Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)[OH:6])=[N+]=[N-].[H][H].C(Cl)(Cl)[Cl:25]>O1CCCC1.CO.Cl.O1CCOCC1.[Pd]>[NH2:1][CH2:4][CH:5]([CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)[OH:6].[ClH:25]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(C(O)CN=[N+]=[N-])C2
Reactant: [H][H]
Reactant: ClC(Cl)Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(C(O)CN)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
2-(2-Azido-1-hydroxyethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.01 g, 3.53 mmol) was dissolved in tetrahydrofuran (100 ml), to which 10% palladium-on-carbon (1.01 g) was added for hydrogen replacement and stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The residue was dissolved in a solvent mixture of methanol (40 ml) and chloroform (10 ml), to which 4N-HCl-dioxane (0.94 ml) was added while cooling in a water bath, followed by condensing under reduced pressure. The resultant residue was recrystallized from methanol-ether to obtain 749 mg of the title compound as pale yellow powdery crystals (71.6%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C>[CH2:23]([O:30][C:31]([NH:1][C@@H:2]([CH2:7][C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]([F:14])[CH:13]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1

Procedure:
Methyl (2S)-2-amino-3-(3,5-difluorophenyl)propanoate (XV, EXAMPLE 11, 0.300 g, 1.40 mmol, 1 equivalent) and water (10 mL) are mixed. Sodium carbonate (0.15 g, 1.40 mmol, 1 equivalent) of is added followed by benzylchloroformate (0.2 mL, 0.24 g, 1.4 mmol, 1 equivalent) and the mixture stirred at 20-25° until complete as measured by HPLC. Once the reaction is complete, ethyl acetate (20 mL) is added and the phases separated. The aqueous phase is extracted with ethyl acetate (2×20 mL), and the combined organic phases are dried over sodium sulfate, filtered, and concentrated. The concentrate is crystallized from hexanes/ethyl acetate to give the title compound, mp=540; NMR (DMSO-d6) δ 7.84, 7.28, 7.06, 4.98, 4.35, 3.68, 3.12 and 2.88.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][CH2:34][NH2:35])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][CH2:34][NH:35][S:44]([CH3:43])(=[O:46])=[O:45])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: NCCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NCCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 189.9 %

Procedure:
To a solution of 3-(pyridin-3-yl)-7-[1-(2-aminoethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (0.20 g, 0.062 mmol), prepared according to the method of Example 59, and triethylamine (13 μL, 0.093 mmol) in THF (15 mL) was added methanesulfonyl chloride (6 μL, 0.074 mmol). The reaction mixture was stirred for two hours at ambient temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. 3-(Pyridin-3-yl)-7-[1-(2-methanesulfonylaminoethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (66 mg) was obtained by flash chromatography on silica gel (98:2 CHCl3, methanol), 1H NMR (CDCl3, 300 MHz) δ2.83 (s, 3H), 3.6 (d, 2H, J=6 Hz), 4.42-4.52 (m, 3H), 4.65 (d, 1H, J=15 Hz), 5.57 (bs, 1H), 6.38 (bs, 1H), 6.46 (bs, 1H), 6.8 (d, 1H, J=3 Hz), 7.15 (t, 2H, J=9 Hz, 11 Hz), 7.47 (d, 2H, J=7 Hz), 7.52 7.65 (m, 3H), 7.8 (d, 1H, J=9 Hz), 7.95 (s, 1H), 8.38 (d, 1H, 9 Hz), 8.55 (bs, 2H). MS (DCI/NH3) m/e 561 (M+H)+. Anal calcd for C29H25FN4O3S2 : C, 62.13; H, 4.49; N, 9.99. Found: C, 61.37; H, 4.57; N, 9.58.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].N1C=CC=CC=1.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(CS(Cl)(=O)=O)C=CC=CC=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:38](=[O:39])[CH2:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)Cc1ccccc1
Reaction time: 8 h
Yield: 18.4 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (28 mg, 0.086 mmol) was dissolved in dichloromethane (1 mL). Pyridine (1 mL) was added followed by 2-phenylethanoyl chloride (14 uL, 0.105 mmol). After stirring overnight, another 14 uL of phenylmethanesulfonyl chloride was added and the reaction mixture was stirred overnight. The solvent was removed and the residue was purified by preparative thin layer chromatogram eluted with dichlormethane/Methanol (95:5) to give N1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2-phenylacetamide (7 mg, 0.0158 mmol). 1H NMR (DMSO-d6) 1.89 (m, 6H), 2.25 (m, 2H), 3.77 (s, 3H), 3.79 (s, 2H), 5.21 (m, 1H), 5.56 (bs, 2H), 6.89 (s, 1H), 6.99 (s, 1H), 7.05 (d, J=8.22, 1H), 7.36 (m, 5H), 7.81 (s, 1H), 8.27 (s, 1H), 8.43 (d, J=8.23 Hz, 1H). LC/MS MH+=442.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Si]([C:14]#[N:15])(C)(C)C.[C:16]1(=O)[CH2:19][CH2:18][CH2:17]1>O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:16]1([C:14]#[N:15])[CH2:19][CH2:18][CH2:17]1
Reactant: C[Si](C)(C)C#N
Reactant: Nc1c(F)cccc1F
Reactant: O=C1CCC1
Solvent: O
Product: N#CC1(Nc2c(F)cccc2F)CCC1
Temperature: 90 °C
Yield: 86.2 %

Procedure:
A mixture of 2,6-difluoroaniline (0.5 g, 3.9 mmol), TMSCN (0.72 mL, 5.8 mmol), and cyclobutanone (0.43 mL, 5.8 mmol) was heated to 90° C. overnight. The mixture was poured in water and the aqueous layer was extracted with EtOAc (3×). The organics were combined, washed with brine. (2×), dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to afford 0.7 g of 1-((2,6-difluorophenyl)amino)cyclobutanecarbonitrile as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.07-7.01 (m, 2H), 6.91-6.81 (m, 1H), 6.15 (s, 1H), 2.65-2.56 (m, 2H), 2.52-2.42 (m, 2H), 2.01-1.91 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11]Br)[S:8][C:5]2=[N:6][CH:7]=1.[OH-].[NH4+:14].[CH3:15][C:16]([O:19][C:20]([O:22]C(OC(C)(C)C)=O)=O)([CH3:18])[CH3:17]>O1CCCC1.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:14][C:20](=[O:22])[O:19][C:16]([CH3:18])([CH3:17])[CH3:15])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: BrCc1nc2cc(Br)cnc2s1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nc2cc(Br)cnc2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution 6-bromo-2-(bromomethyl)thiazolo[5,4-b]pyridine (800 mg, 2.60 mmol) (Journal of Medicinal Chemistry, 53(10), 3927-393 8: 2010) in tetrahydrofuran (10 mL) is added ammonium hydroxide (2 mL) and stirred at room temperature for 16 hours. Reaction is concentrated, diluted with water (5 mL) and extracted using ethyl acetate (3×10 ml). Extracts are dried over Na2SO4 and concentrated to get crude product (650 mg). m/z (Cl) M+244. To a solution of crude amine (350 mg, 1.43 mmol) in tetrahydrofuran (10 mL) and aqueous NaHCO3 (2 mL) is added boc anhydride and resulting mixture stirred at room temperature for over night. Organic solution is separated and aqueous layer extracted with ethyl acetate (5 mL). Combined organic solution is dried over Na2SO4 and concentrated under vacuum to give the title compound (400 mg): 1H NMR (400 MHz, CDCl3) 1.50 (s, 9H), 4.74 (d, 2H), 8.36 (s, 1H), 8.62 (s, 1H). m/z (Cl) M+2 346.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[C:10]([C:13]1[C:14]([OH:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])(=[O:12])[CH3:11].CCN(C(C)C)C(C)C.O>CC#N>[C:7]([O:23][C:14]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=[CH:22][C:13]=1[C:10](=[O:12])[CH3:11])(=[O:8])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COC(=O)c1cccc(C(C)=O)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cccc(C(C)=O)c1OC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
Pyridine-4-carbonyl chloride 42 (705 mg, 5 mmol) was added to a solution of methyl 3-acetyl-2-hydroxybenzoate 38 (650 mg, 3.6 mmol) and DIEA (932 mg, 7.2 mmol) in CH3CN (10 mL). The reaction mixture was stirred at room temperature for 12 h, poured into H2O (20 mL) and extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and concentrated. The residue was purified by prep HPLC to give the product as a yellow solid (855 mg, 83% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:27])[C@@H:4]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[BH4-].[Na+]>O1CCCC1>[Cl:1][CH2:2][C@@H:3]([OH:27])[C@@H:4]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)CCl)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc2ccccc2c1)[C@H](O)CCl)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The foregoing benzyl [3-chloro-1(S)-[(2-naphthyl)methyl]-2-oxopropyl]carbamate was dissolved in100 ml of 10% aqueous tetrahydrofuran, cooled to 0° C. and treated with 0.456 g of sodium borohydride which was added carefully as the solid.The mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. The mixture was evaporated to give a white solid which was partitioned between dichloromethane and water. The stirred mixture was carefully acidified to pH 1 with concentrated hydrochloric acid. The phases were separated and the aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulphate and evaporated to give 4.325 g of crude product of melting point 155°-160° C. This crude product was extracted with boiling n-hexane. After removal of the solvent by evaporation the residue was recrystallized from ethyl acetate/n-hexane to give 1.046 g of pure benzyl [3-chloro-2(S)-hydroxy-1(S)-[(2-naphthyl)methyl]propyl]carbamate of melting point 173°-174° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Oc2ccc3ccccc3n2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Oc3ccc4ccccc4n3)cc2)ccc1Cl

Procedure:
2-(4-Aminophenoxy)quinoline (2.4 moles, 0.56 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (2.4 moles, 0.57 g) were reacted according to procedure C to yield the title compound, 0.8 g. 70%. Mass Spec (FD) 473. Calculated for C23H15ClF3N3OS: C, 58.29; H, 3.19; N, 8.87. Found: C, 58.47; H, 3.48; N, 8.85.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[F:10][C:11]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:12]=1[NH2:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:13][C:12]1[C:11]([F:10])=[CH:17][C:16]([F:18])=[CH:15][C:14]=1[F:19])=[O:8]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: O=C(Cl)CCCCCBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCCCCBr)Nc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
6-Bromohexanoyl chloride (234 mg, 1.1 mmols) was gradually added dropwise to a chloroform (3 ml) solution of 2,4,6-trifluoroaniline (147 mg, 1.0 mmol) and triethylamine (11 mg, 1.1 mmols) cooling in ice bath, and stirred for 1 hour at room temperature. The reaction mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with 1N-HCl, an aqueous saturated solution of sodium hydrogencarbonate, water, and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. Then, the resulting solid was recrystallized from hexane-ether, and 6-bromo-N-(2,4,6-trifluorophenyl)hexan amide 283 mg (yield 87%) was obtained as colorless needle-like crystals. Potassium carbonate (45 mg, 0.33 mmols) and 18-crown-6 (8 mg, 0.03 mmols) were added to (2 ml) solution of the resulting anilide (97 mg, 0.3 mmols) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol), and stirred for 1.5 hours at 80° C. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. And the resulting crystals were recrystallized from hexane-ether, and colorless needle-like crystals 106 mg (yield: 90%) of the intended product as crystals.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[C:13]1([S:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[C:13]1([S:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:25]3[CH2:10][C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:3]3=[O:12])=[CH:22][CH:21]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCc1ccc(Sc2ccccc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1Cc1ccc(Sc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.230 g, 1 mmol), 4-phenylsulfanyl-benzylamine (0.215 g, 1 mmol), and K2CO3 (0.230 g, 1.67 mmol) in toluene (6 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-phenylsulfanyl-benzyl)-2,3-dihydro-isoindol-1-one (0.175 g, 53%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.27 (s, 2H), 4.77 (s, 2H) 7.22-7.49 (m, 12H), 7.88 (d, 1H). GC-MS: m/z 331 (M)+.
Reaction SMILES: [C:1]([O:9][CH2:10]C)(=O)[CH2:2][C:3]([O:5]CC)=O.[CH3:12][O:13]CCBr.[NH2:17][C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1>>[OH:5][CH:3]([CH2:2][CH2:1][O:9][CH3:10])[C:12]([NH:17][C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)=[O:13]
Reactant: COCCBr
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1csc(N)n1
Product: COCCC(O)C(=O)Nc1nc(C)cs1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A16 and Intermediate A2 (Step 2-Step 3) starting from diethyl malonate, 2-bromoethyl methyl ether and 2-amino-4-methylthiazol, 1H NMR (300 MHz, CDCl3) δ 10.07 (br s, 1H), 6.53 (d, 1H), 4.68 (br s, 1H), 4.48 (dd, 1H), 3.68 (m, 2H), 3.37 (s, 3H), 2.33 (s, 3H), 2.20 (m, 1H), 2.14 (m, 1H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+:5].[CH2:6]([N:17]([CH2:29][C:30]([OH:32])=[O:31])[CH2:18][CH2:19][N:20]([CH2:25][C:26](O)=O)[CH2:21][C:22]([OH:24])=[O:23])[CH2:7][N:8]([CH2:13][C:14](O)=O)[CH2:9][C:10]([OH:12])=[O:11]>>[CH2:26]1[N:5]([CH2:2][C:1]([OH:4])=[O:3])[CH2:14][CH2:13][N:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][CH2:6][N:17]([CH2:29][C:30]([OH:32])=[O:31])[CH2:18][CH2:19][N:20]([CH2:21][C:22]([OH:24])=[O:23])[CH2:25]1
Reactant: CC(=O)[O-]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Reactant: [NH4+]
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1

Procedure:
Briefly, ammonium acetate, (10 μL for each mCi of 111In) is added to a reaction vial containing 111In-chloride solution. Subsequently, the DOTA-J591 solution (30 mL or 0.24 mg for each mCi of 111In) is added to the reaction vial and the mixture is gently mixed and incubated at 37° C. for 20–30 min. An aliquot of the mixture is tested to determine labeling efficiency using ITLC (SG and 5 mM DTPA, pH 5). If the binding is optimal (>70%), the reaction is stopped by the addition of 10–40 mL of 5 mM DTPA.
Reaction SMILES: F[C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH2:20]([N:22](CC)CC)C.Cl.CN>C(O)(C)C>[Br:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:8]1[C:9]2[CH:10]=[N:11][C:2]([NH:22][CH3:20])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Fc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CC(C)O
Product: CNc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Temperature: 95 °C
Reaction time: 5 h
Yield: 65.8 %

Procedure:
A mixture of 7-fluoro-4-(3-bromoanilino)-pyrido[4,3-d]pyrimidine (74 mg, 0.23 mmol), triethylamine (7 mL, 50 mmol) and methylamine hydrochloride (3.0 g, 44 mmol) in isopropanol (30 mL) contained in a steel bomb is stirred at 95° C. (oil bath) for 5 h. The resulting mixture is concentrated under vacuum, basified with aqueous Na2CO3, diluted with water and extracted with EtOAc (3×100 mL). Chromatography of this extract on silica gel (3% MeOH/CH2Cl2) gives 4-(3-bromoanilino)-7-methylaminopyrido[4,3-d]pyrimidine (50 mg, 65%) as a pale yellow solid. 1H NMR (DMSO) δ 9.93 (1H, brs), 9.37 (1H, s), 8.47 (1H, s), 8.18 (1H, s), 7.84 (1H, d, J=7.8 Hz), 7.34 (1H, t, J=7.9 Hz), 7.30 (1H, brd, J=8.1 Hz), 7.19 (1H, q, J=4.7 Hz), 6.35 (1H, s), 2.85 (3H, d, J=4.8 Hz)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:10][O:11][CH3:12])[C:7]([OH:9])=[O:8].[C:13](Cl)(=O)C>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:10][O:11][CH3:12])[C:7]([O:9][CH3:13])=[O:8]
Reactant: CC(=O)Cl
Reactant: CON=C(C(=O)O)c1ccco1
Solvent: CO
Product: CON=C(C(=O)OC)c1ccco1
Yield: 92 %

Procedure:
The crude 2-(furan-2-yl)-2-(methoxyimino)acetic acid (Example 2a) was dissolved in 100 mL of MeOH and was added to a solution of acetyl chloride (3.82 ml, 53.5 mmol) in 50 mL of MeOH. After refluxing for 16 hr, solvent was removed on the rotary evaporator and the crude product was added to 100 mL EtOAc and 20 mL of water. The organic layer was washed with 20 mL of a saturated solution of NaCl, dried (MgSO4) and solvent removed to give methyl 2-(furan-2-yl)-2-(methoxyimino)acetate (6.35 g, 32.9 mmol, 92% yield) as a yellow oil. The product is a 4:1 mixture of isomers by H NMR. Major Isomer: 1H NMR (400 MHz, Chloroform-d) δ 7.53 (dd, J=1.7, 0.6 Hz, 1H). 7.31 (dd, J=3.5, 0.6 Hz, 1H), 6.54 (dd, J=3.5, 1.8 Hz, 1H), 4.15 (s, 3H), 3.94 (s, 3H); 13C NMR (101 MHz, Chloroform-d) δ 162.77, 144.82, 143.80, 142.47, 119.34, 111.78, 63.95, 53.10. HRMS-ESI (m/z) calc'd for [C8H9NO4]+, 183.0532. found, 183.0539.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:16]=[C:15]([NH:35][CH:36]3[CH:40]=[C:39]([CH3:41])[NH:38][N:37]3S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=2)(=O)=O)=CC=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[O:55]1[CH2:56][CH2:57][N:52]([CH2:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:16]=[C:15]([NH:35][C:36]3[CH:40]=[C:39]([CH3:41])[NH:38][N:37]=3)[CH:14]=2)[CH2:53][CH2:54]1
Reactant: C1COCCN1
Reactant: CC1=CC(Nc2cc(COS(=O)(=O)c3ccc(C)cc3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)N(S(=O)(=O)c2ccc(C)cc2)N1
Product: Cc1cc(Nc2cc(CN3CCOCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 60 °C
Yield: 86.9 %

Procedure:
A mixture of 6-[(4-methylphenylsulphonyloxy)methyl]-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-2-N-[4-methylphenylsulphonyl]-1H-pyrazol-3-ylamino)pyrimidine (Method 52) (214 mg, 0.295 mmol) and morpholine (5 ml, 83.2 mmol) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was dissolved in methanol (10 ml) and 10M aqueous sodium hydroxide solution (3 ml). The mixture was heated at 60° C. for 1 hour. The volatiles were removed by evaporation and the residue dissolved in water, extracted with dichloromethane. The extracts were combined and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane (100%) and then diethylether (100%). The purified product was triturated with diethylether and collected by filtration to give the title compound (125 mg).
Reaction SMILES: [O:1]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[O:1]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][NH:14]2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ncccc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCCN2
Temperature: 25 °C
Yield: 81.9 %

Procedure:
5-(t-butyldimethylsiloxy)quinoline (1715 mg) was dissolved in ethanol (50 ml), and the air in a reactor was substituted by argon. 10% Pd—C (100 mg) was added to the resultant solution, and the mixture was stirred at room temperature in the reactor in which the atmosphere was replaced by hydrogen. After disappearance of the raw materials was confirmed, the solid was filtered off, and the filtrate was concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=10/1) to obtain the object compound (1426 mg, yield 82%).