Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH:20]1[CH2:23][CH:22]([S:24]([O-:27])(=O)=[O:25])[CH2:21]1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].O=P(Cl)(Cl)[Cl:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([CH:20]1[CH2:23][CH:22]([S:24]([Cl:31])(=[O:27])=[O:25])[CH2:21]1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])C1CC(C(COCc2ccccc2)COCc2ccccc2)C1
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cl)C1CC(C(COCc2ccccc2)COCc2ccccc2)C1
Yield: 67 %

Procedure:
Using the same reaction conditions, procedure and work up as described for the preparation of Intermediate I-25c (below), potassium 3-(1,3-bis(benzyloxy)propan-2-yl)cyclobutane-1-sulfonate (0.5 g, 1.168 mmol) was reacted with POCl3 (0.22 mL, 2.336 mmol), diisopropyl ethyl amine (0.4 mL, 2.336 mmol) and DCM (20 mL) to afford the crude product. Purification by column chromatography on silica gel (8% ethyl acetate in hexane) afforded 0.32 g of the product (68% yield).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1)[CH3:3].[NH2:13][CH2:14][CH2:15][CH2:16][NH2:17].[OH-].[Na+]>O>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:7][N:6]=1)[CH3:3]
Reactant: NCCCN
Reactant: CCOc1ccc(CCl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(CNCCCN)cn1
Yield: 65.2 %

Procedure:
2-Ethoxy-5-pyridylmethyl chloride hydrochloride (9.6 g) in an aqueous solution was added dropwise to the mixed solution of trimethylenediamine (11.1 g) and 20% aqueous solution (22 g) of sodium hydroxide at 0°-5° C. After the reaction mixture was stirred at room temperature for some time, water and excess trimethylenediamine were distilled off under reduced pressure from the contents and after the inorganic salts were filtered off, the produced viscous and oily substance was evaporated in vaccum to give N-(2-ethoxy-5-pyridylmethyl)trimethylenediamine (6.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:25])[N:9]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:37][CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1>O.CN1CCCN(C)C1=O.O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:37][CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)[C:8](=[O:25])[N:9]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]2)=[N:4][CH:3]=1
Reactant: COc1ccc(COCCBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)CCc3ncc(Cl)cc32)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(COCCC2Cc3ncc(Cl)cc3N(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a tetrahydrofuran solution (2 ml) of tert-butyl 4-(7-chloro-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (Reference Example 9-3) (438 mg) was added dropwise at −20° C. a hexane solution (1.0 M, 1.32 ml) of lithium hexamethyldisilazide over 10 minutes. After the reaction solution was stirred for 30 minutes, was added dropwise a tetrahydrofuran solution of 1-(2-bromoethoxymethyl)-4-methoxybenzene (Journal of Medicinal Chemistry, 2007, 50(26), 6580-6595)(324 mg) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (315 mg). The reaction solution was brought to 0° C. over 30 minutes, and then stirred for 90 minutes. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-[7-chloro-3-{2-[(4-methoxybenzyl)oxy]ethyl}-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl]piperidine-1-carboxylate (189 mg).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13]Br>C(OCC)C>[Br:13][CH:5]1[CH2:6][CH2:7][O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]1=[O:8]
Reactant: O=C1CCCOc2ccccc21
Reactant: BrBr
Solvent: CCOCC
Product: O=C1c2ccccc2OCCC1Br
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3,4-dihydro-2H-benzo[b]oxepin-5-one (3.10 g, 12.8 mmol) in diethyl ether at 0° C., bromine (625 μl, 12.2 mmol) was added and stirred for 2.5 hours, gradually raising the temperature to room temperature. Purification on silica and triturating using diethyl ether and hexanes gave 4-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([C:22]1[CH:23]=[C:24]([NH:43][C:44]([NH:46][C@@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]([O:57][C:58]3[CH:59]=[CH:60][C:61]4[N:62]([C:64]([CH:67]([CH3:69])[CH3:68])=[N:65][N:66]=4)[CH:63]=3)[CH2:49][CH2:48]2)=[O:45])[N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][O:36]C3CCCCO3)[CH:28]=2)[N:26]=1)([CH3:21])([CH3:20])[CH3:19]>CO>[C:18]([C:22]1[CH:23]=[C:24]([NH:43][C:44]([NH:46][C@@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]([O:57][C:58]3[CH:59]=[CH:60][C:61]4[N:62]([C:64]([CH:67]([CH3:69])[CH3:68])=[N:65][N:66]=4)[CH:63]=3)[CH2:49][CH2:48]2)=[O:45])[N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][OH:36])[CH:28]=2)[N:26]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Temperature: 55 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
Pyridinium para-toluene sulfonate (44.0 mg, 0.17 mmol) was added to Intermediate 4c (124 mg, 0.17 mmol) in MeOH (3.0 mL). After 2 h, further pyridinium para-toluene sulfonate (100 mg, 0.39 mmol) was added, and the reaction stirred for 12 h. The reaction was then heated to 55° C. for 2 h, then cooled, and the solvent volume reduced to approximately ⅓ of its volume in vacuo. The residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 (50 mL). The aqueous layer was extracted into EtOAc (3×), then the combined organic layers washed with brine, dried (MgSO4) and evaporated in vacuo. The product was purified by FCC, using 0-10% MeOH in DCM, then further purified by HPLC (C18 X-select column, 10-98% MeCN in H2O, 0.1% formic acid) to give the title compound (50.0 mg, 0.08 mmol, 47%). LCMS (Method 5): Rt 4.04 mins, m/z 624 [MH+]. 1H NMR (400 MHz, CDCl3): 1.30 (9H, s), 1.40-1.44 (3H, d, J=6.9 Hz), 1.44-1.47 (3H, d, J=6.9 Hz), 1.84-1.98 (1H, m), 2.00-2.10 (2H, m), 2.18-2.26 (1H, m), 3.16-3.26 (1H, sp, J=6.9 Hz), 3.87-3.92 (2H, m), 4.03-4.07 (2H, m), 5.01-5.09 (1H, td, J 8.9, 5.3 Hz), 5.14-5.17 (1H, t, J=4.0 Hz), 5.47-5.52 (1H, br d, J=8.7 Hz), 6.29 (1H, s) 6.60 (1H, br s), 6.80-6.84 (1H, m), 6.96-7.00 (1H, dd, J 9.9, 2.1 Hz), 7.07-7.11 (2H, m), 7.23-7.30 (5H, m), 7.38-7.40 (1H, d, J=1.6 Hz), 7.53-7.57 (1H, d, J=9.9 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=O)(C)(C)C>CCO.[Pd]>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:25][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)[CH3:31]
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2ccccc2CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccccc1C1NCCc2ccccc21
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (446 mg, 1.0 mmol, 1.0 eq.) in EtOH (4.8 mL) under N2, palladium on activated carbon (10 wt. %, 106 mg) was added. The flask was carefully evacuated and refilled with H2 (3×). The black suspension was stirred at 50° C. under an H2-atmosphere for 48 hours. The black suspension was filtered through Celite. The Celite was rinsed with EtOH. The filtrate was concentrated in vacuo. To an ice-cooled solution of the residue in DCM (1.8 mL), 4M HCl in dioxane (2.6 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was coevaporated with EtOH (3×). The residue, redissolved in DMF (2 mL), was purified by prep. HPLC (column: Atlantis, 19×30 mm, 5 um, UV/MS, acidic conditions) and evaporated to give the desired amine as a yellow oil.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C2C3C(C=C4C=2C=CC=C4)=CC=CC=3C=C1.C1(C2C3C4=C(C=CCC4=C4C=2C=CC=C4)C=CC=3)C=CC=CC=1.C[C:49]1[CH:61]=[CH:60][C:52]2[S:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=3[C:51]=2[CH:50]=1>>[C:2]1([C:57]2[CH:58]=[CH:59][C:54]3[S:53][C:52]4[CH:60]=[CH:61][CH:49]=[CH:50][C:51]=4[C:55]=3[CH:56]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc2sc3ccccc3c2c1
Agent: C1=Cc2cccc3c(-c4ccccc4)c4ccccc4c(c23)C1
Agent: C1=Cc2cccc3cc4ccccc4c(c23)C1
Product: c1ccc(-c2ccc3sc4ccccc4c3c2)cc1

Procedure:
For example, the reaction of aniline with 1H-benzo[de]anthracene of the asphaltene polycyclic core forms the 7-phenyl-1H-benzo[de]anthracene compound as shown (15), and the reaction of aniline with 2-methyldibenzo[b,d]thiophene yields 2-phenyldibenzo[b,d]thiophene (16).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[C:5]([F:14])=[C:6]([CH2:12][OH:13])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1.O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:16][O:15][CH:3]([O:2][CH3:1])[C:4]1[C:5]([F:14])=[C:6]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:12][O:13][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1
Reactant: COc1cc(CO)c(F)c(C(OC)OC)c1
Reactant: BrCCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COCCOC2CCCCO2)c(F)c(C(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3-Dimethoxymethyl-2-fluoro-5-methoxyphenyl)methanol (1.861 g) was dissolved in 10 ml of DMF, and 390 mg of sodium hydride, 300 mg of tetrabutylammonium iodide, and 1.8 ml of 2-(2-bromoethoxy)tetrahydropyran were added thereto. The mixture was stirred at room temperature for 2 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (1.035 g).
Reaction SMILES: II.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:29]([C@:36]1([C:51]([NH:53][CH:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:55]=O)=[O:52])[O:40][C:39](=[O:41])[N:38]([C@@H:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH3:43])[C:37]1=[O:50])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:29]([C@:36]1([C:51]2[O:52][CH:55]=[C:54]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[N:53]=2)[O:40][C:39](=[O:41])[N:38]([C@@H:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH3:43])[C:37]1=[O:50])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)O[C@](Cc2ccccc2)(C(=O)NC(C=O)c2ccccc2)C1=O
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C(=O)O[C@](Cc2ccccc2)(c2nc(-c3ccccc3)co2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To iodine (111 mg, 0.438 mmol) in dichloromethane (2 mL) was added triphenylphosphine (121 mg, 0.46 mmol). After 5 min triethylamine (0.122 mL, 0.876 mmol) was added. After 5 min a solution of the product from Step B (100 mg, 0.219 mmol) in dichloromethane (2 mL) was added. After stirring at ambient temperature for 1 h, a 1:1 mixture of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulfate (5 mL) was added. The biphasic mixture was stirred for 10 min, the layers were separated and the aqueous phase extracted with dichloromethane (3×5 mL). The combined organic phases were washed with saturated aqueous brine (1×5 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The yellow oil was purified by reverse phase HPLC(YMC Pro-C 18 column, gradient elution, 20% to 100% acetonitrile/water with 0.1% TFA) to afford the title compound as a colorless amorphous solid. LC/MS 439.1 (M+1). IC50 value=C rating.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:10]1=[O:21])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:10]1=[O:21]
Reactant: COC(=O)CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CN1CCCC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a round bottom flask was added (S)-methyl 2-(3-(tert-butoxycarbonylamino)-2-oxoazepan-1-yl)acetate (30 mg, 0.10 mmol) and a solution of 4 N HCl in dioxane (1 mL). The reaction was stirred at rt for 2 hr. The reaction was concentrated to give (S)-methyl 2-(3-amino-2-oxoazepan-1-yl)acetate (18 mg, 0.090 mmol, 90% yield) as a white solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[NH2:19][CH2:20][C@@H:21]([C:23]1[CH:24]=[CH:25][C:26]([OH:34])=[C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=1)[OH:22]>>[OH:34][C:26]1[CH:25]=[CH:24][C:23]([CH:21]([OH:22])[CH2:20][NH:19][CH:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:5]4[NH:4][N:3]=[N:2][N:1]=4)=[CH:7][CH:8]=3)[CH2:13][CH2:14]2)=[CH:28][C:27]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: O=C1CCN(c2ccc(-c3nnn[nH]3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(-c4nnn[nH]4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(1H-tetrazol-5-yl)-phenyl]-piperidine-4-one (which was obtained in Example 47) and N-[5-((1R)-2-amino-1-hydroxy- ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 73 as a white solid; mp >175° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.65 (m, 2H), 1.90-2.10 (m, 2H), 2.70-3.10 (m, 5H), 2.95 (s, 3H), 3.70-3.85 (m, 2H), 4.69 (dd, J=9.3, 3.0 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 7.06 (dd, J=8.3, 2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.80 (d, J=8.9 Hz, 2H); MS (ES) m/z: 474.1 (MH+); HRMS Calcd. for C21H28N7O4S(MH+): 474.1918. Found: 474.1912.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:26]=[CH:25][C:19]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:22](=[O:23])[CH2:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:27])([F:28])[F:14])=[CH:26][CH:25]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Product: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC

Procedure:
This compound is prepared by reaction of 3,4-dimethoxyphenylethylamine and 4-(trifluoromethyl)-hydrocinnamic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)=[CH:5][CH:4]=1.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][NH:1][CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:4][CH:5]=4)[N:17]4[C:12]=3[C:13]([NH2:18])=[N:14][CH:15]=[N:16]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Reactant: O=C1CCCCC1
Product: Nc1ncnn2c(-c3ccc(CNC4CCCCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 23 %

Procedure:
Using a procedure similar to that of Example 111 with 7-(4-Aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and cyclohexanone as starting materials, 27 mg (23%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.80 (s, 2 H) 2.4 (m, 1 H), 1.80 (m, 2 H), 1.60 (m, 2 H), 1.20-1.10 (m, 6 H); ES-MS m/z 528.06 [M+H]+, HPLC RT (min) 2.72.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:21]=1[OH:28].[OH-].[Na+].CS(C)=O>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[O:28][C:21]1[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:20]=1[Cl:19]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Oc1ccccc1
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)c(Oc2cc(Cl)c(Cl)cc2Cl)cc1Oc1ccccc1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 28.4 gm of 4,5-dichloro-2-nitro-1-phenoxy-benzene, 21.6 gm of 2,4,5-trichloro-phenol, 10 ml of 10 N sodium hydroxide and 80 ml of dimethylsulfoxide was stirred for 6 hours at 150° C. and then allowed to stand overnight at room temperature. Thereafter, the reaction mixture was stirred into 600 ml of water, the aqueous mixture was made alkaline, and the precipitated reaction product was taken up in chloroform. The organic phase was washed with water, dried and evaporated, and the residue was recrystallized from 200 ml of ethanol, yielding 43 gm (97% of theory) of the light yellow crystalline title compound, m.p. 84° C.
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:20])([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:21])[CH:9]=2)[N:4]=[CH:3]1.[C:22]1(=[O:36])[N:26]([CH2:27][C:28](Cl)=[O:29])[C:25](=[O:31])[C:24]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:23]12>N1C=CC=CC=1>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:11]([C:10]1[CH:9]=[C:8]([Cl:21])[CH:7]=[CH:6][C:5]=1[N:4]([CH:3]=[N:2][NH:1][C:28](=[O:29])[CH2:27][N:26]1[C:22](=[O:36])[C:23]2[C:24](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:25]1=[O:31])[C:28](=[O:29])[CH2:27][N:26]1[C:25](=[O:31])[C:24]2[C:23](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:22]1=[O:36])=[O:20]
Reactant: NN1C=Nc2ccc(Cl)cc2C1(O)c1c(F)cccc1F
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1C(=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 1, 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-(2,6-difluorophenyl)quinazoline with pyridine is reacted with α-phthalimidoacetyl chloride to give 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(2,6-difluorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH3:18])[C:3]=1[O:20][CH2:21][CH3:22].[CH3:23][CH2:24][O:25][C:26]([CH:28](P(OCC)(OCC)=O)[F:29])=[O:27].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:18])=[C:28](/[F:29])\[C:26]([O:25][CH2:24][CH3:23])=[O:27])[C:3]=1[O:20][CH2:21][CH3:22]
Reactant: CCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-109, 1.08 g, 2.96 mmol) and triethyl 2-fluoro-2-phosphonoacetate (2.86 g, 11.84 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 7.4 mL, 11.84 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[C:21]1[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[O:30][CH3:31])[C:8]#[N:9].[N-:41]=[N+:42]=[N-:43].[Na+].[Cl-].[NH4+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[F:1][C:2]([F:39])([F:40])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[C:21]1[CH:26]=[C:25]([CH:27]([CH3:28])[CH3:29])[CH:24]=[CH:23][C:22]=1[O:30][CH3:31])[C:8]1[N:41]=[N:42][NH:43][N:9]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 98.2 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-cyanamide (1.8 g) is dissolved in N,N-dimethylformamide (10 ml), and thereto are added sodium azide (407 mg) and ammonium chloride (335 mg), and the mixture is heated to 100° C. and stirred for 6 hours. The reaction solution is allowed to cool to room temperature, and thereto is added a 10% aqueous citric acid solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=30:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(2H-tetrazol-5-yl)-amine (1.9 g). MS (m/z): 618 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[N:15][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:14]=[N:15][CH:16]=[C:11]([F:10])[CH:12]=2)=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)ccc1I
Reactant: OB(O)c1cncc(F)c1
Product: Cc1cc(Br)ccc1-c1cncc(F)c1

Procedure:
The title compound was prepared from 5-bromo-2-iodotoluene and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISP): 265.8 and 267.9 (M+H)+.