Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:30][C:25]3=[CH:26][N:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)[C:19]2[C:31](=[O:41])[N:32](C(OC(C)(C)C)=O)[CH2:33][C:18]=2[C:17]=1[F:42])=O)(C)(C)C.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:30][C:25]3=[CH:26][N:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)[C:19]2[C:31](=[O:41])[NH:32][CH2:33][C:18]=2[C:17]=1[F:42]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3ccncc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3ccncc3s2)c2c(c1F)CNC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (135 mg, 226 mmol) in DCM (3 mL) was added TFA in DCM (1:1, 10 mL). The reaction mixture was stirred at room temperature for 1 hour. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DMF/DCM (10.0 mL) and was purified via preparative mass trigger LCMS, eluting with a gradient of 10-25% ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and the solvent was stripped to dryness via rotary evaporation to give a TFA salt of the title compound (76 mg, 48% two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-2.06 (m, 8H), 3.83 (br s, 1H), 4.34 (d, J=3.28 Hz, 1H), 4.57 (s, 2H), 7.35 (d, J=6.06 Hz, 1H), 7.88 (br s, 2H), 8.20 (d, J=5.81 Hz, 1H), 8.58 (d, J=5.81 Hz, 1H), 8.81 (s, 1H), 9.47 (s, 1H), 9.61 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20FN5OS, 398. found, 398.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@@H:5]([CH3:31])[CH2:6][CH:7]([NH:23]C(OC(C)(C)C)=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][CH:10]=1)[CH3:2].[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:33].[CH2:1]([O:3][C:4](=[O:32])[C@@H:5]([CH3:31])[CH2:6][CH:7]([NH2:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2ccccc2OC)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, to a solution of (S)-4-tert-butoxycarbonylamino-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester (473 mg, 1.017 mmol) in DCM (5 ml) was added HCl in dioxane (4M, 1 ml), and the resulting mixture was stirred at room temperature for 2 hours. Then, the mixture was concentrated on under reduced pressure. The obtained residue was used for next step without further purification. HPLC Retention time 1.28 minutes (condition A): MS 342.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[Sn](C)C.C[Sn](C)C.I[C:19]1[CH:27]=[C:26]2[C:22]([C:23](/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:19]2[CH:27]=[C:26]3[C:22]([C:23](/[CH:36]=[CH:37]/[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:24][N:25]3[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(Br)cn1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccc(I)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3c(/C=C/c4ccccc4)nn(COCC[Si](C)(C)C)c3c2)cn1
Yield: 40.1 %

Procedure:
A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol), hexamethylditin (1.15 g, 6.10 mmol), and Pd(PPh3)4 (0.28 g, 0.24 mmol) in degassed dioxane (10 ml) was refluxed under for 16 h. 6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (2.90 g, 6.10 mmol) was added to above mixture, followed by Pd(PPh3)4 (0.35 g 0.31 mmol). The reaction mixture was refluxed for 16 h. The mixture was then diluted with ethyl acetate (150 ml), and washed with brine (30 ml). The organics were dried over MgSO4, then concentrated under reduced pressure. Purification by silica gel chromatography gave 6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a yellow solid (1.12 g, 40%). 1H NMR (300 MHz, CDCl3) δ 8.51 (d, 1H, J=2.5 Hz), 8.50 (d, 1H, J=9.1 Hz), 7.93 (dd, 1H, J=2.5, 8.6 Hz), 7.69 (s, 1H), 7.69-7.28 (m, 8H), 6.89 (d, 1H, J=8.6 Hz), 5.83 (s, 2H), 4.03 (s, 3H), 3.64 (t, 2H, J=8.3 Hz), 0.93 (t, 2H, J=8.3 Hz), −0.03 (s, 9H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]1[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16]1)[CH3:14].CI.Cl>O1CCCC1.CCCCCC>[CH3:1][C:17]1([C:19]([OH:21])=[O:20])[CH2:18][CH:15]([CH2:13][CH3:14])[CH2:16]1
Reactant: CC(C)NC(C)C
Reactant: CCC1CC(C(=O)O)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CCC1CC(C)(C(=O)O)C1
Yield: 109.9 %

Procedure:
A solution of 19.9 ml (140 mmol) of dry diisopropylamine in 100 ml of dry tetrahydrofuran was stirred in under an argon atmosphere and 63.6 ml (140 mmol) of a solution of n-butyllithium (2.2 M) in hexane was added dropwise thereto while maintaining the temperature below about 5° C. The resultant mixture was then stirred for 15 min with ice-bath cooling. A solution of 8.2 g (64 mmol) of 3-ethylcyclobutanecarboxlic acid (prepared in Example 1E) in 15 ml of dry tetrahydrofuran was added dropwise to the reaction mixture and stirred with cooling for 15 min. Methyl iodide (4.36 ml, 70 mmol) was added to the reaction mixture dropwise and the resultant mixture was stirred without cooling for 2 hr. The mixture was then stirred with ice-methanol bath cooling as 10% hydrochloric acid was added dropwise until the resultant aqueous phase was acidic (about 25 ml was used). The aqueous phase was separated and extracted twice with ether. The combined ether extract was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield 10 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][CH:9]2[CH:7]([O:8]2)[CH2:6]1)(=[O:4])=[O:3].[Br-:12].[Li+].Cl>O1CCCC1.[Cu](Br)Br>[Br:12][CH:9]1[CH2:10][CH2:11][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]1[OH:8]
Reactant: [Br-]
Reactant: CS(=O)(=O)N1CCC2OC2C1
Agent: Br[Cu]Br
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Br)C(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the epoxide (177 mg, 1 mmol, Example 303) in tetrahydrofuran (8 mL), lithium bromide (543 mg, 6.25 mmol, Aldrich) and copper(II)bromide (725 mg, 3.25 mmol, Aldrich) were added and the mixture was stirred at room temperature overnight. The mixture was poured into 0.1N hydrochloric acid (33 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, washed with water, brine and dried with MgSO4. The solvent was removed to give the desired product as colorless oil after passing through an aluminum column (eluted with 5% methanol/dichloromethane). 237 mg, 92%. H1NMR (300 MHz, CDCl3), ppm: 2.00–2.20 (m), 1H; 2.38–2.52 (m), 1H; 2.70 (br), 1H (OH); 2.99 (s), 3H; 3.0–3.20 (m), 2H; 3.50–3.51 (m), 1H; 3.80–3.97 (m), 2H; 4.0–4.10 (m), 1H. The compound was used directly for the next step.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)(O)[C:27]#[CH:28])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:3]3[CH:28]=[CH:27][C:26]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)([C:23]4[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)[O:1][C:2]=32)=[CH:7][CH:8]=1
Reactant: C#CC(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: COC(=O)c1cc(O)c2cc(OC)ccc2c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(OC)cc2c2c1C=CC(c1ccc(OC)cc1)(c1ccc(OC)cc1)O2
Yield: 38.1 %

Procedure:
A solution of methyl 4-hydroxy-6-methoxy-2-naphthoate (1.0 g, 4.3 mmol) and 1,1-di(4-methoxyphenyl)prop-2-yn-1-ol (1.16 g, 4.3 mmol) in toluene (45 cm3) containing acidic alumina (Brockmann 1), (4.0 g) was refluxed for 45 minutes. The cooled solution was filtered and the alumina was washed well with EtOAc (200 cm3). The organic filtrate was washed with aqueous sodium hydroxide (2M, 2×50 cm3) and water (100 cm3). Removal of the dried (Na2SO4) EtOAc gave an oil which was flash chromatographed over silica using 25% EtOAc in hexane as the eluent to afford a pale yellow solid. Recrystallisation from EtOAc/hexane gave methyl 9-methoxy-2,2-bis(4-methoxyphenyl)-2H-naphtho[1,2-b]pyran-5-carboxylate (yield=0.79 g, theoretical yield=2.08 g 38%, m.p. 162.5-164.0° C. (uncorrected)).
Reaction SMILES: C(O[C:5](=O)[CH3:6])(=O)C.S(=O)(=O)(O)O.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:5]2([CH3:6])[CH2:18][CH2:19][CH2:14][CH2:15][CH2:16]2)[CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: CC1(c2cc(Br)ccc2O)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
There are then slowly added 10.8 ml (117 mmoles) of acetic anhydride and the reaction mixture is stirred at ambient temperature for 18 hours. 2.7 ml (50 mmoles) of concentrated sulfuric acid are then added and in small portions 17.3 g (100 mmoles) of 4-bromophenol. The reaction mixture is stirred at ambient temperature for 24 hours, evaporated to dryness and taken up in 200 ml of water. The pH is adjusted to 7 with sodium bicarbonate and extracted with ethylether. The organic phase is decanted, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a silica column by using as the eluant a 40/60 mixture of dichloromethane and hexane. The solvents are evaporated and 8.97 g (33% yield) of 4-bromo-2-(1-methylcyclohexyl) phenol in the form of a yellowish oil are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:6]=2[CH:24]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[C:30]=4[CH3:31])=[CH:24][C:6]2=3)=[CH:22][CH:21]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)N(c2ccc(Cl)cc2)C[C@@H](C)c2nnc(C)n2-3)cnn1C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
A mixture of (R)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (41 mg, 0.1 mmol), 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (34 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg) and cesium carbonate (65 mg, 0.2 mmol) in toluene, ethanol and water (5 mL, 4:2:1) was stirred at 100° C. for 0.5 hour under microwave (pressure: 3.2 bar, equipment power: 150 W). The reaction mixture was evaporated, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1), to give (R)-6-(4-chlorophenyl)-8-(1,5-dimethyl-1H-pyrazol-4-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as a yellow solid (10 mg, 23%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:25][CH2:26][C:27]#[CH:28])=[N:22][CH:21]=[CH:20][CH:19]=2)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[C:27]([CH2:26][NH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][N:22]=4)[N:17]=[CH:16][C:15]=3[N+:12]([O-:14])=[O:13])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCNc1c([N+](=O)[O-])cnc2cccnc12
Reactant: ON=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Temperature: 40 °C
Yield: 74.7 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (7.6 g, 44 mmol) was added to a heated solution (40° C.) of 3-nitro-N-prop-2-ynyl[1,5]naphthyridin-4-amine (5.0 g, 22 mmol) and anhydrous triethylamine (6.7 mL, 48 mmol) in anhydrous dichloromethane (150 mL). The reaction was heated at 40° C. for 1.7 hours and then concentrated under reduced pressure. The residue was triturated with water; the resulting solid was isolated by filtration, washed sequentially with toluene and a small amount of diethyl ether, and then dissolved in dichloromethane. The solution was concentrated under reduced pressure and dried under high vacuum to provide 6.00 g of N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitro[1,5]naphthyridin-4-amine as a brownish-yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:40]=[CH:39][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=2)[O:28][CH2:29][C@H:30]2[NH:34][C:33](=[O:35])[CH2:32][CH2:31]2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].C(O)C.O>[Fe].C(Cl)Cl>[NH2:15][C:11]1[C:10]([CH3:18])=[C:9]([N:8]([CH2:19][C:20]2[CH:40]=[CH:39][C:23]([O:24][C:25]3[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=3)[O:28][CH2:29][C@H:30]3[NH:34][C:33](=[O:35])[CH2:32][CH2:31]3)=[CH:22][CH:21]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OC[C@@H]4CCC(=O)N4)c3)cc2)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OC[C@@H]3CCC(=O)N3)c2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To the product from Example 278A in a capped test-tube were added iron powder (78.4 mg, 1.4 mmoles), NH4Cl (7.5 mg, 1.4 mmoles), ethyl alcohol (3 mL) and water (1 mL). The reaction mixture was shaken violently at 80° C. overnight. CH2Cl2 (4 mL) was added to extract the product. Then, the reaction mixture was filtered. The CH2Cl2 layer was separated and dried in vaccuo.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:25]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH2:32])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl.C1COCC1>[C:25]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:35])[CH3:36])[NH:32][C:7]([C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[O:6]1)=[O:9])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C1CC[C@@H](C(=O)O)O1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)O1)C(=O)OC(C)(C)C

Procedure:
To a solution of (S)-(+)-5-oxo-tetrahydrofuran-2-carboxylic acid (1.0 g, 7.68 mmols) and N-methylmorpholine (0.84 ml, 7.68 mmols) in anhydrous/THF anhydrous dioxan 2/1 (15 ml), cooled at −15° C. was added dropwise, under stirring, the equivalent quantity of isobutylchloroformate (1.04 ml, 7.68 mmols). After 30 minutes a solution of L-leucine tertbutylester (1.44 g, 7.68 mmols) and anhydrous THF (5 ml) was slowly added, maintaining the mixture under stirring at −15° C. for two hours. The reaction mixtures was diluted with CH2Cl2 (70 ml) and washed with NaCl saturated solution (20 ml) KHSO4 1M (20+10 ml), NaHCO3 saturated solution (20+10 ml) and NaCl saturated solution (20 ml). The organic phase was dried on Na2SO4 and concentrated at reduced pressure. The raw product was purified through chromatography on silica gel (CH2Cl2/i-PrOH 98/2). By grinding in n-hexane the solid raw residue, the N-{[(S)-(5-Oxo-tetrahydrofuran-2-yl)carbonyl]}-L-leucine tertbutyl-ester was obtained as white crystals: 920 mg (40%); m.p. 79-81° C.; [a]D22=−25° (1, methanol); IR (CHCl3): 3415, 2934, 1788, 1727, 1677, 1517, 1369, 1149 cm−1; 1H-NMR (CDCl3): d 0.87 and 0.97 [two s, 6, CH2CH(CH3)2], 1.18-1.62 [m, 3, CH2CH(CH3)2 and 1.40 (s, 9, C(CH3)3], 2.15-2.80 (m, 4, ring CH2CH2), 4.25-4.55 (m, 1, ring CH), 4.62-4.88 (m, 1, aCH), 6.56 (d, 1, NH, J=8 Hz). Calculated for C15H25NO5: C, 60.18; H, 8.42; N, 4.68. Found C, 60.12; H, 8.61; N, 4.65%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:19]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH3:25])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=2)[N:11]=1.[OH-].[Na+].O>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:19]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH3:25])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3nc4ccccc4s3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of methyl 2-(1,3-benzothiazol-2-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (80 mg, 0.20 mmol) in tetrahydrofuran (20 mL) was added NaOH (23.8 mg, 0.60 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo, adjusted the pH to 7 with HCl (3 N). The product was collected and filtered to afford 2-(1,3-benzothiazol-2-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylic acid as a light yellow solid (43.8 mg, 57%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CC#N>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH3:9]
Reactant: CCOC(=O)CCCBr
Reactant: C1COCCN1
Solvent: CC#N
Product: CCOC(=O)CCCN1CCOCC1
Temperature: 80 °C
Yield: 96 %

Procedure:
A solution of ethyl 4-bromobutyrate (681 mg) in MeCN (5.0 mL) was treated with morpholine (0.61 mL) at rt. The reaction mixture was heated to 80° C. for 3 h and cooled down to rt. It was concentrated under reduced pressure, diluted with EA and the org. layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The title compound was obtained, without additional purification, as a yellow oil (643 mg; 96% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:31])[C:5]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[C:13]([O:29][CH3:30])[CH:12]=2)[CH3:10])=[N:6][CH:7]=1.Cl[CH2:33]C1C=CC(C(F)(F)F)=NC=1.C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[I:1][C:2]1[CH:3]=[C:4]2[N:31]=[CH:33][N:8]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)=[C:13]([O:29][CH3:30])[CH:12]=3)[CH3:10])[C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(C(C)Nc2ncc(I)cc2N)ccc1OCc1ccc(C(F)(F)F)nc1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: O
Solvent: CCO
Product: COc1cc(C(C)n2cnc3cc(I)cnc32)ccc1OCc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 5-iodo-N2-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)pyridine-2,3-diamine [prepared from 5-(chloromethyl)-2-(trifluoromethyl)pyridine using the procedures described in Example 3-45-1 through Example 3-45-5] (0.710 g, 1.30 mmol) in ethanol (30 mL) was added triethyl orthoformate (1.0 mL, 5.89 mmol). The yellow solution was treated with p-toluenesulfonic acid monohydrate (0.025 g, 0.13 mmol) and heated to reflux. After 30 min, the mixture was allowed to cool to room temperature and was concentrated. The residue was partitioned between ethyl acetate (50 mL) and saturated potassium carbonate solution (50 mL). The phases were separated, and the organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 0.739 g (>100%) of 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridine as an orange solid.
Reaction SMILES: IC.[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1.[C:39]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([O:29][CH3:39])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H](Cc1cc(C)c(O)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H](Cc1cc(C)c(OC)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
19 μL (0.30 mmol) iodomethane were added to a solution of 100 mg (0.20 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 2 mL DMF and the mixture was stirred for 15 min at RT. Then 131 mg (0.40 mmol) Cs2CO3 was added and the reaction solution was heated to 50° C. for 3 h. The precipitate was filtered, the filtrate was evaporated down to 1 mL down and combined with 3 mL water. The precipitate was suction filtered, dried and further reacted without purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([B:20]4[O:24]C(C)(C)C(C)(C)[O:21]4)=[CH:16][CH:15]=3)[C:10]([CH2:29][CH3:30])=[C:9]([CH3:31])[N:8]=2)=[CH:4][CH:3]=1.F.[F-].[K+].O>CO>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([B:20]([OH:24])[OH:21])=[CH:16][CH:15]=3)[C:10]([CH2:29][CH3:30])=[C:9]([CH3:31])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: F
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
A 18-mL vial was charged with 2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-4-amine (10.3 mg, 0.023 mmol) and potassium hydrogen difluoride (40 mg, 0.5 mmol). Water (0.2 ml) and MeOH (1 ml) were added respectively. The resulting mixture was stirred at rt for 1 hr. Then the volatile material was removed under reduced pressure. The residue was treated with trimethylsilyl chloride (0.1 ml) in a mixture of acetonitrile (1 ml) and water (0.2 ml). After the mixture was stirred at rt for 1 hr, the volatile material was removed the residue was treated with NaHCO3 aq. (5 ml). The precipitate was collected and purified by Preparative TLC plate using 5% of acetone in DCM as mobile phase to give the title compound (2 mg, 23% yield). MW=373.66. 1H NMR (Methanol-d4, 400 MHz) δ 7.87 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.67 (d, J=4.0 Hz, 1H), 6.93 (d, J=4.0 Hz, 1H), 2.67 (q, J=7.6 Hz, 2H), 2.54 (s, 3H), 1.21 (t, J=7.6 Hz, 3H).