Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[N:6][CH:7]=1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:18][CH:19]2[CH:20]3[CH2:28][CH:24]4[CH2:23][C:22]([OH:29])([CH2:27][CH:26]2[CH2:25]4)[CH2:21]3)=[O:14])=[N:6][CH:7]=1
Reactant: O=C(O)c1cccc(Oc2ccc(Cl)cn2)c1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(Oc2ccc(Cl)cn2)c1

Procedure:
Prepared from 3-(5-chloro-pyridin-2-yloxy)-benzoic acid and 4-amino-1-hydroxyadamantane. 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1 H), 7.68 (d, 1 H), 7.51-7.61 (m, 2 H), 7.47 (t, 1 H), 6.94 (d, 1 H), 6.23-6.36 (m, 1 H), 4.08-4.25 (m, 1 H), 2.24 (t, 3 H), 1.51-2.03 (m, 13 H).
Reaction SMILES: C([O:8][C:9]1[C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:24](C1C=CC=CC=1)=[O:25])C1C=CC=CC=1.[Br:32]C1C=CC=CN=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[Br:32][C:14]1[C:9]([OH:8])=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:24]=[O:25]
Reactant: Brc1ccccn1
Reactant: CC1(C)OB(c2cccc(C(=O)c3ccccc3)c2OCc2ccccc2)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
A mixture of 11 (3.7 g, 8.94 mmol, 1.0 equiv), 2-bromopyridine (1.6 g, 0.95 mL, 10 mmol, 1.12 equiv), K2CO3 (3.7 g, 26.8 mmol, 3.0 equiv), dioxane (60 mL) and H2O (10 mL) was degassed with N2 for 5 min. Pd(Ph3P)4 (0.5 g, 0.43 mmol, 4.8 mole %) was added and the mixture refluxed for 8 hr, cooled to room temperature and stirred for 48 hr. The reaction suspension was diluted with EtOAc (100 mL) and the mixture filtered through Celite, washing the Celite pad with EtOAc (100 mL). The filtrate was concentrated under reduced pressure giving a yellow oil. The oil was partitioned between 1:1 EtOAc/heptanes (100 mL) and H2O (50 mL). The organic phase was washed with H2O (3×50 mL), brine (50 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a colorless oil. The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (50 g) packed in hexanes. The column was eluted with hexanes (800 mL), 3% EtOAc/hexanes (500 mL), 6% EtOAc/hexanes (500 mL), 10% EtOAc/hexanes (500 mL), and 15% EtOAc/hexanes (500 mL). Product fractions (eluted with 15% EtOAc/hexanes) were concentrated under reduced pressure yielding an oil that crystallized on pumping under high vacuum to give 1.46 g (42%) of 7 as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:19]=2[CH3:20])=[O:14])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30].C([O-])(=O)C.[Cs+].[Cl-].[NH4+].[Na].C(=O)(O)[O-].[Na+]>CS(C)=O.CCOC(C)=O.[Cu]I>[CH3:28][S:29]([NH:32][C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:19]=2[CH3:20])=[O:14])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cncc(Br)c1
Reactant: CS(N)(=O)=O
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cncc(NS(C)(=O)=O)c1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A solution of 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(5-bromo-pyridin-3-yl)-butyl]-amide (100 mg, 0.22 mmol), methanesulfonamide (85 mg, 0.89 mmol), copper(I) iodide (210 mg, 1.1 mmol) and cesium acetate (260 mg, 1.3 mmol) in DMSO (3 mL) is heated at 130° C. for 18 hours. After cooling to room temperature, saturated aqueous sodium ammonium chloride (2 mL) and saturated aqueous sodium bicarbonate (1 mL) are added and the resultant mixture is stirred for 30 min. The crude mixture is diluted with EtOAc (50 mL) and washed with saturated aqueous sodium ammonium chloride (25 mL), saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (eluted with 0 to 6% MeOH/CH2Cl2) affords 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(5-methanesulfonylamino-pyridin-3-yl)-butyl]-amide as an off-white solid (38 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][C:10]3([C:20]4[C:15](=[CH:16][CH:17]=[N:18][CH:19]=4)[C:14](=[O:21])[O:13]3)[CH2:9][CH2:8]2)[NH:4][N:3]=1.[CH2:22](Cl)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[N:3]([CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[N:4]=[C:5]([CH:7]2[CH2:12][CH2:11][C:10]3([C:20]4[C:15](=[CH:16][CH:17]=[N:18][CH:19]=4)[C:14](=[O:21])[O:13]3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: Nc1cc(C2CCC3(CC2)OC(=O)c2ccncc23)[nH]n1
Reactant: O=C(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(C2CCC3(CC2)OC(=O)c2ccncc23)nn1CC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
3-Amino-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1-cyclohexan]-4′-yl]-1H-pyrazole (180 mg, 0.633 mmol), phenacyl chloride (150 mg, 0.94 mmol) and potassium carbonate (180 mg, 1.27 mmol) were stirred overnight at room temperature in N,N-dimethylformamide (10 mL). The mixture was stirred for further 1 hour at 80° C. The reaction solution was cooled down to room temperature and ethyl acetate was added thereto. The reaction solution was washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to remove the solvent. The residue was separated and purified by a silica gel column chromatography (C-300, methanol:chloroform=1:50 to 1:30) to obtain the title compound (26.5 mg, 10.4%) as a cis and trans mixture.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1>C1COCC1>[N:12]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: C1CNC1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Solvent: C1CCOC1
Product: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with THF (45 mL), 20 (1.66 g, 7.54 mmol), azetidine (531 mg, 9.31 mmol) and stirred at room temperature for 24 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting solid was diluted with a mixture of methylene chloride (15 mL) and 10% aqueous potassium carbonate (15 mL). The aqueous layer was separated and extracted with methylene chloride (2×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 99% yield (1.47 g) of 21 as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 6.74 (s, 1H), 3.97 (s, 3H), 3.55 (s, 2H), 3.22 (t, 4H, J=7.2 Hz), 2.10 (pentet, 2H, J=7.2 Hz); MS (ESI+) m/z 197.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][N:25]1[C:29]([C:30]([F:33])([F:32])[F:31])=[C:28]([C:34](O)=[O:35])[CH:27]=[N:26]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[C:29]=3[C:30]([F:33])([F:31])[F:32])=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cn1ncc(C(=O)O)c1C(F)(F)F
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cnn(C)c3C(F)(F)F)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=508.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][S:5][C:6]=1[CH3:7].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:12][O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][S:5][C:6]=1[CH3:7]
Reactant: COC(=O)c1csc(C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1csc(C)c1OC

Procedure:
Methyl 4-hydroxy-5-methyl-3-thiophenecarboxylate (34 g), potassium carbonate (37 g) and dimethyl sulphate (33.67 g) were stirred in anhydrous acetone (200 ml) at room temperature for 20 days. The reaction mixture was filtered and the solvent removed.
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][C:6]1[S:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1>CO>[CH3:1][O:12][C:11]([C:9]1[S:10][C:6]([CH3:5])=[CH:7][CH:8]=1)=[O:13]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C(=O)O)s1
Solvent: CO
Product: COC(=O)c1ccc(C)s1
Temperature: 25 °C
Yield: 81 %

Procedure:
Acetyl chloride (5 mL) was added to a 0° C. solution of methanol (40 mL) and the solution was allowed to warm to room temperature. 5-Methyl-thiophene-2-carboxylic acid (Lancaster; 1.58 g, 11.1 mmol) was added and the solution was allowed to stir at room temperature over the weekend. The solvents were evaporated under reduced pressure and ethyl acetate was added. The solution was extracted with aqueous sodium hydrogen carbonate and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, and evaporated to give 5-methyl-thiophene-2-carboxylic acid methyl ester (1.40 g, 81%) as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14])=[CH2:2].CC(N=NC(C#N)(C)C)(C#N)C.[C:29]([OH:32])(=[S:31])[CH3:30]>C1C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:29]([S:31][CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:32])[CH3:30]
Reactant: C=Cc1ccc(C(=O)OC)cc1C(=O)OC
Reactant: CC(O)=S
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CCSC(C)=O)c(C(=O)OC)c1
Yield: 27 %

Procedure:
To a degassed solution of dimethyl 4-ethenyl-1,3-benzenedicarboxylate (415 mg, 1.88 mmol) in benzene (6 mL) were added AIBN (33 mg, 0.21 mmol) and thioacetic acid (0.27 mL, 3.78 mmol), and the mixture was refluxed for 5 hours. The reaction mixture was diluted with aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (15 mL) The organic layer was dried over MgSO4 and concentrated. The residual material was purified by silica gel chromatography (hexanes/EtOAc=10:1) to give 0.150 9 of colorless oil (27% yield): 1H NMR (CDCl3) δ 2.32 (s, 3H), 3.16 (t, 2H), 3.28 (t, 2H), 3.94 (s, 6H), 7.42 (d, 1H), 8.09 (d, 1H), 8.58 (s, 1H).
Reaction SMILES: NC1SN=C2C=CC([N+:11]([O-:13])=[O:12])=CC=12.[S:14](=[O:18])(=[O:17])([OH:16])[OH:15]>>[S:14](=[O:16])(=[O:15])([OH:18])[OH:17].[N:11]([O:13][S:14](=[O:16])(=[O:15])[OH:17])=[O:12]
Reactant: Nc1snc2ccc([N+](=O)[O-])cc12
Agent: O=S(=O)(O)O
Product: O=NOS(=O)(=O)O
Reaction time: 1.5 h

Procedure:
16.6 parts of 3-amino-5-nitro-2,1-benzisothiazole are introduced into 130 g of sulphuric acid (96% strength) at 25° C. After 90 minutes' stirring a clear solution has been obtained, to which 31 parts of 50% strength sulphuric acid and 25.8 parts of 42.5% strength nitrosylsulphuric acid are added at an interval of 30 minutes. After a further 30 minutes, the mixture is cooled to 5° C and a solution of 17.6 parts of N-ethyl-N-β-caboxyethyl-m-toluidine in 60 parts of glacial acetic acid is added dropwise at this temperature. After a further 30 minutes, the reaction mixture is poured out onto an ice-water mixture and this mixture is stirred for 4 hours. The dyestuff which has precipitated is filtered off, washed until the wash waters are neutral and then dried. The dyestuff of the formula ##SPC13##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: OB(O)c1ccccc1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2O)nc1-c1ccc(C)cc1
Yield: 70.9 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), 2-hydroxyphenylboronic acid (124 mg; 0.901 mmol), tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to yield 83 mg (49%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[CH2:10]([O:12][C:13](OCC)(OCC)[C:14](OCC)=[O:15])C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:9]=[C:13]([O:12][CH3:10])[C:14](=[O:15])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)C(OCC)(OCC)OCC
Reactant: Nc1ncnc(Cl)c1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC#N
Product: COc1nc2c(Cl)ncnc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.9 %

Procedure:
To a 50 mL round bottom flask at room temperature with a Teflon stir bar was added 6-chloropyrimidine-4,5-diamine (25 g, 172.9 mmol, 1 equiv), and anhydrous acetonitrile (300 mL). Ethyl 2,2,2-triethoxyacetate (36.87 g, 224.8 mmol, 36.9 mL, 1.3 equiv) followed by a catalytic quantity of 10-camphorsulfonic acid (3 g, 12.97 mmol, 0.075 equiv) were then added. The stirred reaction mixture was then heated to reflux for 16 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to approximately 100 mL on a rotary evaporator and poured into 500 mL of vigorously stirring ice water. The resulting slurry was rapidly stirred for 20 minutes, and the resulting tan solid was then filtered through a medium porosity glass fritted funnel and was dried on the vacuum line to give the title compound as a brown solid (25.7 g, 76% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.32 (broad s, 1H), 8.62 (s, 1H), 3.99 (s, 3H). MS (EI) for C7H5ClN4O2: 213 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=Cc1cccnc1N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Product: CC(C)Cc1cccnc1N(C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
1-tert-Butoxycarbonyl-4-[N-methyl-N-(3-(2-methyl-1-propenyl)-2-pyridinyl)amino]-piperidine (XXV, EXAMPLE 27, 1.07 g, 3.1 mmol) is hydrogenated at 20 psi over night using palladium on carbon (10%, 0.1 g) as catalyst. The reaction is filtered, the solvent evaporated and the concentrate is used without further purification, NMR (300 MHz, CDCl3) 0.66, 1.25, 1.34-1.42, 1.50-1.56, 1.72-1.81, 2.28, 2.46, 2.50-2.56, 3.50-3.13, 3.88, 6.70, 7.21 and 7.98.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@@H:15]([CH3:35])[CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (S)-(+)-2-amino-1-propanol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.52 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 4.16 (m, 1H), 3.58 (m, 2H), 2.20 (s, 3H), 1.22 (d, 3H, J=6.0 Hz). ESHRMS m/z 464.1198 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23]
Reactant: OC[C@@H](O)CCc1ccc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: OC[C@@H](O)CCc1ccc2ccccc2c1O
Reaction time: 6 h
Yield: 93.7 %

Procedure:
To a solution of (2S)-4-[1-(benzyloxy)-2-naphthyl]-1,2-butanediol (5.63 g, 17.5 mmol) in ethanol (150 mL), palladium on carbon (10 wt. %, 0.56 g) is added, and the reaction mixture is shaken under an H2 atmosphere (50 psi) for 6 h. The reaction mixture is filtered (celite) and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) provides 3.81 g (94%, 50% ee) of (2S)-4-(1-hydroxy-2-naphthyl)-1,2-butanediol as a colorless oil which crystallizes upon standing. [α]D25=+11.93 (c 10.06 in chloroform, 50% ee); Rf=0.50 (silica, ethyl acetate:hexanes 4:1); mp 105-108° C.; Anal. Calcd. for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.20; H, 7.18.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccccc1F
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3ccccc3F)cc2)no1
Temperature: 90 °C
Yield: 83.8 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-fluorophenol (16 μL, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-fluoro-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (28 mg, 84%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.93 (d, J=8.2 Hz, 2H), 7.60 (d, J=7.2 Hz, 3H), 7.17-7.29 (m, 2H), 7.11 (t, J=7.7 Hz, 1H), 6.87-7.01 (m, 1H), 5.25 (s, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH3:42])=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:40]1[CH:39]=[C:38]([CH3:42])[N:37]=[CH:36][C:35]=1[C:31]1[CH:30]=[C:29]([C:27]2[CH2:26][C:25](=[O:43])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M233) (378 mg, 0.604 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (269 mg, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:14]([C:17]1[CH:23]=[CH:22][C:20](N)=[CH:19][CH:18]=1)([O-:16])=[O:15].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:13])[NH:12][C:20]2[CH:22]=[CH:23][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Using the procedure described for the preparation of 4-{[4(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dioxo-1,2,3,4-tetrahyro-isoquinolin-6-yl)-carbamic acid 4-nitro-phenyl ester 5 g (26.0 mmol) of para-nitroanilin and 4-nitrophenyl chloroformate 14.6 g (72.4 mmol) were reacted to give (4-nitro-phenyl)-carbamic acid 4-nitro-phenyl ester, 11.0 g (100% yield) of yellow solid.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>CCOCC>[Br:19][CH2:20][C:21]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)=[O:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Br)CBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)CBr)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A solution of ethyl isonipecotate (5.1 ml, 33 mMoles) in triethylamine (4.7 ml, 33 mMoles) was added dropwise to a stirred ice-cooled solution of bromoacetyl bromide (2.9 ml, 33 mMoles) in ether (75 ml) and stirring was continued for 1 hour. The resulting suspension was washed sequentially with water (2×20 ml), dilute sodium bicarbonate solution (20 ml), dilute citric acid solution (20 ml), water (20 ml) and saturated brine (30 ml), and then the organic fraction was dried (MgSO4) and concentrated under reduced pressure to give ethyl 1-(bromoacetyl)-piperidin-4-carboxylate (4.6 g) as a yellow oil which was used without further purification; NMR (CDCl3): 1.2 (t,3H), 1.6-2.1 (m,4H), 2.5 (m,1H), 2.9 (m,1H), 3.2 (m,1H), 3.8 (s, 2H+m,1H), 4.15 (q,2H), 4.3 (m,1H); m/e 278/280 (M+H)+.