Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[OH:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:39]2[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][OH:33])[CH2:37][CH2:38]2)[CH:7]=1)=[O:9]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Reactant: OCCN1CCNCC1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(N3CCN(CCO)CC3)c2)c1)c1ccnc(N2CCOCC2)c1
Yield: 62 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(2-hydroxyethyl)piperazine to give the title compound in 62% yield; NMR Spectrum: (DMSOd6) 2.45 (m, 8H), 3.53 (m, 8H), 3.71 (m, 4H), 4.4 (t, 1H), 7.07 (t, 2H), 7.25 (d, 2H), 7.54 (d, 1H), 7.71 (d, 1H), 8.02 (s, 1H), 8.26 (t, 2H), 10.19 (s, 1H), 10.47 (s, 1H): Mass Spectrum: M+H+ 566.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:7]=1.O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]2[C:7]=1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2
Reactant: COc1ccc(F)cc1CCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(F)c2c1CCCC2=O
Temperature: 90 °C

Procedure:
4-(5-Fluoro-2-methoxy phenyl)butanoic acid (15 g) was mixed with polyphosphoric acid (60 g) and stirred with an overhead stirrer. The reaction mixture was heated to 90° C. and stirred at this temperature for 45 minutes. The reaction mixture was allowed to cool, water (100 ml) and ethyl acetate (100 ml) were added. The mixture was neutralised with sodium hydrogen carbonate solution, the organic phase was collected. The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the crude product. This material was recrystallised from hexane-15% ethyl acetate to give the clean product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH2:14][F:15])([CH2:12][F:13])[CH2:8][C@@H:7]2O.N12CCCN=C1CCCCC2.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:42]([C@H:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[O:10][C:9]([CH2:14][F:15])([CH2:12][F:13])[CH2:8]1)=[N+:43]=[N-:44]
Reactant: O[C@H]1CC(CF)(CF)Oc2c(Cl)cccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=N[C@@H]1CC(CF)(CF)Oc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of Example 2B (7.75 g, 31.2 mmol) and THF (116 mL) was cooled to <5° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.91 mL, 53.0 mmol) and diphenylphosphoryl azide (10.09 mL, 46.8 mmol) were added. The yellow slurry was warmed slowly to ambient temperature, becoming a brown solution. After 14 hours, the mixture was concentrated, diluted with MTBE (200 mL), and washed with 2N NaOH (50 mL×2), brine (50 mL), 2N HCl (50 mL×2), and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to give the title compound. This material was used without further purification in the next step.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:19][C:20]1[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].C(O)(C)C>O>[F:19][C:20]1[CH:25]=[C:24]([C:13]2[CH:12]=[CH:11][C:10]([CH:7]3[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[CH:23]=[CH:22][C:21]=1[OH:27]
Reactant: CCCC1CCC(c2ccc(B(O)O)cc2)CC1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CCCC1CCC(c2ccc(-c3ccc(O)c(F)c3)cc2)CC1
Temperature: 70 °C
Yield: 55.2 %

Procedure:
Dichlorobistriphenylphosphinepalladium (0.143 g) was added to a mixture of 4-(4-propylcyclohexyl)phenylboronic acid (10.0 g), 2-fluoro-4-bromophenol (7.76 g), potassium carbonate (11.2 g) and isopropyl alcohol (90 ml) under a stream of nitrogen, and the mixture was heated to reflux at 70° C. for 4 hours. The reaction mixture was poured into water, which was extracted with diethyl ether. The extract was washed with water three times and the solvent was distilled off. The residue was purified by silica gel-column chromatography (solvent: toluene/ethyl acetate=10/1 by volume), and then by recrystallization-filtration (solvent: toluene/heptane=0.5/2 by volume) to give colorless crystals of 3-fluoro-4′-(4-propylcyclohexyl)biphenyl-4-ol (7.0 g, GC purity: 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[NH2:27])=[O:5])[CH3:2].[CH3:28][CH2:29][O-].[Na+].C(Br)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:28][CH3:29])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[N:8]=[C:7]1[NH2:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCBr
Solvent: CCO
Product: CCOC(=O)C1=C(C)N=C(N)C(CC)(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A solution of 37.4 g of 2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol is brought to the boil and treated with 10.9 g of ethyl bromide. After boiling for a further 60 minutes under reflux, the mixture is concentrated by distillation and the residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water. Concentration of the organic phase and recrystallization from ethanol gave 2-amino-3-ethyl-6-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 122°-3°C (16.5 g, 41% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([OH:30])=O)[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:44][CH2:45][CH2:46][OH:47].[Cl-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([NH:44][CH2:45][CH2:46][OH:47])=[O:30])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1
Reactant: NCCO
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)O)n1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCO)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.81 g (4 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylic acid (Example 20A) are dissolved in 16 ml of absolute DMF, and 1.94 g (12 mmol) of N,N-carbonyldiimidazole are added. The reaction mixture is stirred at RT for 1.5 h and, after addition of 144 μl of water, stirred at RT for 10 min. Then 366 mg (6 mmol) of 2-aminoethanol are added, and the mixture is stirred at RT for 1 h. The reaction mixture is mixed with saturated sodium chloride solution and extracted twice with ethyl acetate. The combined extracts are washed once each with 10% strength citric acid, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried with magnesium sulphate and concentrated in vacuo. The residue from evaporation is purified by chromatography on silica gel with dichloromethane/methanol as eluent.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][C:10]=1[O:25][CH3:26]>CN(CN(C)C)C>[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([C:16](=[O:24])[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH2:1])[CH:12]=[CH:11][C:10]=1[O:25][CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)Cc2ccccc2)c(Cl)c1Cl
Agent: CN(C)CN(C)C
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (100 ml.) is added dropwise to a suspension of 2,3-dichloro-4-phenylacetylanisole (29.5 g., 0.01 mole) in bis(dimethylamino)methane (100 ml.) under nitrogen with cooling to maintain the reaction mixture temperature below 60° C. The reaction mixture is stirred at 25° C. for 2 hours, and poured into ice water (1500 ml.) to precipitate 7.4 g. of 2,3-dichloro-4-(2-phenylacryloyl)anisole which melts at 87°-89° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]([C:30]([N:32]1[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33]1)=[O:31])[C@H:9]([CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([N:27]=[CH:28][N:29]=3)[CH:26]=2)=[CH:17][CH2:16]1)[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]([C:30]([N:32]1[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33]1)=[O:31])[C@H:9]([CH:15]1[CH2:16][CH2:17][CH:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([N:27]=[CH:28][N:29]=3)[CH:26]=2)[CH2:19][CH2:20]1)[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)[C@@H](C1CC=C(c2ccc3ncnn3c2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)[C@@H](C1CCC(c2ccc3ncnn3c2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reaction time: 24 h

Procedure:
The material from Step C (0.79 g, 1.5 mmol) was placed under 1 atmosphere of hydrogen gas in the presence of 10% palladium on carbon (1.6 g) in methanol (40 mL). After 24 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a mixture of cis and trans diastereomers. These diastereomers were separated by chiral HPLC (Chiralcel OD column eluting with 20% isopropanol in heptane) to afford the title compounds as single isomers (Analytical retention times: Diastereomer A Tr=11.8 min, Diastereomer B Tr=13.9 min. LC/MS 549.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14]C(=O)C2C3C(=CC=CC=3)CCN2)[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]([N:34]1[CH:38]=[CH:37]N=[CH:35]1)(N1C=CN=C1)=[O:28].[BH4-].[Na+]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:14][C:27]([N:34]2[CH2:35][CH2:5][C:6]3[C:37](=[CH:4][CH:3]=[CH:2][CH:7]=3)[CH2:38]2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(CC(=O)C1NCCc2ccccc21)c1ccc(Cl)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 183.7 %

Procedure:
Beta-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-delta-oxo-isoquinolinepentanoic acid, (14 g) in EtOAc (300 mL) was treated with carbonyldiimidazole (7.25 g) and N,N-dimethylaminopyridine (440 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (6.7 g) in H2O (150 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (500 mL) and washed with 1N HCl (1×200 mL), sat. NaHCO3 (1×200 mL) and water (1×200 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude compound as a oil. Silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 gave the title compound (12.4 g). Mass spectrum (CI): 378.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]=2[N+:13]([O-:15])=[O:14])[CH:4]1[OH:24].CO.C([BH3-])#N.[Li+].[CH3:31][C:32]([CH3:34])=O>O>[ClH:1].[CH2:17]([O:16][C:8]1[C:9]([N+:13]([O-:15])=[O:14])=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]([OH:24])[CH:3]([NH:2][CH:32]([CH3:34])[CH3:31])[CH2:12][CH2:11]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC1CCc2c(ccc(OCc3ccccc3)c2[N+](=O)[O-])C1O
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CC(C)NC1CCc2c(ccc(OCc3ccccc3)c2[N+](=O)[O-])C1O

Procedure:
To a solution of 5.0 g. of 2-amino-6-benzyloxy-1-hydroxy-5-nitro-1,2,3,4-tetrahydronaphthalene hydrochloride in 50 ml. of methanol are added 5.0 g. of lithium cyanoborohydride and 150 ml. of acetone, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is added in water and the resulting crystals are recovered by filtration, rinsed with water, dried and dissolved in alcoholic hydrochloric acid. After treatment with activated carbon, ethyl ether is added, whereupon 4.7 g. of 6-benzyloxy-2-isopropylamino-5-nitro-1-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride is obtained as colorless needles melting at 268°-270° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]([O:9]C2C=CC=CC=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:19][N:20]1[CH2:25][CH:24]=[CH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]([NH:19][N:20]2[CH2:21][CH:22]=[CH:23][CH2:24][CH2:25]2)=[O:9])=[CH:16][CH:17]=1
Reactant: NN1CC=CCC1
Reactant: O=C(Nc1ccc(F)cc1)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(F)cc1)NN1CC=CCC1
Yield: 45.1 %

Procedure:
A solution of 4-fluoro-N-phenoxycarbonylaniline (2.29 g), N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (1.02 g) in chloroform (25 ml) was refluxed for 20 hours. After evaporation of chloroform, the residue was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) using chloroform as an eluent to give N-[[(4-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (1.05 g). mp: 156°-157° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C-]#N.[K+].[C:15](#[N:17])[CH3:16]>C1OCCOCCOCCOCCOCCOC1>[C:15]([CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:17]
Reactant: CC#N
Reactant: COC(=O)c1cccc(Br)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
To a solution of methyl 3-bromobenzoate (10.0 g, 44 mmol) in acetonitrile (100 mL) were added potassium cyanide (5.7 g, 87 mmol) and 18-crown-6 (1.0 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtrated, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70). The combined solution was concentrated under reduced pressure to give the title compound (7.0 g, 91%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>CN(C)C=O.C(OCC)(=O)C>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:13][C:8]1[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[C:7]=1[OH:14])=[O:25]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1ccccc1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 61.3 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (80 mg, 0.32 mmol) and 2-bromophenylisocyanate (47 μL, 0.38 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (20/80, v/v), followed by recrystallization from ethyl acetate and hexane, gave the desired product (88 mg, 62%). EI-MS (m/z) 446.2, 448.3, 450.3 (M−).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:27]#[N:28].[K+].[I-].[K+].O>CN(C=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][C:27]#[N:28])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 24 h
Yield: 96.7 %

Procedure:
A solution of methanesulfonic acid 2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester (1.21 g, 3.07 mmol), potassium cyanide (0.799 g, 12.27 mmol) and potassium iodide (0.25 g) in 50 mL of DMF was heated to 95° C. under argon with stirring for 24 hours. The reaction mixture was cooled and poured into 500 mL of water. The aqueous mix was extracted three times with EtOAc, and the combined organic phases were washed with water, saturated brine, and dried (MgSO4). Evaporation of the solvent under reduced pressure gave an oil that was purified by elution on silica gel (hexanes:EtOAc 1:1). Removal of the solvent under reduced pressure yielded 0.950 g (2.97 mmol, 95.1% of 3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionitrile as a white crystalline solid. MS: 326 (M+H)+.
Reaction SMILES: COC1C=CC=CC=1C([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=O.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1>>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[C@@H:8]([NH:7][C:26]([C:25]1[CH:24]=[N:23][C:22]([C:21]([F:20])([F:32])[F:31])=[CH:30][CH:29]=1)=[O:28])[CH2:9]2
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: COc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(C(F)(F)F)nc1

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 19S, using 6-(trifluoromethyl)nicotinic acid in place of o-methoxybenzoic acid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.84 (s, 1H), 8.34 (dd, J=8 Hz, 1H), 8.23 (s, 1H), 8.12 (dd, J=8 Hz, 1H), 4.18 (m, 1H), 3.39 (ddd, J=10, 14 Hz, 1H), 2.95-2.87 (m, 4H), 2.67 (ddd, J=16 Hz, 1H), 2.06 (m, 1H), 1.79-1.74 (m, 3H), 1.50 (m, 1H). C14H16F3N3O=299.12 LCMS (M+H): m/z 300
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:17][NH:18][C:19]3[N:24]=[C:23]([N:25]4[CH2:30][CH2:29]C(C)(O)CC4)[CH:22]=[CH:21][N:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.ClC1C=CN=C(NCC2N3C=C(Cl)C=CC3=NC=2C2C=CC=CC=2)N=1.N1CC[CH2:60][C@@H:59]1[CH2:63][OH:64]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:17][NH:18][C:19]3[N:24]=[C:23]([N:25]4[CH2:30][CH2:29][CH2:60][C@@H:59]4[CH2:63][OH:64])[CH:22]=[CH:21][N:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: OC[C@H]1CCCN1
Reactant: CC1(O)CCN(c2ccnc(NCc3c(-c4ccccc4)nc4ccc(Cl)cn34)n2)CC1
Agent: Clc1ccc2nc(-c3ccccc3)c(CNc3nccc(Cl)n3)n2c1
Product: OC[C@H]1CCCN1c1ccnc(NCc2c(-c3ccccc3)nc3ccc(Cl)cn23)n1

Procedure:
The title compound was prepared in the same fashion as that described for compound 187 from 4-chloro-N-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine and (R)-pyrrolidin-2-ylmethanol. m/e 435 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[C:11](/[CH:28]=[CH:29]\[CH3:30])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C=O)C>[CH2:35]([O:8][C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[C:11](/[CH:28]=[CH:29]\[CH3:30])[CH:10]=1)([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:31])[F:32])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
tert-Butyl (Z)-4-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(prop-1-en-1-yl)phenyl]piperazine-1-carboxylate (85 mg, 0.181 mmol) was dissolved in N,N′-dimethylformamide (1.8 mL), added sodium hydride (9.5 mg, 217 mmol) and benzyl bromide (23 μL, 0.190 mmol) under ice-cold conditions, and the mixture was stirred at room temperature overnight. The reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (67 mg) was obtained as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:22]=1[NH2:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:10]([OH:14])[C:11]([NH:23][C:22]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:21]=1[CH3:20])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(O)C(CC(F)(F)F)NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 287 mg (1 mmol) of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2(RS)-hydroxyvaleric acid, 363 mg (3 mmol) of 2,4-dimethylaniline, 288 mg (1.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 150 mg (1.1 mmol) of 1-hydroxybenzotriazole in 10 ml of dichloromethane was stirred at room temperature for 2 hours. The solution was diluted with diethyl ether, washed with 2M hydrochloric acid and saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulphate, filtered and evaporated to give 363 mg of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2(RS)-hydroxy-2′,4′ dimethylvaleranilide as a white solid, 1H NMR (250 MHz, CDC3) δ: 1.4 (s,4H), 1.45 (s,5H), 2.1 (s,1.5H), 2.15 (s, 1.5H), 2.3 (s,3H), 2.2-2.6 (m,1H), 2.7-3(m,1H), 4.2-4.6 (m,2H), 5.3 (d,0.5H), 5.6 (d,0.5H), 5.9 (d,0.5H), 6.2 (d,0.5H), 7.0 (m,2H), 7.6 (d,0.5H), 7.7 (d,0.5H), 8.6 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[N:7][CH:6]=1
Reactant: Cc1cnc(Cl)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncc(CBr)cn1
Yield: 38 %

Procedure:
In 30 ml of carbon tetrachloride, 1.04 g (8.13 mmol) of 2-chloro-5-methylpyrimidine was dissolved. To this solution, 1.73 g (9.75 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added, followed by heating under reflux for 6 hours. After completion of the reaction, the reaction liquid was returned to room temperature, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1). Thus, 641 mg of 5-bromomethyl-2-chloropyrimidine was obtained (Percentage Yield: 380).