Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[CH3:17][C:18]([NH2:21])([CH3:20])[CH3:19]>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:21][C:18]([CH3:20])([CH3:19])[CH3:17])[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: FC(F)(F)c1nc2cccc(Br)c2nc1Cl
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1C(F)(F)F
Yield: 77 %

Procedure:
A solution of 5-bromo-3-chloro-2-(trifluoromethyl)quinoxaline (239 mg, 0.767 mmol) and 2-methylpropan-2-amine (243 μl, 2.302 mmol; Aldrich) in DMSO (7.6 ml) was stirred at 100° C. for 7 h (more 2-methylpropan-2-amine (243 μl, 2.302 mmol) was added after 3 h). The mixture was then diluted with DCM (150 ml), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel (100% hexanes to 20% EtOAc in hexanes) provided 8-bromo-N-(tert-butyl)-3-(trifluoromethyl)quinoxalin-2-amine (224d, 77% yield) as a light yellow solid. MS (ESI, pos. ion) m/z: 348.0/350.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24][OH:25].O>C1COCC1.[H-].[Na+]>[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24][O:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])cn1
Yield: 49.5 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (25 g) and 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (32.1 g) in THF (250 ml), sodium hydride in oil (60%, 6.92 g) was added gradually while the solution was stirred under ice cooling conditions. The reaction mixture was stirred at room temperature for 15 more hours, after which it was added to water and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residual crystal was collected by filtration and recrystallized from ethanol to yield 2-[2-(5-methyl-2-phenyl-4-oxazolyl]ethoxy]-5-nitropyridine (25.4 g, 49%) as a yellow-brown crystal.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][CH3:12])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:13][C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][CH:26]=O)[CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21]>>[F:13][C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][CH:26]2[NH:9][CH2:8][CH2:7][N:5]3[C:4]([CH2:10][CH2:11][CH3:12])=[N:3][C:2]([I:1])=[C:6]23)[CH:17]=[CH:18][C:19]=1[C:20]([F:21])([F:22])[F:23]
Reactant: CCCc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(C(F)(F)F)c(F)c1
Product: CCCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(4-iodo-2-propyl-imidazol-1-yl)-ethylamine (6.840 mmol) and 3-(3-fluoro-4-trifluoromethyl-phenyl)-propionaldehyde (2.195 g; 9.970 mmol) afforded 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-3-propyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.81 min.; [M+H]+=481.75 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:12]1([CH:18]=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=CC1CCCCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: O
Solvent: CCO
Product: O=C1CC(C2CCCCC2)Oc2ccc(Br)cc21
Yield: 84.4 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (50 g, 0.23 mol), cyclohexanecarbaldehyde (26 g, 0.23 mol) and borax (89 g, 0.23 mol) in ethanol (300 mL) and H2O (500 mL) was refluxed overnight. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product, which was purified by column chromatography to give 6-bromo-2-cyclohexylchroman-4-one (60 g, 83%). 1H-NMR (CDCl3): 1.05-1.33 (m, 5H), 1.67-1.81 (m, 5H), 1.95 (d, 1H), 2.64 (m, 2H), 4.15 (m, 1H), 6.86 (d, 1H), 7.51 (m, 1H), 7.94 (s, 1H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[O:5]1[C:7]([CH3:9])([CH3:8])[CH2:6]1>>[CH:1]([NH:4][CH2:6][C:7]([CH3:9])([CH3:8])[OH:5])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC1(C)CO1
Product: CC(C)NCC(C)(C)O

Procedure:
Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-Isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3-isopropyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)C.[OH-].[Na+]>C(O)C.O>[Cl:21][C:17]1[CH:16]=[C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21

Procedure:
A mixture of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (6.0 g, 0.019 mole), sodium hydroxide pellets (0.9 g, 0.023 mole), and 50 ml of ethanol-water (2:1) was refluxed for 1 hour. The reaction mixture was cooled and the ethanol evaporated in vacuo. The residual aqueous mixture was diluted with water (40 ml) and extracted with diethyl ether (2×25 ml). The aqueous portion was acidified with concentrated hydrochloric acid to a pH of 5-6. After precipitation was complete, the solid was collected by filtration, giving 5.9 g (100%). Recrystallization from ethanol gave 4.7 g of cream colored needles, mp 214°-216° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cn2c(nc1=O)O[C@@H]1C[C@H]2O[C@@H]1CO

Procedure:
There are a variety of known techniques for converting a nucleoside into an anhydronucleoside. For example, the anhydronucleoside can be prepared by mixing thymidine with triphenylphosphine and azeotropically drying with portions of acetonitrile (MeCN). The resulting mass is suspended in MeCN and then cooled. The mixture is rapidly stirred and diisopropylazodicarcobxylate in MeCN is added dropwise to the mixture. The resulting mixture is treated with water to form a suspension that is filtered to afford anhydrothymidine. (Grierson, J. R., Shields, A. F., Nuclear Medicine and Biology, 2000, 27 143-156; Balagopala, M. I., Ollapally, A. P., and Lee, H. J., Nucleosides-Nucleotides, 1996, 15(4) 899-906).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])[CH:4]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:19])([F:18])[F:17])=[O:41])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:27])([F:28])[F:29])[CH:4]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C#N)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C#N)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 81.6 %

Procedure:
0.19 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 88 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.16 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C(N(CC)C(C)C)(C)C.[I-].[K+]>CN(C=O)C>[N:1]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(CCO)cc1
Reactant: ClCCOCCCl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCCc1ccc(N2CCOCC2)cc1
Yield: 58 %

Procedure:
4-Aminobenzeneethanol (20.2 g), 2-chloroethyl ether (21.1 g), N,N-diisopropylethylamine (38.1 g) and potassium iodide (48.8 g) in DMF were heated to 80° under nitrogen for 60 h. The solvent was evaporated and the residue (~143 g) was purified by FCC eluting with ER-CX (1:1→1:0) to give the title compound as a pink-white solid (17.7 g) m.p. 57°.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].O1CCCC1.[NH2:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([CH:20]=[O:21])=[C:15]([Cl:22])[N:14]=1>O>[NH2:12][C:13]1[N:14]=[C:15]([Cl:22])[C:16]([CH:20]([OH:21])[CH2:5][CH2:4][CH:3]=[CH2:2])=[C:17]([Cl:19])[N:18]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: C=CCCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(O)c1c(Cl)nc(N)nc1Cl
Temperature: 27.5 °C
Yield: 78 %

Procedure:
4-Bromo-1-butene (14.54 mL) was added to a mixture composed of a magnesium piece (3.17 g) and dehydrated tetrahydrofuran (150 mL) in a nitrogen atmosphere over one hour. After confirming that the internal temperature was increased, the mixture was stirred at an internal temperature of 25 to 30° C. while cooling in an ice bath for one hour to prepare a Grignard reagent. The Grignard reagent was added to a mixture composed of 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde (5.00 g) and dehydrated tetrahydrofuran (100 mL) under cooling in a dry ice-acetone bath over three hours, followed by stirring for 1.5 hours. Water (100 mL) was added to the reaction mixture, and the dry ice-acetone bath was removed. A saturated ammonium chloride solution (200 mL) was added to the reaction mixture. Then, ethyl acetate (200 mL) was added and the organic layer was separated off. The aqueous layer was extracted with ethyl acetate, and then the combined organic layers were washed with brine. The organic layers were dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain a crude product of the title compound (5.06 g, 78%) as a solid. The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: [C:1](O)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:8]([C:10](=[S:12])[NH2:11])[NH2:9].[OH-].[NH4+]>S(=O)(=O)(O)O>[C:2]([C:1]1[S:12][C:10]([NH2:11])=[N:8][N:9]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)O
Reactant: NNC(N)=S
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nnc(N)s1
Temperature: 2 °C

Procedure:
To a solution of pivalic acid (85.1 g, 0.833 mol) in concentrated sulfuric acid (280 ml) was slowly added hydrazinecarbothioamide (76.0 g, 0.833 mol) such that the internal temperature was maintained at 0-4° C. After addition was complete, the resulting mixture was heated to 80° C. and monitored by TLC. After the reaction was complete, the resulting yellow solution was cooled to room temperature, poured into ice, and then adjusted the pH to 7 by the addition of aqueous ammonium hydroxide. The resulting precipitate was filtered to obtain 5-tert-butyl-1,3,4-thiadiazol-2-amine which was used directly without purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O:20]CC)=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([OH:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@H](COCC(C)C)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)O
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
Crude ethyl (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (164.54 g) synthesized according to the process described in Patent reference 1 was dissolved in ethanol (520 mL). While the solution was cooled with ice (at a temperature of 10° C. or below), 1 mol/L aqueous sodium hydroxide solution (522 mL) was dropped. After the solution was stirred for 1.5 hours while the temperature was kept, ethanol was removed under reduced pressure. Water (340 mL) was added, and then the mixture was filtered through Celite to remove insoluble materials. The mixture was washed twice with ethyl acetate (300 mL). While the aqueous portion was cooled with ice, 6 mol/L aqueous hydrochloric acid (110 mL) was dropped to adjust the pH value to 1 and then the mixture was extracted twice with ethyl acetate (300 mL). The ethyl acetate portion was washed with water (300 mL) and with aqueous saturated sodium chloride solution (200 mL), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]-carbamoyl]oxirane-2-carboxylic acid (139.61 g, 93.1%) as orange oil. The NMR data were the same as those in Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:5]([O:4][C:3]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:2]=3[Cl:1])=[CH:6][CH:7]=[N+:8]2[O-:26])=[CH:13][CH:12]=1
Reactant: Fc1ccc(Oc2ccnc3cc(Cl)ccc23)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(Oc2ccc(F)cc2Cl)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of 5.0 g (16.22 mmol) of 4-(2-chloro-4-fluorophenoxy)-7-chloroquinoline, 4.20 g (19.47 mmol) of 80% 3-chloroperoxybenzoic acid, and 50 ml of CH2Cl2 was stirred at 0° C. for six hours. The CH2Cl2 was removed by reducing pressure, and the residue was dissolved in ethyl acetate and washed with base. After removing solvent from the organic layer by reducing pressure, a white solid formed. This was recrystallized in ethyl acetate. Yield 3.04 g (58%). M.P. 177°-178° C.
Reaction SMILES: [CH:1](=[N:8][S:9][C:10]1[C:11]([Cl:16])=[N:12][CH:13]=[CH:14][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:18].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH:1](=[N:8][S:9]([C:10]1[C:11]([Cl:16])=[N:12][CH:13]=[CH:14][N:15]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: Clc1nccnc1SN=Cc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S(N=Cc1ccccc1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1.25 grams (0.005 mole) of N-benzylidene-2-chloropyrazine-3-sulfenamide in 25 milliliters of chloroform was added to a rapidly stirring mixture of 0.69 gram (0.25 millimole) of sodium bicarbonate and the resulting mixture cooled to 0° C. To the cooled solution, a solution of gram (5.5 millimole) of m-chloroperbenzoic acid in 25 milliliter of chloroform was added dropwise over a 15 minute period. After completion of the addition, stirring was continued for 15 hours. At the end of this period, chloroform layer was separated from the aqueous layer, dried over anhydrous potassium carbonate, and subjected to reduced pressure to remove the solvent and to recover as residue an oil which solidified on standing. The latter was purified by crystallization from ethanol to obtain the desired N-benzylidene-2-chloropyrazine-3-sulfinamide product, m.p. 113°-114° C. Elemental analyses were as follows:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](Br)[CH:15]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3ccccn23)CC1
Yield: 35.4 %

Procedure:
To a solution of 1.15 g of 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)-piperidine (from Example 292, Step C) in 15 mL ethanol was added 388 mg of 2-aminopyridine. After refluxing for 18 hours, the solvent was evaporated. The mixture was partitioned between EtOAc and saturated sodium bicarbonate solution. Aqueous layer was extracted with EtOAc (3×). The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography with 50% EtOAc in hexanes, followed by 100% EtOAc to give 401 mg of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ1.48 (s, 9H), 1.70 (m, 2H), 2.06 (d, J=13 Hz, 2H), 2.93-3.02 (m, 3H), 4.26 (br, 2H), 6.87 (t, J=6.8 Hz, 1H). 7.21(m, 1H), 7.44(s, 1H), 7. 69(d, J=9.2 Hz,1H), 7.99 (d, J=6.9 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=5)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([N:23]3[CH2:24][CH2:25][CH:26]([C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=5)[N:32]=[CH:31][N:30]=4)[CH2:27][CH2:28]3)=[O:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4)CC3)c2cc1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)CC3)c2cc1OC
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a solution of 4-(4-{[4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl]-amino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5 mg, 0.009 mmol), as prepared in Example 61, in MeOH (5 mL) was added 10% Pd/C (5 mg). The solution was degassed and was kept stirring under hydrogen atmosphere for 2 h. It was filtered through a pad of celite and the filtrate was evaporated to afford the desired product (3.7 mg, 74% yield). 1H NMR (300 MHz, CD3OD) δ 8.94 (s, 1H), 7.57 (s, 1H), 7.32 (s, 1H), 7.30 (d, J=8.29 Hz, 2H), 7.15 (d, J=8.51 Hz, 2H), 4.35 (m, 2H), 4.20 (m, 2H), 4.06 (s, 3H), 4.03 (s, 3H), 3.91 (m, 1H), 3.21 (m, 2H), 2.85 (br, 2H), 2.67 (m, 1H), 1.93-2.10 (m, 4H), 1.80 (m, 2H), 1.57 (m, 2H), 1.48 (s, 9H). LC-MS (ESI) calcd mass 575.3, found 576.6 (MH+).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(OC([N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C@H:24]([C:31]([N:33]1[CH2:45][CH2:44][CH2:43][C@H:34]1[C:35]([NH:37][CH2:38][CH2:39][C:40]([NH2:42])=[O:41])=[O:36])=[O:32])[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)=[O:22])=O)C1C=CC=CC=1.C(OC(N1C(=O)CC[C@H]1C(N[C@H](C(N1CCC[C@H]1C(NCCC(N)=O)=O)=O)CC1N=CNC=1)=O)=O)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:15]1[C:19](=[O:20])[CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C@H:24]([C:31]([N:33]1[CH2:45][CH2:44][CH2:43][C@H:34]1[C:35]([NH:37][CH2:38][CH2:39][C:40]([NH2:42])=[O:41])=[O:36])=[O:32])[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)=[O:22]
Reactant: NC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1

Procedure:
100 mg of benzyloxycarbonyl-L-pyroglutamyl-L-histidyl-L-prolyl-β-alaninamide hemiacetate were dissolved in 20 ml of 0.5-N acetic acid and hydrogenated with the addition of palladium/carbon. The catalyst was filtered off and the filtrate lyophilised. Yield: 80 mg.
Reaction SMILES: [NH3:1].C(=O)=O.CC(C)=O.Cl[C:10]1[C:11]2[N:12]([C:16]([CH:29]3[CH2:32][CH2:31][CH2:30]3)=[N:17][C:18]=2[C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[CH:13]=[CH:14][N:15]=1>N.CC(O)C>[CH:29]1([C:16]2[N:12]3[CH:13]=[CH:14][N:15]=[C:10]([NH2:1])[C:11]3=[C:18]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[N:17]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: Clc1nccn2c(C3CCC3)nc(-c3ccc4cccnc4c3)c12
Reactant: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4cccnc4c3)c12
Temperature: 110 °C

Procedure:
Gaseous NH3 was condensed into a cooled (dry ice/acetone) solution of 7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinoline (203.2 mg, 0.607 mmol) in 2M NH3/iPrOH (6 mL) in a pressure tube until the volume was doubled, then the tube was sealed and heated to 110° C. (bath temp.) for 19 h. The ammonia was evaporated, the crude material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 1:1 (1-6)→2% MeOH in CH2Cl2 (7-27)→4% MeOH in CH2Cl2 (28-37)→5% MeOH in CH2Cl2 (38-53)→7% MeOH in CH2Cl2 (54-67)], yielding the title compound as a yellow solid, >98% pure by HPLC, mp. 94-96° C.; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.10 (m, 1H), 2.12-2.25 (m, 1H), 2.47-2.57 (m, 2H), 2.61-2.73 (m, 2H), 3.85 (quint, J=8.4 Hz, 1H), 5.23 (brs, 2H), 7.10 (d, J=4.4 Hz, 1H), 7.16 (d, J=4.4 Hz, 1H), 7.44 (dd, J=4.2, 8.2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.36 (s, 1H), 8.95-9.00 (m, 1H); MS (ES+): m/z 316.2 (30) [MH+].
Reaction SMILES: O[CH2:2][C:3]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([O:20][CH3:21])[CH:4]=1.P(Br)(Br)[Br:23]>C1COCC1>[Br:23][CH2:2][C:3]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([O:20][CH3:21])[CH:4]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(CO)cc1OC
Solvent: C1CCOC1
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(CBr)cc1OC

Procedure:
To a solution of methyl 4-[4′-(hydroxymethyl)-2′-methoxy-5′-nitrophenoxy]butanoate (6) (750 mg, 2.52 mmol) in anhydrous THF (10 cm3) was added PBr3 (0.24 cm3, 2.52 mmol). The resulting deep yellow solution was refluxed for 3 hours, after which time no visible changes had occurred. The reaction mixture was cooled then poured onto ice. The resulting aqueous solution was extracted with ether (3×30 cm3). The combined organic extracts were washed with 5% NaHCO3 solution (2×30 cm3) and water (2×30 cm3) before being dried (MgSO4) and concentrated in vacuo. The desired compound 7 was furnished as a yellow oil. The oil was then purified via column chromatography (SiO2, hexane:EtOAc, 2:1 v/v) thus providing 7 as a yellow powder (580 mg, 64%). m.p. 68-70° C. Found C, 43.2; H, 4.5; N, 4.0; Br, 21.9; C13H16NO6Br requires C, 43.1; H, 4.4; N, 3.9; Br, 22.1%; Rf 0.63 (SiO2, hexane:EtOAc 2:1 v/v); νmax (KBr disc)/cm−1 3000-2800 (m), 1720 (s), 1610, 1580, 1530, 1280, 1220; δH (200 MHz, CDCl3) 2.20 (2H, q, J=6.7 Hz, CH2), 2.56 (2H, t, J=6.7 Hz, CH2), 3.70 (3H, s, OCH3), 3.97 (3H, s, OCH3), 4.13 (2H, t, J=6.7 Hz, CH2), 4.86 (2H, s, CH2), 6.92 (1H, s, H-3′), 7.67 (1H, s, H-6′) ppm; δC (100 MHz, CDCl3) 24.1 (CH2), 30.1 (CH2), 51.6 (OCH3), 56.4 (OCH3), 68.0 (CH2), 68.3 (CH2), 109.7 (CH), 113.8 (CH), 127.3, 140.0, 148.1, 153.5, 173.2 (COOCH3) ppm; m/z (FAB) 362 [(MH+), 100%].