Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:43][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][Si](C(C)(C)C)(C)C)[N:18]=4)[C:15]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:14]([O:40][CH3:41])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:42]=[C:3]2[O:2]1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]1[O:43][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[N:18]=4)[C:15]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:14]([O:40][CH3:41])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:42]=[C:3]2[O:2]1
Reactant: COc1ccc2c(c(CCCCO[Si](C)(C)C(C)(C)C)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2c(c(CCCCO)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
After 2,3-(methylenedioxy)-6-[4-(t-butyldimethylsiloxy)butyl]-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (532 mg, 0.89 mmol) was dissolved in tetrahydrofuran (6 mL), acetic acid (102 μL, 1.78 mmol) and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 1.78 mL) were added to the solution. The mixture was stirred at room temperature. The reaction solution was concentrated in vacuo. The residue was diluted with methylene chloride (30 mL), which was then washed with water. After the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (eluted with 1% methanol-methylene chloride) to give 2,3-(methylenedioxy)-6-(4-hydroxybutyl)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (372 mg, yield 87%) as light yellow needles.
Reaction SMILES: C([O:8][CH:9]([CH2:36][O:37][C:38]1C=CC(F)=[CH:40][CH:39]=1)[CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[C:15](=[O:33])[CH2:14][S:13]1(=O)=O)C1C=CC=CC=1.C(OC(COCCC)CCC1N(CCCCCCC(OCC2C=CC=CC=2)=O)C(=O)CS1)C1C=CC=CC=1>>[OH:8][CH:9]([CH2:36][O:37][CH2:38][CH2:39][CH3:40])[CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:15](=[O:33])[CH2:14][S:13]1
Reactant: O=C(CCCCCCN1C(=O)CS(=O)(=O)C1CCC(COc1ccc(F)cc1)OCc1ccccc1)OCc1ccccc1
Agent: CCCOCC(CCC1SCC(=O)N1CCCCCCC(=O)OCc1ccccc1)OCc1ccccc1
Product: CCCOCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O

Procedure:
This compound is prepared essentially by the method described in Example 5, Step E, except that the benzyl 7-{2-[3-benzyloxy-4-(4-fluorophenoxy)butyl]-1,1,4-trioxo-3-thiazolidinyl}heptanoate is replaced by benzyl 7-[2-(3-benzyloxy-4-propoxybutyl)-4-oxo-3-thiazolidinyl]heptanoate. This method provides the title compound as a viscous, pale yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>C(O)C>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2ccccc2N)cc1

Procedure:
A mixture of 4-methanesulphonyliodobenzene (18 g), 2-bromonitrobenzene (12.7 g) and copper powder (12 g) was heated at 120° C. for 30 hours to yield a residue which was purified by chromatography on a silica column eluted successively with 5:95 mixture, a 10:90 mixture, a 25:75 mixture and then a 40:60 mixture of ethylacetate and hexane to give 4'-methanesulphonyl-2-nitrobiphenyl (m.p. 178° C.). 4'-methanesulphonyl-2-nitrobiphenyl (5 g) was heated at 90°-95° C. for 6 hours with hydrated sodium sulphide (17.3 g) and ethanol (100 ml) to give 2-amino-4'-methanesulphonylbiphenyl (m.p. 164°-165° C.).
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.[CH3:40][N:41]([CH3:47])[CH2:42][CH2:43][C:44](O)=[O:45].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:40][N:41]([CH3:47])[CH2:42][CH2:43][C:44]([O:21][CH:3]([C:2](=[O:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:45]
Reactant: CN(C)CCC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To a solution of (6Z,9Z,27Z,30Z)-19-hydroxyhexatriaconta-6,9,27,30-tetraen-18-one (1.0 g, 1.9 mmol), 3-(dimethylamino)propanoic acid hydrogen chloride (876 mg, 5.7 mmol) and EDCI (1.2 g, 6.3 mmol), in dichloromethane (20 mL) was added DIPEA (1.0 mL, 5.7 mmol) and DMAP (20 mg). The solution was stirred at room temperature for 16 hours under nitrogen. Upon completion, the reaction was diluted with dichloromethane (50 mL) and washed with sodium bicarbonate solution (50 mL). The dichloromethane layer was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% ethyl acetate) to afford the title compound as a colorless oil (675 mg, 57%). 1H NMR (400 MHz, CDCl3): δ 5.43-5.28 (m, 8H), 5.03-4.98 (m, 1H), 2.80-2.75 (m, 4H), 2.74-2.56 (m, 4H), 2.54-2.36 (m, 2H), 2.28 (s, 6H), 2.09-2.01 (m, 8H), 1.82-1.64 (m, 2H), 1.63-1.52 (m, 2H), 1.42-1.23 (m, 30H), 0.93-0.86 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9][C:8]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:34])[CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:22][CH:21]=3)=[O:18])=[CH:7][C:6]=2[CH:35]=1.B([O-])([O-])O[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH3:50])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH3:50])=[CH:40][CH:39]=3)=[CH:35][C:6]=2[CH:7]=[C:8]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:34])[CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][CH:25]=2)=[O:18])[CH2:9][CH2:10]1)[CH2:13][CH:14]([CH3:15])[CH3:16]
Reactant: CC(C)CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
In toluene/ethanol/water (=10/1/1, 31.5 ml) was dissolved 7-bromo-1-isopentyl-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.66 g). To the solution were added 4-(2-propoxyethoxy)phenyl borate (0.33 g) and potassium carbonate (0.37 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (56 mg), and the mixture was heated to reflux for 16 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1). The purified residue was dissolved in ethyl acetate and filtered to give a solution. The solvent was removed under reduced pressure, followed by recrystallization from isopropyl ether/ethyl acetate to give 1-isopentyl-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 86) (80 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:24][CH3:25])[CH3:23])=[CH:18][CH:17]=1)=[O:14]>CCO>[CH:22]([C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:13](=[O:14])[C:12]3[C:11](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:10]=[C:8]2[C:5]2[CH:4]=[N:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:17][CH:18]=1)([CH2:24][CH3:25])[CH3:23]
Reactant: O=Cc1ccc(F)nc1
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(F)nc3)nc3ccccc3c2=O)cc1
Yield: 15 %

Procedure:
2-fluoro-5-formylpyridine (0.55 mmol) and anyhydrous CuCl2 (0.150 g, 1.10 mmol) were added to a solution of 2-amino-N-(4-sec-butylphenyl)benzamide (0.205 g, 0.55 mmol) in anyhydrous EtOH (10 mL). After heating at reflux temperature for 2.5 hours, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 50% EtOAc in heptane, afforded the title compound as a white solid (15%). 1H-NMR (300 MHz, DMSO-d6): δ 8.17-8.33 (m, 2H), 7.87-8.02 (m, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.62-7.66 (m, 1H), 7.23-7.33 (m, 2H), 7.12-7.22 (m, 2H), 6.98-7.11 (m, 1H), 2.54-2.65 (m, 1H), 1.32-1.66 (m, 2H), 1.15 (d, J=6.9 Hz, 3H), 0.60 (t, J=7.4 Hz, 3H). MS (APCI) m/z: 374 (M+H)+.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH:5]=1)([O-])=O.[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:13]1([C:11]([NH:10][C:6]2[CH:5]=[C:4]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20]4)[CH:9]=[CH:8][N:7]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Reactant: O=C(O)c1cnc2ccc(O)cc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2c1
Temperature: 150 °C

Procedure:
N-(4-Nitropyridin-2-yl)cyclopropanecarboxamide (Int-23, 150 mg, 0.722 mmol), 6-hydroxyquinoline-3-carboxylic acid (Int-15, 150 mg, 0.794 mmol), and cesium carbonate (706 mg, 2.17 mmol) were weighed into a 2-5 mL microwave vial. N,N-dimethylformamide (3.5 mL) was added and the vial was capped. The reaction mixture was heated in the microwave for 3 h at 150° C. The vial was allowed to cool to room temperature and the cap was removed. The reaction mixture was diluted with water (5 mL) and stirred for a few minutes. The resulting clear solution was acidified by addition of 1N HCl and extracted three times with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. A solid precipitated in the extracts, was isolated by filtration and found to be the product. Solid product was combined with product isolated by extraction (0.245 g, 97%). LC-MS: (FA) ES+ 350; 1H NMR (400 MHz, d6-DMSO) δ ppm 13.67-13.47 (m, 1H), 10.92 (s, 1H), 9.30 (d, J=2.1 Hz, 1H), 8.98 (d, J=2.0 Hz, 1H), 8.25 (d, J=5.7 Hz, 1H), 8.21-8.17 (m, 1H), 8.01-7.99 (m, 1H), 7.75 (dd, J=9.1, 2.7 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 6.81 (dd, J=5.7, 2.4 Hz, 1H), 1.95 (tt, J=7.6, 7.6, 4.9, 4.9 Hz, 1H), 0.81-0.67 (m, 4H).
Reaction SMILES: F[C:2]1[C:7]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:6][C:5]([C:23]2[S:24][CH:25]=[C:26]([CH3:28])[CH:27]=2)=[CH:4][N:3]=1.Cl.[O:30]1CCOCC1>>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][CH2:8][C:7]3[C:2](=[O:30])[NH:3][CH:4]=[C:5]([C:23]4[S:24][CH:25]=[C:26]([CH3:28])[CH:27]=4)[CH:6]=3)=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: C1COCCO1
Reactant: COc1ccc2c(OCCc3cc(-c4cc(C)cs4)cnc3F)ccnc2c1
Agent: Cl
Product: COc1ccc2c(OCCc3cc(-c4cc(C)cs4)c[nH]c3=O)ccnc2c1
Temperature: 105 °C

Procedure:
To a 4 mL microwave tube was added 4-(2-(2-fluoro-5-(4-methylthiophen-2-yl)pyridin-3-yl)ethoxy)-7-methoxyquinoline (0.025 g, 0.063 mmol), aq. HCl (5N, 2 mL), and dioxane (3 mL). The resulting mixture was sealed and heated to reflux (105° C.) in closed system for 20 h. The reaction mixture was partitioned between EtOAc/satd. NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSO4 and concentrated. The crude product was purified using SiO2 chromatography with CH2Cl2:EtOAc:MeOH (2M NH3) (90%:6%:4%) to afford the product as whit solid (15 mg). MS (ESI pos. ion) m/z (MH+): 393.3. Calc'd exact mass for C22H20N2O3S: 392.1. 1H NMR (300 MHz, MeOH-d4) δ ppm 2.24 (s, 3 H) 3.20 (t, J=6.28 Hz, 2 H) 3.93 (s, 3 H) 4.54 (t, J=6.28 Hz, 2 H) 6.90 (s, 1 H) 6.94 (d, J=5.55 Hz, 1 H) 6.96 (s, 1 H) 7.11 (dd, J=9.21, 2.48 Hz, 1 H) 7.27 (d, J=2.34 Hz, 1 H) 7.55 (d, J=2.63 Hz, 1 H) 7.88 (d, J=2.48 Hz, 1 H) 8.10 (d, J=9.21 Hz, 1 H) 8.57 (d, J=5.55 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>ClCCl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][Br:43]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(-c2nc(Cc3cccc(CO)c3)c(C)o2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(Cc3cccc(CBr)c3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl alcohol (3.52 g) was dissolved in 60 ml of dichloromethane. After addition of 3.77 g of triphenylphosphine and 5.17 g of carbon tetrabromide, the mixture was stirred for 30 minutes at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 3.96 g of the objective compound as colorless crystals. M.p. 101–102° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:16]([F:19])([F:18])[F:17])[C:3]=1[NH2:4].[N+:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([O-:22])=[O:21].O.C(OCC)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:14])([F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:16]([F:17])([F:18])[F:19])[C:3]=1[NH:4][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1c(Br)cc(C(F)(F)C(F)(F)F)cc1C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1c(Br)cc(C(F)(F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 5.7 %

Procedure:
To a solution of 2.50 g (6.99 mmol) of 2-bromo-4-(perfluoroethyl)-6-(trifluoromethyl)aniline in 20 ml of pyridine was added 2.72 g (14.7 mmol) of 3-nitrobenzoyl chloride, followed by stirring at 100° C. for 12 hours. To the reaction liquid were added water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. To the obtained residue were added THF and an aqueous sodium hydroxide solution, followed by stirring at room temperature for 8 hours. The reaction liquid was extracted/dried in the same manner as described above, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=7:1→5:1) to prepare 0.202 g (yield 6%) of a target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16]O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:30]4[C:26](=[O:36])[C:27]5=[CH:35][CH:34]=[CH:33][CH:32]=[C:28]5[C:29]4=[O:31])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, 8-chloro-1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine in dioxane is treated with phthalimide, triphenylphosphine and subsequently with diethyl azodicarboxylate to give 8-chloro-1-(2-phthalimidoethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][CH:5]([C:6]#[N:7])[C:8]#[N:9]
Reactant: N#CC(C#N)=Cc1ccc(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C#N)Cc1ccc(F)cc1Cl
Yield: 5.4 %

Procedure:
Using 10.0 g of (2-chloro-4-fluorobenzyliden)malononitrile, 200 ml of ethanol and 0.6 g of sodium borohydride, and according to the process described in the Reference Production Example 3, there was obtained 0.55 g of (2-chloro-4-fluorobenzyl)malononitrile (the intermediate (24)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:10]=3[CH2:9][CH2:8][C:4]=2[CH:3]=1
Reactant: COc1cccc(C(=O)O)c1CCc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cccc2c1CCc1cc(Cl)ccc1C2=O

Procedure:
For the synthesis of the title compound, 16.6 g (0.057 mol) of [2-(3-chlorophenyl)-ethyl]-3-methoxybenzoic acid, 7.25 g (0.06 mol) of SOCl2, 250 ml of methylene chloride and 10 g of AlCl3 are employed in method K. Purification is carried out by column chromatography (flash; SiO2; hexane 90%/ethyl acetate 10%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH3:38])=[O:34]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[C:7]=2[O:24][CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH3:38])=[O:34])[CH2:3][CH2:2]1
Reactant: CCCNC(=O)CBr
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNC(=O)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OCC1CC1
Temperature: 70 °C
Yield: 30.7 %

Procedure:
4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (100 mg, 0.308 mmol) in acetonitrile (15 mL) was added potassium carbonate (127 mg, 0.925 mmol) and 2-bromo-N-propylacetamide (110 mg, 0.616 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-45% ethyl acetate in pet ether) to afford the title compound as a solid (40 mg, 30.7%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M71) (0.45 g, 0.81 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (205 mg, 58%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][O:18][CH2:19][CH2:20][OH:21].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:21][CH2:20][CH2:19][O:18][CH3:17]
Reactant: COCCO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-methoxyethanol and DBU in dioxane. ES-MS m/e (%): 316 (M{81Br}+H+, 96), 314 (M{79Br}+H+, 100), 258 ([M{81Br}+H-MeOCH═CH2]+, 70), 256 ([M{81Br}+H-MeOCH═CH2]+, 75).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([NH:37][CH3:38])[N:34]=[C:33]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH:32]=2)[CH:28]=[N:29][CH:30]=1.C(Cl)Cl>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:38][NH:37][C:35]1[N:34]=[C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH:32]=[C:31]([C:27]2[CH:28]=[N:29][CH:30]=[C:25]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:10]=3)[CH:26]=2)[CH:36]=1
Reactant: CNc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: CN1CCN(Cc2cccc(B(O)O)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNc1cc(-c2cncc(-c3cccc(CN4CCN(C)CC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
To a solution of 3-((4-Methyl-piperazin-1-yl)methyl)-phenyl boronic acid (Intermediate B1) (1.2 eq, 0.704 mmol, 0.165 g) and 2M Na2CO3 (2.0 eq, 1.17 mmol, 0.6 ml) in DME (3 ml) is added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) (1 eq, 0.586 mmol, 0.2 g) followed by [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.058 mmol, 0.043 g). The reaction mixture is heated using microwave radiation at 90° C. for 4 hours. The reaction mixture is dissolved in EtOAc and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2 M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 451.