Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[OH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:17][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:19][CH:20]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2ccc(Br)cc2C=O)cc1
Temperature: 170 °C
Yield: 95.5 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (4.04 g, 20 mmol) (Alfa) in N,N-dimethylacetamide (30 mL) was added anhydrous K2CO3 (2.76 g, 20 mmol), and methyl 4-hydroxybenzoate (3.1 g, 20 mmol, Aldrich). The reaction mixture was heated at 170° C. for 1 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc: hexanes=1:8 then 1:4) to give 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester as a white solid (Yield 6.4 g, 95%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[F:19][C:16]([F:18])([F:17])[C:13]1[N:11]2[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:26][C:25]4[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Product: FC(F)(F)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 4-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47](O)=[O:48].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[C:13]([NH:17][C:18]([C@@H:20]1[C:24]([CH3:25])([CH3:26])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH:39][C:47](=[O:48])[CH2:46][O:45][C:44]1[C:43]([CH3:42])=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:54])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: Cc1cccc(C)c1OCC(=O)O
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)COc2c(C)cccc2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
EDC-HCl (63 mg) was added to a solution of the compound obtained in Step 2 of Example 17 (127 mg), 2,6-dimethylphenoxyacetic acid (54 mg), and HOBt (41 mg) in DMF, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% Na2CO3 (×2), 1N HCl, and 5% NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography and recrystallized from a mixture of EtOAc and n-hexane to obtain the title compound (130 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.ClCCl.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Temperature: 50 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of Example 206a (6.88 g, 20.57 mmol) in a mixture of methanol (180 mL) and dichloromethane (20 mL) was added Raney nickel (50% in water, 3 g). This suspension was purged with hydrogen and stirred under hydrogen of 40 psi at 50° C. for 6 hours. Solid material was removed, and the filtrate was concentrated to provide the title product. Yield: 100%. MS (DCI) m/z 305 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.47-1.59 (m, 2H), 1.84 (d, J=11.87 Hz, 2H), 2.33 (s, 3H), 2.44-2.71 (m, 12H), 3.28-3.48 (m, J=12.21 Hz, 4H), 3.73 (s, 2H), 6.29 (dd, J=8.31, 2.54 Hz, 1H), 6.46-6.54 (m, 2H).
Reaction SMILES: CN(/[CH:4]=[N:5]/[C:6]([C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[C:18]1[N:14]([CH:15]=[C:16]([C:22]3[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[C:24]([CH3:30])[N:23]=3)[N:17]=1)[CH2:13][CH2:12][O:11]2)=O)C.Cl.[NH:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[NH2:33]>C(O)(=O)C>[CH:27]([N:26]1[C:22]([C:16]2[N:17]=[C:18]3[C:19]4[CH:20]=[CH:21][C:8]([C:6]5[N:32]([CH:34]6[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]6)[N:33]=[CH:4][N:5]=5)=[CH:9][C:10]=4[O:11][CH2:12][CH2:13][N:14]3[CH:15]=2)=[N:23][C:24]([CH3:30])=[N:25]1)([CH3:28])[CH3:29]
Reactant: CN1CCC(NN)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)/N=C/N(C)C)cc2OCC3)n(C(C)C)n1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ncnn4C4CCN(C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Yield: 34.3 %

Procedure:
A mixture of N-[(1E)-(dimethylamino)methylidene]-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-12-carboxamide (100 mg, 0.246 mmol) and 4-hydrazinyl-1-methylpiperidine hydrochloride (81 mg, 0.49 mmol) in acetic acid (10 mL) was heated at 100° C. for 1 h. The solvent was removed under reduce pressure, and the residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 255 (40 mg, 34% yield) as a white solid. LCMS (ESI): RT=4.28 min, m/z: 474.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.58-8.57 (d, J=8.0 Hz, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.44-7.42 (dd, J=8.0, 1.5 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 5.86 (m, 1H), 4.58 (s, 4H), 4.31 (m, 1H), 2.86-2.84 (m, 2H), 2.26 (s, 3H), 2.18 (s, 3H), 2.13-2.07 (m, 2H), 2.01-1.96 (m, 2H), 1.91-1.89 (m, 2H), 1.47 (d, J=6.5 Hz, 6H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[OH-:16].[Na+].O.Cl>O1CCOCC1>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([OH:16])[N:3]=1)[CH2:14][CH3:15]
Reactant: [OH-]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCNc1nc(O)nc(NCCC)n1
Temperature: 140 °C
Yield: 74.8 %

Procedure:
A vial was charged with 6-chloro-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (XXXIV) (800 mg, 3.48 mmol), NaOH (696 mg, 17.40 mmol), water (3 mL) and 1,4-dioxane (3 mL). The reaction mixture was heated at 140° C. for 30 min under microwave irradiation. The mixture was acidified with 1N HCl to pH 5, precipitate were filtered, washed with water. The product was dissolved in 50% trifluoroacetic acid (30 mL), the indissoluble residue was filtered off. The filtrate was neutralized with saturated NaHCO3 solution, the formed precipitate was filtered, washed with water, acetone and dried to give 550 mg (75%) of 4,6-bis(propylamino)-1,3,5-triazin-2-ol (CLXXVIII). 400 MHz 1H NMR (DMSO-d6+CF3COOD, ppm) 3.18-3.34 (4H, m), 1.45-1.59 (4H, m), 0.86 (6H, t). ESI-MS (m/z): 212 [M+H]+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([CH3:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>CO.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([CH3:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
In 50 ml of MeOH is dissolved 500 ml of Z-Tyr-(D)-Leu-Gly-Phe-NH-NH-CO-CH3, and following addition of 1 ml ofacetic acid, catalytic reduction is carried out with palladium black as thecatalyst. The catalyst is filtered off, the solvent is distilled off, the residue is treated with water and the insolubles are filtered off. The filtrate is lyophilized and the resulting powders are put on a column of Sephadex LH-20 (2.5×120 cm).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2.[CH3:47][Si:48]([C:51]#[CH:52])([CH3:50])[CH3:49]>C(N(CC)CC)C.C(OCC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:47][Si:48]([CH3:50])([CH3:49])[C:51]#[C:52][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(C#C[Si](C)(C)C)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.5 g) in triethylamine (5 mL) were added trimethylsilylacetylene (0.2 mL), tetrakis (triphenylphosphine) palladium (0) (81 mg) and copper (I) iodide (27 mg), and the mixture was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The insoluble material was removed by filtration. The filtrate was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1-2/1) to give 4-(2-trimethylsilylethynyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.4 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added tetra(n-butyl) ammonium fluoride (0.15 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (0.33 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ncccc1OCc1ccccc1
Yield: 82.8 %

Procedure:
A suspension of 3-hydroxypicolinonitrile (3.00 g, 25.0 mmol), which was prepared according to “Synthesis” 316 (1983) and “J. Org. Chem.” 48 1375 (1983), potassium carbonate (5.40 g, 39.1 mmol) and benzyl bromide (5.10 g, 29.8 mmol) in acetone (150 mL) was stirred at room temperature for 20 hrs. The reaction mixture was filtrated and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane=1/3 to 1/2) followed by recrystallization from ethyl acetate/n-hexane=1/4 to give 3-benzyloxypicolinonitrile as a colorless solid (4.354 g, yield; 83%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[S:6][CH:7]=1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1>>[F:20][C:2]([F:19])([F:1])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:22]3[CH:23]=[N:24][CH:25]=[N:26][CH:27]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Reactant: Brc1cncnc1
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, light yellow solid, MS (ISP): m/e=381.0 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-bromo-pyridine.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:20]#[N:21])=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24].[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(#N)C>[N:29]1([CH2:28][CH2:27][NH:26][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:20]#[N:21])=[CH:8][N:9]3[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=2[N+:23]([O-:25])=[O:24])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: NCCN1CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(NCCN3CCOCC3)cc21
Yield: 62 %

Procedure:
A mixture of 1.25 g (3.29 mmol) of 7-chloro-6-nitro-4-oxo-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile and 1.07 g (8.2 mmol) of 4-(2-aminoethyl)-morpholine in 21 mL of acetonitrile is heated at reflux temperature for 17 hours. After cooling, the mixture is concentrated under reduced pressure and the residue is partitioned between methylene chloride and brine. The separated organic layer is dried over sodium sulfate and filtered. Removal of the solvent yields a residue which is flash chromatographed (elution with methylene chloride, then a gradient of 99:1 to 98:2 methylene chloride/methanol), giving 966 mg (61.9%) of the product as a yellow solid, mp 294–216° C.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]=3)[CH:9]=[C:10]([OH:11])[C:5]=2[CH:4]([CH2:19][C:20]([O:22]CC)=[O:21])[O:3]1.[OH-].[Li+].Cl>CCO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]=3)[CH:9]=[C:10]([OH:11])[C:5]=2[CH:4]([CH2:19][C:20]([OH:22])=[O:21])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a solution of ethyl 2-(1,4-dihydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (100 mg, 0.31 mmol) in EtOH (5 ml) was added an aqueous solution of lithium hydroxide (26.1 mg, 0.62 mmol) in water (1 mL). The reaction mixture was stirred at room temperature overnight and acidified with 1 N HCl to pH=3. The resulting mixture was extracted with EtOAc (20 mL) and combined organic layers were washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (17 mg, yield: 18%). 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.13 (s, 1H), 9.19 (s, 1H), 8.54 (s, 1H), 8.38 (d, J=2.8 Hz, 1H), 8.24 (d, J=1.2 Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 5.44 (m, 1H), 3.22 (m, 1H), 2.18-2.11 (m, 1H). MS (ESI) m/z=303 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:25])[C:23]#[CH:24]>O1CCCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:25][CH2:22][C:23]#[CH:24])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCNC(=O)N1CC(Oc2ccc(F)cc2)C1
Yield: 174.6 %

Procedure:
A mixture of 5.52 g (0.022 mole) of crude 3-(4-fluorophenoxy)-1-azetidine carbonyl chloride and 3 g (0.02 mole) of potassium carbonate in 30 ml of tetrahydrofuran was cooled in an ice bath and while stirring treated with 1.1 g (0.02 mole) of propargylamine added dropwise. After stirring for 5 hr, the reaction mixture was diluted with 250 ml of water and the resulting solid collected by filtration to yield 8.67 g of wet product. Recrystallization from acetone after filtration to remove some amorphous material, gave a tacky solid. A second recrystallization from benzene after treating with charcoal yielded 2.7 g (50%) of beige crystals, m.p. 106°-108° C.
Reaction SMILES: C[C:2]1[N:6]2[C:7]([NH2:15])=[C:8]([Cl:14])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]2=[N:4][C:3]=1[CH3:16].[CH3:17][O:18][CH2:19][C:20]([CH3:31])([CH3:30])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1>>[NH2:15][C:7]1[N:6]2[CH:2]=[C:3]([CH3:16])[N:4]=[C:5]2[C:10]([C:11]([NH:29][CH2:28][CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:20]([CH3:31])([CH3:30])[CH2:19][O:18][CH3:17])[CH2:27][CH2:26]2)=[O:13])=[CH:9][C:8]=1[Cl:14]
Reactant: COCC(C)(C)CN1CCC(CN)CC1
Reactant: Cc1nc2c(C(=O)O)cc(Cl)c(N)n2c1C
Product: COCC(C)(C)CN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(C)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the Step 6 in EXAMPLE 1 from 5-amino-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 1, Step 5) and {[1-(3-methoxy-2,2-dimethylpropyl)piperidin-4-yl]methyl}amine (EXAMPLE 9, Step 1).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]2[N:11]3[CH:10]=[N:9][C:8]([C:5]4[N:4]=[C:3]([CH2:2][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)[O:7][N:6]=4)=[C:12]3[CH2:13][N:14]([CH3:24])[C:15](=[O:23])[C:16]=2[CH:21]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCCC4)n3)ncn2-c2ccc(F)cc2C1=O
Yield: 74.8 %

Procedure:
1.04 g (3.0 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one, 0.64 g (7.5 mmol) of piperidine and 10 ml of N,N-dimethylformamide were stirred at room temperature for 4 hours. The reaction mixture was concentrated, the residue was dissolved in methylene chloride and the solution was made alkaline with 4N sodium hydroxide solution. The solution was washed once with saturated sodium chloride solution, dried with magnesium sulfate and evaporated. By chromatography of the residue on silica gel while eluting with methylene chloride/methanol 9/1 there was obtained 0.89 g (75%) of 8-fluoro-5-methyl-3-[5-(piperidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl]-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 182°-4°, which was converted into the hydrochloride of m.p. 254°-6°.
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH2:39]([O:41][C:42]([C:44]1[S:48]C(N)=[N:46][C:45]=1[CH3:50])=[O:43])[CH3:40]>CCCCCCC.C(OCC)(=O)C>[CH2:39]([O:41][C:42]([C:44]1[S:48][C:4]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:34][CH2:35]4)[CH2:25][CH2:24]3)=[O:22])=[CH:9][C:8]=2[Cl:36])=[N:46][C:45]=1[CH3:50])=[O:43])[CH3:40]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)nc1C

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (commercially available, CAS RN 7210-76-6) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Yellow solid (0.182 g; 67%). MS (ESI): m/z=652.12 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][C:8]=2[C:9]=1[C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]#[N:21])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]>CO.[Ni]>[CH2:1]([C:5]1[O:6][C:7]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:23][C:8]=2[C:9]=1[C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCC#N)cc1
Agent: [Ni]
Solvent: CO
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.0 g of N-[2-butyl-3-{4-[2-cyanoethoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide is dissolved in 300 ml of methanol and 5 g of Raney-Ni catalyst is added. The mixture is stirred at 25° C. at 10 bar H2 pressure for 24 hours. The catalyst is filtered and the solvent is evaporated.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][C:9]1[C:10]([N+:20]([O-:22])=[O:21])=[C:11](N)[C:12]([CH3:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]>CN(C)C=O>[CH3:8][C:9]1[C:10]([N+:20]([O-:22])=[O:21])=[CH:11][C:12]([CH3:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1N
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1
Temperature: 65 °C
Yield: 83.4 %

Procedure:
To a solution of t-butyl nitrite (t-BuONO) (7.32 g) in dimethyl formamide (DMF) (50 mL, from Mallinckrodt) at 65° C. was added dropwise a solution of 3,6-dimethyl-2,4-dinitro-phenylamine (10 g, from above) in DMF (50 mL) during 5-10 min. The mixture was heated at 65° C. for 15 min and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (300 mL) and half-saturated sodium chloride solution. The dichloromethane solution was washed with additional half-saturated sodium chloride solution (300 mL) and dried over magnesium sulfate. After evaporation of the solvent, the residue was taken up in dichloromethane (250 mL) and passed through a short column (silica gel). Eluting with dichloromethane gave 2,5-dimethyl-1,3-dinitro-benzene (7.75 g).