum (ESI+): m/z=430 [M+H]+.