Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[NH:33][CH:30]1[CH2:32][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(NC3CC3)c3cc(Cc4ccccc4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C22H18FN5O2, 403.1
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([NH:9]C(=O)C(C)(C)C)[C:3]=1[C:16]#[C:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].O>C(O)(C)(C)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][C:17]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:16][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2c(NC(=O)C(C)(C)C)ncc(F)c2Cl)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)c(F)cnc3[nH]2)CC1

Procedure:
A mixture of Example 255A (1000 mg, 2.283 mmol), 18-crown-6 (302 mg, 1.142 mmol), and potassium 2-methylpropan-2-olate (512 mg, 4.57 mmol) in 15 mL t-butanol was heated under microwave (Biotage) conditions at 135° C. for 35 minutes. Water was added and the mixture was extracted with dichloromethane. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether and filtered to afford the title compound. MS (ESI(+)) m/e 354 (M+H)+.
Reaction SMILES: [Si]([O:18][C:19]1[CH:65]=[CH:64][C:22]([O:23][CH2:24][C@@H:25]([OH:63])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:62]=[CH:61][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([NH:51][C:52]([NH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[O:53])=[CH:47][CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:55]([NH:54][C:52](=[O:53])[NH:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][NH:43][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:61]=[CH:62][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:63])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:65][CH:64]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])=[CH:50][CH:49]=1)[CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCNC(=O)Nc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCNC(=O)Nc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 75.5 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)aniiino]-N-(4-{[(hexylamino)carbonyl]amino}benzyl)-1-piperidinecarboxamide (0.143 g, 0.159 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.077 g, 0.12 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH3:19]>CC#N>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: CCI
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution of 3-bromophenylacetic acid (10.0 g, 46.5 mmol) in CH3CN (150 mL) was added K2CO3 (7.39 g, 53.5 mmol) followed by ethyl iodide (5.6 mL, 70.0 mmol). The mixture was heated at reflux for 2.5 h and was cooled to room temperature. The volatiles were removed in vacuo and water was added. The aqueous solution was extracted with EtOAc (3×) and the combined organic extracts were washed with brine. The organic solution was dried (MgSO4), filtered, and concentrated to provide (3-bromo-phenyl)-acetic acid ethyl ester (9.30 g) as an oil. 1H NMR (400 MHz, CDCl3) 6 7.43 (s, 1H), 7.38 (m, 1H), 7.21-7.16 (m, 2H), 4.14 (q, 2H), 3.56 (s, 2H), 1.24 (t, 3H).
Reaction SMILES: [CH:1]1([N:4]([CH3:20])[C:5]2[C:6](=[O:19])[NH:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.N1C=CC=CC=1.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>C(Cl)Cl>[CH:1]1([N:4]([CH3:20])[C:5]2[C:6]([O:19][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C3CC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (240 mg, 0.88 mmol) in DCM (50 mL) was added pyridine (280 mg, 3.54 mmol) and Tf2O (496 mg, 1.76 mmol). The resulting solution was stirred 3 h at room temperature and then dissolved in water/ice (100 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford methyl 3-(cyclopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as a red oil (300 mg, crude), which was used to the next step directly.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[C:17]([O:18]C)=[CH:16][CH:15]=[C:14]([C:20]([NH:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[O:21])[C:12]=2[CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[C:1]([C:9]1[O:10][C:11]2[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([C:20]([NH:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[O:21])[C:12]=2[CH:13]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cccc2Cl)c2cc(C(=O)c3ccccc3)oc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc2c(C(=O)Nc3c(Cl)cccc3Cl)ccc(O)c2o1
Temperature: -78 °C
Yield: 51.6 %

Procedure:
Under a nitrogen atmosphere, Compound 168 (0.04 g) obtained in Example 168 was dissolved in dry dichloromethane (2 ml) and the solution was cooled to −78° C. A 2.4M solution (0.125 ml) of boron tribromide in dichloromethane was slowly and dropwise added to the solution, and then the mixture was warmed to the room temperature and stirred one night. Distilled water (5 ml) was added to the mixture followed by stirring for one hour. The reaction solution was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Compound 169 (0.02 g, 46.9%) as a pale-yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5]C=CC=1.[CH2:8]1[O:10][C@H:9]1[CH2:11]Cl.[OH-].[Na+].CN(C)C=[O:18]>O>[CH2:11]([O:7][CH2:1][CH:6]1[O:18][CH2:5]1)[CH:9]1[O:10][CH2:8]1
Reactant: CN(C)C=O
Reactant: Oc1ccccc1
Reactant: ClC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C(OCC1CO1)C1CO1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of the starting phenol derivative (7.44 g) of the following formula: ##STR27## as prepared in Preparation 1, the same R-(-)-epichlorohydrin (9.16 g) as used in Preparation 2, 50 wt. % aqueous sodium hydroxide (1.74 g) and dimethylformamide (77 ml) is stirred at 60-70° C. for 3 hours. The reaction is cooled and thereto is added water, and the mixture is extracted with dichloromethane. The extracted product is purified by silica gel chromatography to give S isomer of glycidyl ether (6.90 g ) of the following formula: ##STR28##
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:35][OH:36]>[Cl-].[Na+].O.CN(C=O)C>[CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][C:19]([NH:35][OH:36])=[O:20])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(O)CNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C=C1c2ccccc2-c2ccccc21)NCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
2-(2-(9H-fluoren-9-ylidene)acetamido)acetic acid (279 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (132 mg, 45%) as a yellow solid. LC-MS (m/z) 295 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:32]([O-])=O)=[CH:4][C:5]([O:30][CH3:31])=[C:6]([CH:29]=1)[C:7]([NH:9][CH2:10][CH2:11][N:12]1[CH2:28][CH2:27][C:15]2([N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][NH:17][C:16]2=[O:26])[CH2:14][CH2:13]1)=[O:8].[H][H]>[Ni].C(O)(=O)C>[NH2:32][C:3]1[C:2]([Cl:1])=[CH:29][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:27][CH2:28]2)=[O:8])=[C:5]([O:30][CH3:31])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
A mixture of 6 parts of 5-chloro-2-methoxy-4-nitro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5] dec-8-yl)ethyl]benzamide in 150 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 1 part of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the whole is alkalized. The precipitated product is filtered off and crystallized twice from ethanol, yielding 1.7 parts of 4-amino-5-chloro-2-methoxy-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]-dec-8-yl)ethyl]benzamide; mp. 247.4° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(OCC)(=O)C.[Cl:15][C:16]([Cl:23])([Cl:22])[CH2:17][O:18][C:19](Cl)=[O:20]>N1C=CC=CC=1>[Cl:15][C:16]([Cl:23])([Cl:22])[CH2:17][O:18][C:19]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:20]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(OCC(Cl)(Cl)Cl)ON1C(=O)CCC1=O

Procedure:
Dissolve 5.75 gm. of N-hydroxysuccinimide in 200 ml. ethyl acetate and 4 gm. of pyridine; cool the resultant solution to 0° C. To this solution add 10.6 gm. 2,2,2-trichloroethylchloroformate dropwise over a period of 1.5 hours. Filter the resultant mixture and evaporate the filtrate to dryness. Wash the thereby formed needles with hexane to obtain N-(2,2,2-trichloroethoxycarbonyloxy) succinimide, mp. 98°-101° C; νmax (CHCl3) 1825, 1790, 1750, 1185, 826 cm.-1, δ(CDCl3) 2.85 (4H,s,--CO (CH2)2CO--) and 4.90 ppm. (2H,s,--COOCH2CCl3).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH2:13]1COCC1>>[CH3:1][C:2](=[CH:11][CH2:10][CH2:9][CH:8]=[CH2:13])[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: C=CCCC(C)=O
Product: C=CCCC=C(C)CCC=C
Temperature: 25 °C

Procedure:
5-methyl-1,5,9-decatriene was synthesized from 7.3 mL of 5-hexene-2-one, and an ylide prepared from 26.3 g. of 1-pentenyl-triphenylphosphonium bromide and 32 mL of 2.0 molar solution of n-butyllitium in THF at -78° C. The mixture was allowed to warm to room temperature over six hours, during which all of the salt dissolved and the ylid was apparent by the red color of the solution. This mixture was then cooled to -70° C. and 7.3 mL of 5-hexene-2-one in 20 mL of dry THF was added slowly with stirring. This reaction solution was then warmed to room temperature, followed by refluxing for 12 h. The THF was then distilled out of the reaction flask and 100 mL of pentane added along with 100 mL of water. The pentane was decanted and the water was extracted with another 100 mL of pentane. The combined pentane layers were washed with 50 mL portions of dilute HCl, water, 5% solution of NaHCO3 and water. The pentane layer was dried over MgSO4 and filtered through alumina. The pentane was distilled off. The isolated product was distilled at 78° C. at 15 mm Hg. Then, the monomer was distilled from CaH2 degassed by several freeze-thaw cycles, and vacuum transferred to successive sodium mirrors and stirred until no reaction was observed. The resulting product was 5-methyl-1,5,9-decatriene. FIGS. 1 and 3 show the 1H and 13C NMR spectra of the resulting product.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:24]=[CH:23][C:11]([C:12]([N:14]3[CH2:19][CH2:18][C:17]4[CH:20]=[CH:21][O:22][C:16]=4[CH2:15]3)=[O:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:21]1[O:22][C:16]2[CH2:15][N:14]([C:12](=[O:13])[C:11]3[CH:23]=[CH:24][C:8]([C:6](=[O:7])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=4)=[CH:9][CH:10]=3)[CH2:19][CH2:18][C:17]=2[CH:20]=1)[CH3:29]
Reactant: CNC
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccc(Cl)cc3)cc1)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.280 g (0.765 mmol) of 6-[4-(4-chlorobenzoyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 0.10 ml (1.2 mmol) of 50% aqueous dimethylamine and 0.09 ml (1.2 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1 to 100/3) to yield the desired product.
Reaction SMILES: C(Cl)(Cl)Cl.[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]4[C:41]5[C:36](=[C:37]([NH2:42])[CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][C:33]4=[O:43])[CH2:26][CH2:25]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.[C:44](Cl)(=[O:46])[CH3:45].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]4[C:41]5[C:36](=[C:37]([NH:42][C:44]([CH3:45])=[O:46])[CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][C:33]4=[O:43])[CH2:26][CH2:25]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To 2 mL of a chloroform solution containing 60 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 14 mg of triethylamine and 11 mg of acetyl chloride were added, and stirred at room temperature for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 60 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-acetamino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow foam.
Reaction SMILES: [C:1]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1(O)[C:28]2[C:19](=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(O)[C:17]2[C:8]1=[CH:9][C:10]1[C:15]([CH:16]=2)=[C:14]2[CH:42]=[CH:43][CH:44]=[CH:45][C:13]2=[CH:12][CH:11]=1.I.C(=O)([O-])O.[Na+]>C(OC(C)C)(C)C.ClCCl>[C:1]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[C:17]([C:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[C:19]3[C:28]=1[CH:27]=[C:26]1[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]1)=[CH:20]3)=[CH:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]3[CH:45]=[CH:44][CH:43]=[CH:42][C:14]3=1)[CH:9]=2
Reactant: OC1(c2ccccc2-c2ccccc2)c2cc3ccccc3cc2C(O)(c2ccccc2-c2ccccc2)c2cc3c(ccc4ccccc43)cc21
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: c1ccc(-c2ccccc2-c2c3cc4ccccc4cc3c(-c3ccccc3-c3ccccc3)c3cc4c(ccc5ccccc54)cc23)cc1
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
In 150 ml of isopropyl ether and 75 ml of dichloromethane, 1.5 g (2.3 mmole) of 8,15-bis(p-biphenylyl)-8,15-dihydro-8,15-dihydroxybenzo[a]-pentacene was suspended. To the obtained suspension, 40 ml of a 57% aqueous solution of hydrogen iodide was added under the refluxing condition and the obtained mixture was stirred for 5 minutes. After the reaction was completed, the reaction solution was added to 500 ml of a saturated aqueous solution of sodium hydrogencarbonate and the obtained mixture was stirred for 10 minutes. The formed precipitates were separated by filtration and washed once with ion-exchanged water, once with a saturated aqueous solution of sodium disulfite and then three times with ion-exchanged water. The washed precipitates were dried under heating at a reduced pressure and 0.84 g (the yield: 51%) of a light purple solid of 8,15-bis(p-biphenylyl)benzo[a]pentacene was obtained. The obtained product was purified by sublimation at 320° C. under 4.0×10−6 Torr for 2 hours and 450 mg of a deep purple amorphous solid was obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH:15]1[CH:16]=[CH:17][N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[NH:21][CH2:20][C:19]=12.C(N(C(C)C)CC)(C)C>ClCCl>[N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([N:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[CH2:24][N:18]4[CH:17]=[CH:16][CH:15]=[C:19]4[CH2:20]3)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(Cl)c1ccc(-n2cccn2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-n2cccn2)cc1)N1Cc2cccn2Cc2ccccc21
Reaction time: 18 h
Yield: 76.7 %

Procedure:
The 4-(pyrazol-1-yl)benzoyl chloride (0.75 g) was added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.61 g) and diisopropylethylamine (0.47 g) in dichloromethane (25 ml). After 18 hours at room temperature, the reaction mixture was washed with water and a saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.90 g), m.p. 179-181° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:24])[CH2:4][CH2:3]1.[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.C([BH3-])#N.[Na+]>>[O:24]=[C:11]1[N:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:36][C:34]3[CH:33]=[CH:32][C:29]4[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=4[N:35]=3)[CH2:3][CH2:4]2)[C:15]2[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)c1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Yield: 13 %

Procedure:
Methyl 4-[2-(4-aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (Intermediate 84), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 13% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Li+].[OH-]>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 64.9 %

Procedure:
To methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (3.51 g, 7.54 mmol) in methanol (22.6 mL) and water (11.30 mL), was added LiOH.H20 (1.582 g, 37.7 mmol). This was stirred at room temperature for 19 h. MeOH was removed under vacuo. The aqueous layer was acidified with HCl (1 N) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford the title compound (2.2082 g, 65%). LC-MS m/z 452 (M+H)+.