Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][N:9]=[C:8]([C:11]([O:13]CC)=[O:12])[N:7]=2)=[N:2]1.[OH-].[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][N:9]=[C:8]([C:11]([OH:13])=[O:12])[N:7]=2)=[N:2]1
Reactant: CCOC(=O)c1noc(-c2ccon2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1noc(-c2ccon2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 155.5 %

Procedure:
Ethyl 5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylate (1.893 mmol, 0.396 g) was dissolved in ethanol (5 ml) and cooled to 0° C. with an ice bath. NaOH 1 M solution (4 ml) was slowly added and the mixture was heated to 60° C. for 3 h. Ethanol was evaporated and the residue was diluted with MTBE. The mixture was cooled to 0° C. and acidified by adding 2 M HCl. The mixture was stirred at RT overnight. Water was added and the phases were separated and the water phase was evaporated. 0.533 g of the title compound was obtained. 1H-NMR (400 MHz, D2O): δ 6.68 (d, 1H), 8.65 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:23]([C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)([CH3:25])[CH3:24].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:23]([C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1)([CH3:25])[CH3:24]
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC(C)[C@@H]1COC(=O)N1c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (600 mg, 1.7 mmol), (R)-4-isopropyl-2-oxazolidinone (322 mg, 2.5 mmol), copper(I) iodide (96 mg, 0.5 mmol), N,N-dimethylglycine hydrochloride (140 mg, 1.0 mmol) and potassium carbonate (923 mg, 6.7 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (555 mg, 80%) as a white solid: LC/MS m/e calcd for C24H28N2O4 (M+H)+: 409.50, observed: 409.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:4]2[N:3]=1.[I:19]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:18])[C:17]([I:19])=[C:4]2[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc2nc(Cl)cc(-c3cccc(Cl)c3)n2n1
Solvent: ClCCl
Product: Cc1nn2c(-c3cccc(Cl)c3)cc(Cl)nc2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
5-Chloro-7-(3-chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (186 mg) is dissolved in CH2Cl2 (40 mL) and N-iodosuccinimide (NIS, 323 mg) is added to the reaction solution. The reaction mixture is stirred at room temperature for 16 hours. The reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (237 mg). 1H NMR (CDCl3, 300 MHz) δ 7.99 (s, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.53 (m, 3H), 6.85 (s, 1H), 2.51 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][NH:14][O:15][CH3:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:16][O:15][N:14]([CH3:13])[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.483 g (3 mmol) 1H-Indole-5-carboxylic acid, 0.351 mg (3.6 mmol) N,O-dimethylhydroxylamine, 1.155 g (3.6 mmol) TBTU and 1.163 g (9 mmol) DIPEA in 15 mL DMF was stirred at room temperature for 2 h and evaporated. NaHCO3 aq. was added and the mixture was extracted with DCM. The combined organic layers were dried with MgSO4, evaporated and the title compound was used crude in the subsequent reaction.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(c2ccc(C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1
Temperature: 100 °C
Yield: 59.5 %

Procedure:
1,4-Dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (4 g) was dissolved in DMF (189 ml) at RT under an argon atmosphere. Then, 1-bromo-4-(trifluoromethyl)benzene (6.39 g), N,N′-dimethylethylenediamine (sym) (3.34 g), cuprous iodide (5.41 g) and K3PO4 (7.13 g) were added and the mixture was heated at 100° C. for 12 hours. The reaction mixture was cooled to RT, filtered and saturated aqueous NH4Cl solution was added. The mixture was then extracted twice with AcOEt, the combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated off in vacuo. The crude product was purified by flash chromatography (silica gel, gradient of 0% to 25% of acetronitrile in CH2Cl2) to give the title compound as white crystalline solid (4 g). MS (m/e): 356.146 [MH+].
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)C(O)C(C)(C)C
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4R)-4-amino-2,2-dimethyl-hexan-3-ol (52 mg, 3.41 eq, 0.36 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 7.3 mg (17%). (55% de 4R,3S: 45% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.99-1.03 (m, 12H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.56 & 1.58 (2×d, 6H, J=6.63 & 6.79 Hz, —CH(CH3)2), 1.69-1.91 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.55 (d, 1H, J=1.74 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.76-3.87 (m, 1H, —NHCH(CH2CH3)CH(C (CH3)3)OH), 4.57-4.70 (m, 1H, —CH(CH3)2), 4.80-4.89 (m, 2H, —HNCH2-Pyr), 5.22-5.35 & 6.07-6.23 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.24-7.36 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.55 (s, 1H, Pyr-H), 7.74 (d, 1H, J=7.58 Hz, Pyr-H), 8.50-8.74 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 412 ([M+H]+, 100), 324 (80). Accurate Mass (M+H): Actual: 412.2825, Measured: 412.2835.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)=[O:18])=[C:12]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41]C)[CH:11]=[CH:10]2>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:23][CH:24]=1)=[O:18])=[C:12]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41])[CH:11]=[CH:10]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3OC)ccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(Cc2ccccc2O)ccc2cc(O)ccc12
Reaction time: 1 h
Yield: 26.1 %

Procedure:
Add BBr3 (0.3 mL) dropwise to a stirred solution of [6-methoxy-2-(2-methoxy-benzyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (650 mg, 1.28 mmol) in CH2Cl2 (15 mL) at room temperature. Stir for 1 h and add an additional aliquot of BBr3 (0.2 mL). Continue stirring for 1 h and quench with MeOH and 2-methyl-2-butene. Load the resulting solution on an SCX cartridge, wash with MeOH and elute with 2M NH3/MeOH. Purify the resulting product by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2) to afford [6-hydroxy-2-(2-hydroxy-benzyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (161 mg, 26%).
Reaction SMILES: Br[CH:2]([C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:17]([NH:20][C:21]([NH2:23])=[S:22])[CH2:18][CH3:19]>CO>[C:10]1([C:9]2[N:23]=[C:21]([NH:20][CH2:17][CH2:18][CH3:19])[S:22][C:2]=2[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCNC(N)=S
Reactant: COC(=O)CCC(Br)C(=O)c1ccccc1
Solvent: CO
Product: CCCNc1nc(-c2ccccc2)c(CCC(=O)OC)s1
Yield: 70.3 %

Procedure:
A mixture of methyl 4-bromo-5-oxo-5-phenylpentanoate (5.00 g), N-propylthiourea (2.01 g) and methanol (50 ml) was refluxed for 2 hrs. The reaction solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. The obtained solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give methyl 3-[4-phenyl-2-[N-(1-propyl)amino]-5-thiazolyl]propionate (3.64 g, yield 70%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 67–68° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([O:20][CH3:21])=[O:19])=[N:6][C:7]=1[C:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([O:20][CH3:21])=[O:19])=[N:6][C:7]=1[CH:8]1[CH2:9][CH2:10][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc(F)c(C2=CCC3(CC2)OCCO3)n1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(F)c(C2CCC3(CC2)OCCO3)n1
Reaction time: 8 h
Yield: 91 %

Procedure:
To a degassed solution of methyl 5-fluoro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)picolinate (1.0 equiv.) in MeOH (0.07M) was added 10% Pd/C (0.1 equiv.) and the reaction was stirred under a hydrogen balloon overnight. The solution was then filtered, rinsed with MeOH, and the filtrate was concentrated to afford methyl 5-fluoro-6-(1,4-dioxaspiro[4.5]decan-8-yl)picolinate in 91% yield. LC/MS=296.2 (M+H), Rt=0.83 min.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([N:24]2[CH:28]=[C:27]([C:29](=[O:31])[NH2:30])[C:26]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[N:25]2)([CH2:21][C:22]#[N:23])[CH2:17][CH2:16]1)=[O:14])[CH3:11])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl>[C:29]([C:27]1[C:26]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[N:25][N:24]([C:18]2([CH2:21][C:22]#[N:23])[CH2:17][CH2:16][N:15]([C:13]([O:12][CH:10]([CH3:11])[CH2:9][OH:8])=[O:14])[CH2:20][CH2:19]2)[CH:28]=1)(=[O:31])[NH2:30]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(CO)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (Example 30-51) (86 mg, 0.15 mmol) in THF (1.0 mL) was added a solution of TBAF.3H2O (316 mg, 1.00 mmol) in THF (1.0 mL). The resulting mixture was allowed to stir at ambient temperature for 3 hours. The mixture was then diluted with DCM, washed with water, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by MPLC on silica gel (using a gradient elution of 0-20% MeOH/DCM) to afford the title compound, Example #31.
Reaction SMILES: Br.[N:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([OH:16])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[C:18]1([C:24]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:32]3[CH:28]([CH2:29][NH:30][CH2:31]3)[S:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([N:30]2[CH2:31][CH:32]3[C:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:25][CH2:26][S:27][CH:28]3[CH2:29]2)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Agent: Br
Agent: Cl
Product: O=C(Cc1ccccc1N1CCCC1)N1CC2SCCC(c3ccccc3)(c3ccccc3)C2C1
Yield: 30.9 %

Procedure:
By carrying out the procedure as in Example of Use 1, using 1.85 g of [2-(1-pyrrolidinyl)phenyl]acetic acid hydrobromide and 2.0 g of (4aRS,7aRS)4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride, 0.90 g of (4aRS,7aRS)6-{[2-(1-pyrrolidinyl)phenyl]acetyl}4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole is obtained in the form of white crystals; melting point 166° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Br)C.[C:36](=[O:38])=[O:37].O>C1COCC1.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([C:36]([OH:38])=[O:37])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: O=C=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc(C(=O)O)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a cooled (−30° C.) solution of 3-ethyl-1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (500 mg; 0.910 mmol) in anhydrous THF (10 ml) was added dropwise 1M ethylmagnesium bromide in THF (2.0 ml; 2 mmol). The resulting colorless suspension was allowed to warm-up to rt in 30 min., and was again cooled to −35° C. before continuous injection of carbon dioxide during 2 h. Water and EA were then added, and the resulting reaction mixture was allowed to warm-up to rt. The organic layer was further washed with aq. sat. NH4Cl, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the expected product 3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester as a colorless foam (350 mg; 0.748 mmol; 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)=[CH:14][C:13]=2[F:29])=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[NH2:34][CH2:35][CH2:36][CH2:37][OH:38]>C1COCC1>[F:29][C:13]1[CH:14]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:34][CH2:35][CH2:36][CH2:37][OH:38])[N:20]=2)[CH:16]=[CH:17][C:12]=1[NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:30]([F:33])([F:32])[F:31])[CH:4]=1)=[O:10]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)n1
Reactant: NCCCO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc(NCCCO)n2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 98 mg (0.194 mmol) 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[2-fluoro-4-(2-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-urea, 32 mg (0.43 mmol) 3-amino-propan-1-ol and 5 ml THF was stirred at r.t. for 12 h. The reaction mixture was evaporated and the residue purified by chromatography on silica (dichloromethane/ethanol 96:4). Yield 20 mg (21%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[NH:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1.C(=O)([O-])[O-].[Na+].[Na+].CCO>COCCOC.C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH:12]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)[CH:14]=[N:13]1
Reactant: Brc1ccc2cnccc2c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: c1cc2cc(-c3cn[nH]c3)ccc2cn1
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A mixture of 6-bromoisoquinoline (500 mg, 2.40 mmol) (commercially available from Kalexsyn Product List (Order Number 2003-005)), pyrazole-4-boronic acid pinacol ester (560 mg, 2.88 mmol) (commercially available from Acros Organics (Order Number 38294)), trans-dichlorobis(triphenylphosphine)palladium(II) (118 mg, 0.17 mmol), and sodium carbonate (764 mg, 7.21 mmol) in DME:EtOH:H2O=7:2:3 (4 mL) was heated at 140° C. for 10 minutes in a Biotage Initiator® microwave. After cooling to room temperature, the mixture was diluted with saturated aqueous NaHCO3 and extracted with 25% i-PrOH/CHCl3 (3×). The combined organic layers were dried over Na2SO4, filtered and adsorbed onto silica gel. The residue was purified using column chromatography (acetone/hexanes=0-50%) to provide the product as an off-white solid (177 mg, 37%). LCMS (API-ES) m/z: 196 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[NH:20]1[C:28]2[C:23](=[C:24]([CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[NH:20]1[C:28]2[C:23](=[C:24]([CH2:29][NH:30][C:2]3[CH:7]=[C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:3]=3)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Reactant: NCc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(-c2nc(NCc3cccc4[nH]ccc34)cc(-c3cccnc3)n2)nc1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-6-pyridin-3-yl-2-pyridin-2-yl-pyrimidine (Intermediate A) (1 eq, 0.2 g), C-(1H-indol-4-yl)-methylamine (1.1 eq, 0.12 g) and K2CO3 (3 eq, 0.308 g) in NMP (6 ml) is heated using microwave radiation at 120° C. for 1 hour. After cooling to room temperature, the mixture is partitioned between EtOAc/water and the organic portion is separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue is purified by mass directed preparative HPLC eluting with acetonitrile in water—0.1% TFA and the appropriate fractions are combined and concentrated in vacuo. The resulting residue is loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum to afford the title compound [M+H]+=379.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.O[CH2:9][CH:10]([CH2:12]O)O>>[N:4]1[C:3]2[C:2](=[N:1][CH:9]=[CH:10][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OCC(O)CO
Reactant: Nc1cccnc1
Product: c1cnc2cccnc2c1

Procedure:
Thus 3-amino pyridine III may be condensed with a glycerol of formula IV to give the ##STR3## 1,5-naphthyridine of formula V which is reduced e.g. by hydrogenation over platinum oxide to the 1,2,3,4-tetrahydro-1,5,-naphthyridine of formula (VI). In formula IV, V and VI R1, R2 and R3 are as defined in connection with formula I.
Reaction SMILES: [FH:1].[CH3:2][O:3][C@@H:4]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][C@H:5]1[N:12]1[C:21]2[N:20]=[C:19](N)[N:18]=[C:16]([NH2:17])[C:15]=2[N:14]=[CH:13]1.C(ON=O)(C)(C)C.C(=O)(O)[O-].[Na+].C(=O)=O>N1C=CC=CC=1.O.C(OCC)(=O)C.CO>[CH3:2][O:3][C@@H:4]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][C@H:5]1[N:12]1[C:21]2[N:20]=[C:19]([F:1])[N:18]=[C:16]([NH2:17])[C:15]=2[N:14]=[CH:13]1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Reactant: F
Agent: *CC*
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(F)nc21
Temperature: -20 °C

Procedure:
A 2 L polyethylene bottle was equipped with a magnetic stirrer, thermometer, dry ice/acetone bath and a stream of argon gas. Anhydrous pyridine (200 mL) was added and the solution was cooled to −20° C. To this was added 70% hydrogen fluoride in pyridine (100 mL) while maintaining the temperature below 0° C. 2′-O-Methyl-2-aminoadenosine, (2, 30 g, 0.101 mol, R.I. Chemical, Orange, Calif., Reliable Bio-pharmaceuticals, St. Louis, Mo.) was dissolved in the solution. Tert-butylnitrite (42 mL, 0.35 mol) was added in one portion and the reaction was stirred at 5-13° C. until the reaction was complete as judged by TLC (2 h, Rf 0.15, starting material; Rf 0.28, product, ethyl acetate-methanol 9:1). Sodium bicarbonate (600 g) was suspended with manual stirring in water (1 L) in a 20 L bucket. The reaction solution was slowly poured (to allow for evolution of carbon dioxide) into the aqueous layer with vigorous stirring. The resulting solution (pH 7-8) was extracted with ethyl acetate (5×400 mL). The organic layers were combined and concentrated to an oil which was triturated with methanol (70 mL) to form a solid. The solid was collected by filtration and washed with ethyl acetate (3×50 mL) and dried (1 mm Hg, 25° C., 24 h) to 16.5 g of product as a cream colored microcrystalline solid, mp 239-241° C. The filtrate was concentrated under reduced pressure to about half volume and a second crop was collected as above to give as additional 1.0 g or 17.5 g total (58%). More product remained in the mother liquor. H-NMR (DMSO-d6) δ 3.36 (s, 3, 2′—O—CH3) 3.50-3.75 (m, 2, 5′ and 5″-H), 3.98 (m, 1, 4′-H), 4.32 (m, 2, 3′-H and 2′-H), 5.14 (t, 1, 5′-OH), 5.31 (d, 1, 3′-OH), 5.92 (d, 1, 1′-H), 7.92 (br s, 2, NH2) 8.40 (s, 1, 8-H).