Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11](Cl)=[C:10]([N+:15]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.[C:20]1([CH:27]=[CH:26][C:24]([OH:25])=[CH:23][CH:22]=1)[OH:21]>>[NH2:15][C:10]1[CH:9]=[C:8]([O:7][CH2:6][C:5]2[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][C:11]=1[O:21][C:20]1[CH:27]=[CH:26][C:24]([OH:25])=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccc(Br)cc2)ccc1Cl
Reactant: Oc1ccc(O)cc1
Product: Nc1cc(OCc2ccc(Br)cc2)ccc1Oc1ccc(O)cc1

Procedure:
4-(4-Bromo-benzyloxy)-1-chloro-2-nitro-benzene (from Example 16A) was reacted with hydroquinone according to the procedure from Example 39A and reduced according to the procedure from Example 39B to provide the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10]C1CCCCO1.[Li]CCCC.[B:22](OC(C)C)(OC(C)C)[O:23]C(C)C.Cl>C1COCC1.O.CCOC(C)=O>[B:22]1([OH:23])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][O:10]1
Reactant: Brc1ccccc1CCOC1CCCCO1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OB1OCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 2-[2-(2-bromo-phenyl)-ethoxy]-tetrahydro-pyran (1.0 g, 3.5 mmol, 1.0 eq.) in THF (20 mL) at −78° C. was slowly added BuLi (2.4 mL, 2.5 M solution in THF, 3.8 mmol, 1.1 eq.) under nitrogen atmosphere. Triisopropyl borate (1.2 mL, 5.25 mmol, 1.5 eq.) was then added and the mixture was allowed to warm to room temperature gradually and stirred overnight. After carefully adding HCl (10 mL, 6N), the yellowish solution was stirred at room temperature for another 1 h and then poured into a mixture of EtOAc (30 mL) and H2O (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×30 mL). Combined organic extracts was washed with H2O (50 mL), brine (50 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The oily residue was applied to silica chromatography eluting with EtOAc/Heptanes (0:100 to 100:0) to give 3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol as a light yellow solid. 1H NMR (acetone) δ: 7.73 (d, J=7.2 Hz, 1H), 7.33-7.39 (m, 1H), 7.15-7.26 (m, 3H), 4.10 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H). Amount obtained 497 mg, 95.9% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[CH2:10][N:11](CC)CC.[Si](C#N)(C)(C)C>CC#N.C(Cl)Cl>[F:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cccc(F)c1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ncccc1F
Yield: 77.3 %

Procedure:
To a solution of 3-fluoropyridine 1-oxide (1.21 g, 10.7 mmol) in CH3CN (10 mL) was added Et3N (4.4 mL, 31.6 mmol) followed by TMSCN (4.3 mL, 32.2 mmol) and the reaction was stirred at reflux for 6.5 hours. The mixture was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2 (3×40 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated to give a crude dark red oil. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 98:2) afforded the title compound as a yellow solid (1.01 g, 77%). 1H NMR (CDCl3): δ7.58-7.67 (m, 2H), 8.54-8.57 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].C1(=O)O[CH2:18][CH2:17][O:16]1.[I-].[K+].CN(C)C=O>C(OCC)(=O)C>[OH:16][CH2:17][CH2:18][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14]
Reactant: O=C1OCCO1
Reactant: Oc1ccccc1-c1ccccc1O
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCOc1ccccc1-c1ccccc1O
Temperature: 150 °C
Reaction time: 4 h

Procedure:
To a 2000 ml 3 neck round bottom equipped with an overhead stirrer, temperature probe, heating mantel was added 2,2′-dihydroxy-biphenyl (500 g, 2.68 mole, 1.0 eq), ethylene carbonate (520.2 g, 5.9 mole, 2.2 eq.), potassium iodide (5 g, 0.03 mole, 0.01 eq.), N,N-dimethyl formamide (DMF) (47 g, 50 ml) and heated to 150° C. The reaction was monitored by GC and after 4 hours the reaction was complete. The reaction was cooled to 40° C., added 1000 ml ethyl acetate and washed 3 times with 500 ml sodium chloride brine. The ethyl acetate was dried over MgSO4, filtered and concentrated in vacuo to recover a dark brown product (736 g, 99%).
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][O:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C(O)(=O)C.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][O:10][CH:9]3[OH:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1OCCC12CCC1(CC2)OCCO1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: OC1OCCC12CCC1(CC2)OCCO1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1,4,10-Trioxadispiro[4.2.4.2]tetradecan-9-one (880 mg, 4.15 mmol) in toluene (30 mL), under nitrogen, was cooled to −78° C. and treated with 1M DIBAL-H (1M in toluene) (4.56 mL, 4.56 mmol). The reaction mixture was stirred at −78° C. for 2 hours. The resulting mixture was treated with 10% aqueous acetic acid solution (18 mL)/ice 60 g) and stirred for 5 mins with chloroform (150 mL). The aqueous was separated and extracted with chloroform (×3) and the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]2[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=[C:4]2[CH:3]=1.[OH-].[Na+].C(COC)OC.Cl>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]2[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn2c(cc(Cl)c3ccc(Cl)cc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1cn2c(cc(Cl)c3ccc(Cl)cc32)n1

Procedure:
1.24 g of ethyl 5,8-dichloroimidazo-[1,2-a]-quinoline-2-carboxylate were hydrolyzed with 3 ml of 2 N sodium hydroxide solution in 120 ml of 50--50 mixture of dimethoxyethane and ethanol. The resultant mixture was neutralized with 3.3 ml of 2 N hydrochloric acid by the method of Example 20 to obtain fine off-white crystals of 5,8-dichloroimidazo-[1,2-a]-quinoline-2-carboxylic acid melting at ≈305° C. (decomp).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.S1(=O)(=O)C=CC=C1>>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2o1
Agent: O=S1(=O)C=CC=C1
Product: Cc1nc2ccc(N)cc2o1

Procedure:
This compound was prepared from 2-methyl-6-nitrobenzoxazole (2.0 g, 13.5 mmol) in the same manner described for 5-aminobenxo[b[thiophene 1,1-dioxide, affording 1.57 (94%) of the title compound as a brown solid. MS LC-MS (M+H)+=149.1, RT=0.77 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:31])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]=[N+:29]=[N-:30])[O:24][CH2:23]2)[CH:17]([CH:32]([OH:34])[CH3:33])[C:16]3=[O:35])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]>O1CCCC1.ClC(OCC(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:31])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]=[N+:29]=[N-:30])[O:24][CH2:23]2)[CH:17]([CH:32]([O:34][C:12]([O:11][CH2:10][CH:7]([CH3:8])[CH3:6])=[O:13])[CH3:33])[C:16]3=[O:35])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)COC(=O)OC(C)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Yield: 106.1 %

Procedure:
The title compound is prepared by the procedure of Example 185 using 1.00 g of product from Example 63 in 20 ml of tetrahydrofuran, 0.26 ml of isobutyl chloroformate and 2.2 ml of 0.1M lithium bis(trimethylsilyl)amide to give 0.636 g of the desired product after chromatography.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:24]([N:26]3[CH2:30][C@H:29]([S:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])(=[O:33])=[O:32])[CH2:28][C@H:27]3[C:41](O)=[O:42])=[O:25])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:24]([N:26]3[CH2:30][C@H:29]([S:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])(=[O:32])=[O:33])[CH2:28][C@H:27]3[C:41]([NH:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C:3](=[O:10])[C:4]([NH:6][CH:7]3[CH2:8][CH2:9]3)=[O:5])=[O:42])=[O:25])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide and (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxylic acid in step 1. MS (m/e)=634.15 [M+H+].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(OC(F)(F)F)cc1

Procedure:
4-(trifluoromethoxy)phenol (1.36 ml, 10.6 mmol), 2-fluoro-1-nitrobenzene (0.74 ml, 7 mmol), potassium carbonate (1.46 g, 10.5 mmol) were mixed together in DMF (4 ml) and heated at reflux for 5 h. Allowed to cool, and evaporated in-vacuo. Residue partitioned between diethyl ether and sodium hydroxide (1 M). Organic layers combined and dried over anhydrous magnesium sulphate and evaporated in-vacuo, to afford a yellow oil, 2.34 g, >100%. Rf: 0.72 (DCM), 1HNMR (CDCl3, 270 MHz) δ 7.03 (3H, m, Ar HD, Ar HF), 7.20 (2H, dd, J=0.9, 10.1 Hz, Ar HE), 7.23 (1H, m, Ar HB), 7.53 (1H, m, Ar HC), 7.97 (1H, dd, J=1.5, 8.2 Hz, Ar HA).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:19]=[CH:18][C:9]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:8]=2[CH:7]=1)[CH3:5])=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH:4]([C:6]1[CH:19]=[CH:18][C:9]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:8]=2[CH:7]=1)[CH3:5]
Reactant: CCOC(=O)c1cc2ccc(C(C)N=[N+]=[N-])cc2s1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2ccc(C(C)N)cc2s1
Reaction time: 4 h

Procedure:
To a solution of ethyl 6-(1-azidoethyl)-1-benzothiophene-2-carboxylate (1.7 g, 6.17 mmol) in EtOAc (50 mL) was added 10% Pd/C (170 mg), and the resultant slurry was hydrogenated under 1 atm of H2 for 4 h at RT. The reaction mixture was filtered via Celite and the filtrate was concentrated and dried to give the desired product. 1H NMR (CDCl3, 600 MHz) δ 8.01 (d, J=0.9 Hz, 1H), 7.84 (m, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.38 (dd, J=8.2, 0.9 Hz, 1H), 4.39 (q, J=7.3 Hz, 2H), 4.25 (q, J=6.8 Hz, 1H), 1.44 (d, J=6.8 Hz, 3H), 1.40 (t, J=7.3 Hz, 3H). MS: cal'd 250 (MH+), exp 250 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)=[CH:4][C:3]=1[CH3:16].[O-:17][C:18]#[N:19].[Na+].C(=O)([O-])O.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N:9]2[C:10]([CH3:15])([CH3:14])[C:11](=[O:13])[NH:19][C:18]2=[O:17])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(NC(C)(C)C(=O)O)cc(C)c1Br
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a mixture of 2-((4-bromo-3,5-dimethylphenyl)amino)-2-methyl propanoic acid (5.79 g of the compound obtained from Reaction 1-1) in dichloromethane (62 mL) and acetic acid (62 mL), sodium cyanate (5.03 g, 59.8 mmol) was added at room temperature. The mixture was stirred at room temperature for three hours. A saturated solution of sodium hydrogen carbonate (400 mL) was added to adjust the pH to 7-8 using a 5 N aqueous sodium hydroxide, and this mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained solid was washed sequentially with ethyl acetate-hexane and then with dichloromethane-hexane to obtain 1-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (3.80 g, 66%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2sccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2sccc21
Yield: 22 %

Procedure:
In close analogy to the procedure described above, 4-Methyl-6,7-dihydro-thieno[3,2-c]pyridine is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[O:14][CH2:15][CH2:16]Br.O.C(OCC)(=O)C>C1COCC1.CCCCCC>[Br:13][C:9]1[C:8]2[O:14][CH2:15][CH2:16][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: BrCCOc1c(Br)cccc1Br
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: Brc1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of 2.5M n-BuLi (13.0 ml, 32.5 mmol) was added to a solution of 1,3-dibromo-2-(2-bromo-ethoxy)-benzene (11.5, 32.0 mmol) in 115 ml of THF and 28 ml of hexane at −78° C. over 30 mins. The reaction was continued at −78° C. for 30 minutes, then warmed to 0° C. The mixture was poured into water (100 ml) and the aqueous phase was extracted with ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a pale yellow oil. Silica gel chromatography using a gradient of ethyl acetate in hexanes to give 7-bromo-2,3-dihydro-benzofuran as colorless needles (5.00 g, 78%). 1H NMR (500 MHz, DMSO-d6) δ 7.27 (dd, 1 Hz, 8 Hz, 1H), 7.20 (dd, 1 Hz, 7.5 Hz, 1H), 6.75 (t, 7.8 Hz, 1H), 4.59 (t, 9 Hz, 2H), 3.28 (t, 8.8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.Cl.Cl.[C:24]1([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][N:41]2[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][CH2:35][CH2:34][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[CH2:43][CH2:42]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: c1ccc2c(CCCCN3CCNCC3)cccc2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)CN2CCN(CCCCc3cccc4ccccc34)CC2)cc1
Temperature: 25 °C

Procedure:
In 6.0 ml of chloroform was dissolved 0.69 g of 4-methoxyphenacyl bromide, and 3.0 ml of N-ethyldiisopropylamine and 1.20 g of 1-(4-naphthalen-1-yl-butyl)piperazine dihydrochloride were added, followed by reflux with heating for an hour. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. To the residue was added a saturated aqueous sodium bicarbonate solution and, after extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure to give a crude 1-[2-(4-methoxyphenyl)-2-oxoethyl]-4-(4-naphthalen-1-yl-butyl)piperazine.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][C:10]([CH3:13])(C)C)(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:5]([CH:4]([CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[C:3]([O:9][CH2:10][CH3:13])=[O:8])(=[O:6])[CH3:7]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccncc1)C(C)=O
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 19.9 %

Procedure:
Anhydrous N,N-dimethylformamide (41 ml) was added to sodium hydride (2.81 g, 70.3 mmol) under a nitrogen atmosphere, and the mixture was stirred under ice-cold water-cooling. A solution of t-butyl acetoacetate (6.33 g, 40.0 mmol) in N,N-dimethylformamide (20 ml) was added dropwise to the mixture over 10 minutes, after 10 minutes, 4-(chloromethyl)pyridine hydrochloride (5.00 g, 30.5 mmol) was added thereto little by little under a nitrogen stream over three minutes, and the temperature was raised to room temperature. After two hours, a saturated aqueous sodium hydrogencarbonate solution (150 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (100 ml). The organic layer was washed with water (100 ml) and saturated brine (50 ml) successively and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1.34 g (18%) of ethyl 2-acetyl-3-(4-pyridyl)propionate as a pale yellow oily matter.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[CH3:22][C:23](=[CH2:31])[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:31][C:23](=[CH2:22])[CH2:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:27][CH2:26]1
Reactant: C=C(C)CN1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Product: C=C(C)CN1CCN(CCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 45 %

Procedure:
Using the procedure of Example 2, 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one was reacted with 1-(2-methyl-allyl)-piperazine to obtain a 45% yield of 5,11-dihydro-11-{3-[4-(2-methyl-allyl)-1-piperazinyl]-propionyl}-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 210°-211° C. after crystallization from ethanol.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=3[Cl:48])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OC)(=O)C1OC1>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=3[Cl:48])[N:39]=[CH:40][C:33]=12)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Clc1cccc(-n2ncc3c(Cl)ncnc32)c1Cl
Agent: COC(=O)C1CO1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
Sodium hydride (0.167 g, 4.17 mmol) was added to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (1.4 g, 3.48 mmol) in anhydrous THF (25 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AR2) (1.432 g, 3.83 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% EtOAc in isohexane. Fractions containing the product were evaporated to dryness to afford crude product which unfortunately was contaminated with starting alcohol and Methyl glycidate. The crude product was repurified by flash silica chromatography, elution gradient 0 to 30% EtOAc in toluene to afford the product (0.860 g, 37.1%). 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 3.80-3.69 (5H, m), 3.85 (2H, t), 4.15-4.08 (1H, m), 4.20 (1H, dd), 5.87 (1H, dd), 7.48-7.33 (8H, m), 7.75-7.60 (5H, m), 8.32 (1H, s), 8.54 (1H, s). m/z (ES+) (M+H)+=667; HPLC tR=3.8 min.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10])=[O:5].[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][NH:37][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:6]([C:4](=[O:5])[C:3]2[CH:16]=[CH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[CH:19][C:2]=2[Cl:1])[CH:7]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NOCc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: Cc1ccc(C(=O)NOCc2ccccc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
Compound 424 (100 mg, 0.25 mmol) and O-benzyl-hydroxylamine (80 mg, 0.50 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 80/20 to 60/40) provided the title compound. 13C NMR (CDCl3) δ 195.3, 165.8, 159.3 (dd), 155.7 (dd), 148.2, 142.2, 139.8, 135.4, 135.1, 133.8, 131.7, 129.4, 129.1, 128.9, 128.7, 127.8, 124.6 (dd), 124.1 (dd), 116.2, 112.8, 111.7 (dd), 105.0 (dd), 78.5, 20.4
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:7]3[CH2:17][CH2:18][C:19](=[O:20])[C:5]([C:6]=23)=[CH:4][CH:3]=1>[OH-].[K+].CO.[C].[Pd]>[C:11]1([C:8]2[NH:9][C:10]3[CH:2]=[CH:3][CH:4]=[C:5]4[C:19](=[O:20])[CH2:18][CH2:17][C:7]=2[C:6]=34)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCc2c(-c3ccccc3)[nH]c3c(Cl)ccc1c23
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
A portion (2.4 g) of the compound obtained in Example 60 was dissolved in a solution of potassium hydroxide (3 g) in methanol (150 ml) and to the solution was added 10% palladium-carbon (500 mg). The mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10:1-2:1) to yield 700 mg (39%) of the titled compound.