Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH2:11][CH2:12][C:13]([OH:15])=[O:14]>O>[CH2:2]([O:9][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCO
Reactant: O=C(O)CCCl
Agent: [Na]
Solvent: O
Product: CCCCCCCOCCC(=O)O
Temperature: 150 °C
Yield: 53.1 %

Procedure:
25.3 g (1.1 mole) of sodium dissolved in 464.8 g (4 mole) of heptyl alcohol was heated to 150° C and 54 g (0.49 mole) of 3-chloropropionic acid were added thereto dropwise with stirring. The mixture was heated for a further 2 hours and a precipitate appeared. The mixture was cooled and 1.5 liters of water were added. The mixture was extracted with ether and the aqueous phase was acidified with concentrated sulfuric acid. The mixture was extracted with ether and the ether phase was washed with water, dried and was concentrated. The residue was rectified to obtain 49 g (52% yield) of 3-heptyloxy-propionic acid as a colorless oil boiling at 165° C at 15 mm Hg and having a refractive index nD22 = 1.436.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21].Cl>C(Cl)Cl>[CH2:19]([NH:23][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH:20]([CH3:22])[CH3:21]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CN
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a solution of 4-methoxybenzenesulfonylchloride (1 g, 4.8 mmol) in DCM (20 mL) was added pyridine (1.17 mL, 14.5 mmol) followed by isobutylamine (961 μL, 9.7 mmol) and the reaction was stirred at room temperature for 16 hours. 1 M aqueous HCl was added, extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (100% DCM) to give N-isobutyl-4-methoxy-benzenesulfonamide (1.03 g, 88%). LCMS (m/z, Method A) ES− 242 [M−1]−.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][CH:14]([NH2:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH3:13][CH:14]([NH:21][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: CCCCCCC(C)N
Product: CCCCCCC(C)NC(=O)CCCc1ccccc1

Procedure:
4-Phenylbutyryl chloride was reacted with 1-methylheptylamine to provide N-(1-methylheptyl)-4-phenylbutyramide, which, when reduced by reaction with dibroane in tetrahydrofuran, provided N-(1-methylheptyl)-4-phenylbutylamine. The amine so formed was reacted with formic acid and formaldehyde to give N-methyl-N-(1-methylheptyl)-4-phenylbutylamine.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([NH2:11])[CH:10]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:29](OCCC(C)C)=O>C1C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]2[C:8]([CH:12]=[N:29][NH:11]2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Oc2ccccc2F)cc1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: Fc1ccccc1Oc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a suspension of 5-(2-fluoro-phenoxy)-2-methyl-phenylamine (2.4 g, 11.04 mmol), acetic anhydride (3.36 g, 33.12 mmol) and potassium acetate anhydrous (1.10 g, 11.16 mmol) in benzene (36 mL) at 80° C. was added dropwise over 30 minutes isoamyl nitrite (2.22 mL, 16.56 mmol) and the reaction mixture was stirred at this temperature overnight. After cooling to room temperature, the precipitate formed was filtered and the filtrate was concentrated under vacuum and the residue treated with 5N HCl (4.5mL) then concentrated HCl (2.5 mL); the mixture was heated at 55° C. for 2.5 h then 60° C. for 15 min. The reaction was cooled to room temperature extracted into benzene (15 mL), the aqueous layer was basified with NH4OH the extracted into EtOAc (2×25 mL), the combined organic layers were dried over Na2SO4 filtered, concentrated and the residue was purified by flash chromatography eluting with Hex:EtOAc 7:3 to yield 1.8 g of 6-(2-fluoro-phenoxy)-1H-indazole: MS: 229 (M+H).
Reaction SMILES: N#N.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[Br:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17](Br)[N:16]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Br:14][C:15]1[N:16]=[C:17]([NH:11][C:7]2[CH:6]=[C:5]([C:4]([F:3])([F:12])[F:13])[CH:10]=[CH:9][N:8]=2)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Cc1cc(Br)nc(Br)c1
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Product: Cc1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Temperature: 75 °C
Yield: 91.5 %

Procedure:
N2 was bubbled through a solution of 4-(trifluoromethyl)pyridin-2-amine (12.0 g, 74.0 mmol) and 2,6-dibromo-4-methylpyridine (18.57 g, 74.0 mmol) in 1,4-dioxane (240 mL) for five minutes. Sodium tert-butoxide (7.83 g, 81 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.204 g, 1.851 mmol) were added and the solution was heated to 75° C.; the mixture was stirred using a magnetic stirrer. Upon completion, the reaction mixture was cooled and then partitioned between EtOAc (200 mL) and 5% aqueous ammonium chloride solution (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (gradient of 0-40% EtOAc/hexane) to provide 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (22.5 g, 67.7 mmol, 92%). MS ESI calcd for C12H9BrF3N3 [M+H]+ 332, found 332. 1H NMR (600 MHz, CDCl3) δ 8.39 (s, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.33 (s, 1H), 7.05 (s, 1H), 6.92 (d, J=2.7 Hz, 1H), 2.31 (d, J=3.6 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH3:21])[CH:12]=2)=[CH:6][N:5]=1.[Cl-].[Ca+2].[Cl-].C(O)C>[Fe].O>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([O:10][C:7]2[CH:6]=[N:5][C:4]([CH2:3][O:2][CH3:1])=[CH:9][CH:8]=2)[CH:16]=[CH:15][C:14]=1[NH2:17]
Reactant: COCc1ccc(Oc2ccc([N+](=O)[O-])c(OC)c2)cn1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCc1ccc(Oc2ccc(N)c(OC)c2)cn1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 2-(methoxymethyl)-5-(3-methoxy-4-nitrophenoxy)pyridine (27.0 g), iron (powder, 25.9 g), calcium chloride (1.03 g), ethanol (400 mL) and water (100 mL) was refluxed for 6 h. Then iron (powder, 12.9 g) and calcium chloride (1.03 g) were added to the mixture, and the whole was refluxed for further 2 h. The mixture was cooled to room temperature and filtered with celite. The filtrate was concentrated in vacuo to remove ethanol. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3 to 3:1, volume ratio) to give the title compound (20.1 g, 83%) as a brown oil. MS 261 (MH+).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[O:37]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38]1>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:42]([CH:39]2[CH2:40][CH2:41][O:37][CH2:38]2)=[O:43])[CH2:7]1)#[N:2]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: O=C(O)C1CCOC1
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)C2CCOC2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 77 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and tetrahydrofuran-3-carboxylic acid. LCMS (M+H)+: m/z=594.2.
Reaction SMILES: CO.Cl.CON.[Cl:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][O:13][C@@H:14]2[C@@H:18]([CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[O:17][CH:16]([OH:29])[C@H:15]2[F:30])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][O:13][C@H:14]([C@H:18]([OH:17])[CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C@@H:15]([F:30])[CH:16]=[O:29])=[CH:10][CH:9]=1
Reactant: OC1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccc(Cl)cc2)[C@@H]1F
Agent: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C[C@H](F)[C@H](OCc1ccc(Cl)cc1)[C@H](O)COCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 106.9 %

Procedure:
In a nitrogen atmosphere, 14 mL of methanol and 0.72 g of O-methylhydroxylamine hydrochloride were added to 2.89 g of (3S,4R,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorooxolan-2-ol, and thereafter, 1.21 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 12 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50), so as to obtain 3.09 g of (2R,3R,4R)-3,5-bis((4-chlorobenzyl)oxy)-2-fluoro-4-hydroxypentanal=O-methyl=oxime in the form of a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[Cl:20].[BH4-].[Na+].O>CO>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH:23][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.4 %

Procedure:
4-Trimethylsilanyl-benzaldehyde (800 mg, 4.5 mmol) and 2-(3,4-dichloro-phenyl)-ethylamine (1023 mg, 5.4 mmol) were dissolved in methanol (5 ml) and the solution was stirred at rt for 5 min. Sodium borohydride (166 mg, 4.5 mmol) was added under nitrogen and the reaction mixture was stirred at rt for 1 h. Water was added and methanol was evaporated in vacuo. The reaction was extracted twice with diethyl ether and the combined organic layers were washed once with water and once with sat. aq. NaCl solution, dried with sodium sulfate, filtered and concentrated in vacuo to yield [2-(3,4-dichloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine (1640 mg, 100%) as a colorless oil. MS (ISP): 352.2/354.2 (100/74) (M+H)+. 1HNMR (CDCl3, 300 MHz): δ 7.48 (d, 2H), 7.25-7.35 (m, 4H), 7.02 (dd, 2H), 3.79 (s, 2H), 2.75-3.00 (m, 4H), 0.26 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20]CC)=[O:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:23])[C:10]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O[Li].O>C1COCC1.CO.O>[C:27]([O:26][C:24]([C:10]1[C:11]([CH3:23])=[N:12][C:13]2[N:14]([CH:15]=[C:16]([C:18]([OH:20])=[O:19])[N:17]=2)[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(C(=O)OC(C)(C)C)c(C)nc2n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc2nc(C(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirred solution of 6-tert-butyl 2-ethyl 5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2,6-dicarboxylate (Example 54, Step 4, 3 g, 6.66 mmol) in THF (6 mL) and MeOH (2 mL) was added LiOH.H2O (0.42 g, 9.99 mmol) in H2O (2 mL). After 1 h, the reaction was quenched by 1N HCl till pH to 2. The organic volatiles were removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure and recrystallization from 1:2 EtOAc/hexanes afforded 6-(tert-butoxycarbonyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid (2.78 g, 90%) as a cream solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[N:14]#[N:15].[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH:24]=[C:23]([S:30]([NH:33][C@H:34]([C:42](Cl)=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])(=[O:32])=[O:31])[CH:22]=[CH:21]2>C(Cl)(Cl)Cl>[N:14]#[N:15].[C:1]([O:5][C:6](=[O:13])[CH2:7][N:8]([C:42](=[O:43])[C@H:34]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])[NH:33][S:30]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:24]=1)(=[O:32])=[O:31])[CH2:9][CH2:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Reactant: CCCCNCC(=O)OC(C)(C)C
Agent: N#N
Solvent: ClC(Cl)Cl
Product: CCCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Reaction time: 1 h
Yield: 82 %

Procedure:
To a stirred solution of 2.64 g of N-butylglycine tert-butyl ester in 20 ml of chloroform was carefully added N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour. At the end of this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness. The residue was triturated with a small amount of water to give a crystalline material. This was collected by filtration and recrystallized from ethanol-ethyl ether to give 2.28 g (82 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester, M.P. 164°-166° C, I.R. (KBr): 3,390, 3,165, 1,735, 1,370 cm-1.
Reaction SMILES: [C:1]([O:20]CC)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.C(O)(=O)CCCCCCC/C=C\CCCCCCCC.CCOC([C@@H](N[C@@H]1C(=O)N2N(CCC[C@H]2C(O)=O)CCC1)CCC1C=CC=CC=1)=O.O>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CCCN2CCC[C@@H](C(=O)O)N2C1=O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)O
Temperature: 37.77777777777778 °C
Reaction time: 2 h

Procedure:
1.500 Grams of ethyl stearate, 6.25 mg of PGE 2 and 62.5 mg of oleic acid were placed in a Pyrex test tube and heated to about 100° F. on a hot plate with periodic agitation. The mixture rapidly melted to afford a clear solution. A standard laboratory micropipette (Justor 1100BG manufactured by Nichiryo and available from Sigma, St. Louis, Mo. USA with volume dispensed adjustable from 10.0 to 100.0 microliters; and Sigma pipette tips—catalog #B-6429) was repeatedly dipped into this solution and aspirated with the volume set at 37 microliters. The solution rapidly solidified at ambient room temperature (71° F.) and the resultant suppository was removed by pressing a paper clip into the tip of the pipette. Approximately 100 suppositories were made in a two hour period using this method. Subsequent weighing showed that 96% of the suppositories weighed 31±0.5 mgs. Similar results were obtained when palmitic acid was substituted for oleic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.Cl[C:23]1[C:32]([C:33]#[N:34])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[N:28][CH:29]=2)[N:24]=1.C(N(C(C)C)CC)(C)C>CCO>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23]2[C:32]([C:33]#[N:34])=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[N:28][CH:29]=3)[N:24]=2)=[CH:8][CH:7]=1
Reactant: N#Cc1cc2cnccc2nc1Cl
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(Nc2nc3ccncc3cc2C#N)cc1)NC(=O)OC(C)(C)C
Yield: 34.8 %

Procedure:
A solution of (S)-3-(4-Aminophenyl)-2-tert-butoxycarbonylaminopropionic acid methyl ester (0.25 g, 0.84 mmol), 2-chloro[1,6]naphthyridine-3-carbonitrile (0.15 g, 0.77 mmol) (prepared according to the method of E. M. Hawes et al., J. Med. Chem. 1973,16, 849) and diisopropylethylamine (0.11 g, 0.84 mmol) in EtOH (1 ml) were heated under reflux for 3 h. The solvent was removed under reduced pressure and the resulting crude was purified by flash chromatography (CH2Cl2;AcOEt, 1:1) to yield (S)-2-tert-Butoxycarbonylamino-3-[4-(3-cyano[1,6]naphthyridin-2-ylamino)phenyl]propionic acid methyl ester (0.12 g, 34%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1.[Br:26]NC(=O)CCC(N)=O.C([O-])(=O)C.[NH4+].[OH-].[Na+]>ClCCl>[Br:26][C:3]1[C:4]([NH:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:5][C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=2)=[N:7][C:2]=1[Cl:1]
Reactant: N#Cc1ccc(Nc2nc(Cl)cc(NC(=O)c3ccccc3)n2)cc1
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(Nc2nc(Cl)c(Br)c(NC(=O)c3ccccc3)n2)cc1
Reaction time: 4 h

Procedure:
1000 ml of dichloromethane and 100 g of N-[6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yl]benzamide were added to a reaction vessel. To this was added 76.5 g of N-bromosuccinamide and 2.2 g (10M %) of ammonium acetate and stirred for 4 hrs. After completion of the reaction, the pH was adjusted to 10-11 with 5% of aqueous sodium hydroxide solution (10 g in 200 ml water). The reaction mass was filtered and the wet cake was slurried in 1000 ml of hot water at 55-60° C. for 1 hr and filtered. The obtained solid was dried under vacuum (0.5 kg/cm2) at 55-60° C. overnight.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc([N+](=O)[O-])cc2)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using 4-nitrobenzyl bromide in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to afford the title compound as a yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:16]([S:26][CH3:27])[C:17]([NH:19][C:20]([CH3:25])([C:22]#[C:23][CH3:24])[CH3:21])=[O:18]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH:16]([S:26][CH3:27])[C:17]([NH:19][C:20]([CH3:21])([C:22]#[C:23][CH3:24])[CH3:25])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#CC(C)(C)NC(=O)C(Cl)SC
Reactant: Oc1cccc(Oc2ccccc2)c1
Product: CC#CC(C)(C)NC(=O)C(Oc1cccc(Oc2ccccc2)c1)SC

Procedure:
In a similar procedure, 3-phenoxyphenol was reacted with 2-chloro-2-methylthio-N-(2-methylpent-3-yn-2-yl)acetamide to give 2-(3-phenoxyphenoxy)-2-methylthio-N-(2-methylpent-3-yn-2-yl)acetamide (Compound No. 4 of Table 1).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[F:16][C:17]([F:34])([F:35])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:14][C:12]3[CH:11]=[CH:10][C:9]4[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[CH:6][O:7][C:8]=4[CH:13]=3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Reactant: FC(F)(F)c1ccc(COc2ccc(CCl)cc2)cc1
Product: O=C(O)Cc1coc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc12

Procedure:
The title compound was prepared in the manner analogous to example 1E using (6-hydroxy-benzofuran-3-yl}-acetic acid methyl ester (example 24A) and 1-(4-trifluoromethyl-benzyloxy)-4-chloromethyl-benzene (example 5E). MS m/z 471 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]#[N:29].[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35]Br)[CH3:31]>C1COCC1>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][CH:27]([C:28]#[N:29])[C:21]1[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:26])[CH3:31]
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)CCC(C#N)c1c(Cl)cccc1Cl
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
A solution of diisopropylamine (19.2 mL, 0.135 tool) in THF (75 mL) was added dropwise at room temperature to n-BuLi in hexane (67.5 mL, 0.135 mol) under argon atmosphere. The mixture was stirred for 0.5 h and then brought to -78 ° CC. A solution of 2, 6dichlorophenyl acetonitrile (25 g, 0.135 mol) in THF (50 mL) was added dropwise while the reaction mixture was maintained at -78 ° CC. The resulting mixture was stirred for 1 h, whereafter a solution of ethyl-3-bromopropionate (17.2 mL, 0.135 mol) in THF (50 mL) was added dropwise. The resulting mixture was stirred for 1 h, and then allowed to reach room temperature. After an additional 1 h at 25 ° CC., the mixture was quenched with 10% aqueous hydrochloride solution. The phases were separated and the aqueous phase was extracted with diethyl ether (3×75 mL). The combined organic phases were dried (MgSO 4), filtered, and concen-trated in vacuo affording ethyl-4-cyano-4-(2,6-dichlorophenyl)-butanoate (37 g) as an oil. A solution of the butanoate (3.53 g, 15 mmol) in HCl-saturated ethanol (100 mL) was hydrogenated at 50 psi over PrO2 (0.9 g) in a Parr apparatus. Removal of the catalyst by filtration, followed by evaporation of tie EtOH, yielded an oily residue. The oil was taken up in 15% NaOH and was extracted with diethylether (3×30 mL), dried, filtered, and concentrated in vacuo. The oily residue was purified by flash chromatography using CH2Cl2 /MeOH (19/1) as eluent, affording pure racemic-69 (0.9 g, 85%): MS m/e 244.95 (M+ +1, 15.1), 243.95 (M+, 3.5), 242.95 (M+ -1, 24.1), 208.00 (19.3), 179.00 (29.3), 173.9 (61.3), 171.9 (100), 137.00 (31.6), 115.00 (20.5)