Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:19][C:20]([C@@H:22]1[CH2:35][C:34]2[CH:33]=[C:32]3[C:27]([O:28][C@@H:29]([C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[C:30](=[O:37])[N:31]3[CH3:36])=[CH:26][C:25]=2[CH2:24][N:23]1[C@H:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:46][CH3:47])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:55][C:56]1[CH:57]=[C:58]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:59]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:19][C:20]([C@@H:22]1[CH2:35][C:34]2[CH:33]=[C:32]3[C:27]([O:28][C@@H:29]([C:38]4[CH:39]=[CH:40][C:41]([O:44][CH2:59][C:58]5[CH:61]=[CH:62][C:63]([Cl:64])=[C:56]([Cl:55])[CH:57]=5)=[CH:42][CH:43]=4)[C:30](=[O:37])[N:31]3[CH3:36])=[CH:26][C:25]=2[CH2:24][N:23]1[C@H:45]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:46][CH3:47])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (68 mg, 0.091 mmol) was dissolved in 2 mL of DMF and 3,4-dichlorobenzyl bromide (0.46 mmol) and potassium carbonate (0.46 mmol) were added. The mixture was stirred at room temperature for 8 hours and was poured onto ethyl acetate and 10% sodium carbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 7-3-0.1) to provide (S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (17 mg, LC/MS: m/z 903).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:31])[CH:7](P(OCC)(OCC)=O)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:14]=1)[CH3:4].[CH:32](=O)[CH2:33][CH3:34]>C1COCC1>[CH2:3]([O:5][C:6](=[O:31])[C:7]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:13][CH:14]=1)=[CH:32][CH2:33][CH3:34])[CH3:4]
Reactant: CCC=O
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of NaH (290.5 mg, 60% in mineral oil, 7.5 mmol) in THF (25 mL) at 0° C. was added a solution of 3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-(diethoxy-phosphoryl)-propionic acid ethyl ester (2.5 g, 5.81 mmol) in THF (30 mL). The reaction mixture was allowed to stir at 0° C. for 1 h. To the reaction was added propionaldehyde (725 mg, 12.5 mmol) dropwise at 0° C. The reaction mixture was allowed to stir at room temperature for 16 h. Propionaldehyde (2.5 g) was added and the mixture was stirred at room temperature for an additional 16 h. The reaction was quenched with the slow addition of saturated aqueous NH4Cl (30 mL). The mixture was extracted with EtOAc, washed with brine and dried. The crude product was purified by column chromatography (EtOAc/hexane, 1:8) to give 2-(6tert-butoxycarbonylamino-pyridin-3-ylmethyl)-pent-2-enoic acid ethyl ester as a mixture of isomers (1.2 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17].[N-:20]=[N+:21]=[N-:22].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][N:20]=[N+:21]=[N-:22].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: [N-]=[N+]=[N-]
Agent: COc1ccc(CCCCOS(C)(=O)=O)c(OC)c1
Agent: [Na+]
Product: COc1ccc(CCCCN=[N+]=[N-])c(OC)c1

Procedure:
Azide 78 was prepared by typical procedure C from ester 77 (4.6 g, 0.015 mol) and sodium azide (1.5 g, 0.023 mol). Compound 77 (4.06 g, 75%) was isolated as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.62 (m, 4H), 2.58 (m, 2H), 3.30 (m, 2H), 3.80 (s, 6H), 6.43 (m, 2H), 7.00 (m, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([CH3:16])=[C:12]([CH2:14]O)[N:13]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[ClH:2].[Cl:19][CH2:14][C:12]1[N:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[NH:10][C:11]=1[CH3:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1[nH]c(-c2ccc(Cl)cc2)nc1CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(-c2ccc(Cl)cc2)nc1CCl
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred slurry of 10.4 g (0.04 mole) of 2-p-chlorophenyl-4-hydroxymethyl-5-methyl-imidazole hydrochloride in 250 ml of chloroform is added 10 g (0.08 mole) of thionyl chloride in CHCl3. The reaction mixture is warmed to reflux for 6 hours with stirring and then cooled to room temperature. White crystals of 4-chloromethyl-2-p-chlorophenyl-5-methylimidazole hydrochloride in 98% yield, m.p., 224°-226° C (dec.) are obtained. This material is collected and dissolved in 50 ml of warm DMSO and added to a solution of 10 g (0.2 mole) of sodium cyanide in 150 ml of hot DMSO. The mixture is warmed to 60° C for 16 hours and then stirred at room temperature for 16 hours. The reaction mixture is poured over 1 liter of ice and stirred. The tan solid that forms is filtered, collected and air-dried. The crude solid is taken up in 2 liters of ether, charcoaled and filtered. Concentration on a steam bath with hexane addition yields pale green crystals of product. Additional recrystallizations from ether-hexane and methylene chloridehexane gives about 4.5 g (49%) of pale yellow crystals of 2-(p-chlorophenyl)-4-cyanomethyl-5-methyl-imidazole, m.p., 163° - 165° C. Treatment with a mineral acid, e.g., hydrochloric, nitric, sulfuric and the like, affords the corresponding acid addition salts.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si](C(C)(C)C)(C)C)[CH2:38]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][CH:37]2[O:42][C:41](=[O:43])[CH2:40][CH:39]([OH:44])[CH2:38]2)=[CH:10]1
Reactant: CCC(Oc1ccc(C(C)C)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C(C)C)cc1)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CCC3CC(O)CC(=O)O3)[C@H]21

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.42 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(4-isopropylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as describedin Example 115, above] and 38.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 80 mg of the titlecompound as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH2:28][O:29][C:30]([NH:32][C:33]1[NH:34][C:35](=[O:46])[C:36]2[N:37]=[CH:38][N:39]([CH2:42][C:43](O)=[O:44])[C:40]=2[N:41]=1)=[O:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:43](=[O:44])[CH2:42][N:39]1[CH:38]=[N:37][C:36]2[C:35](=[O:46])[NH:34][C:33]([NH:32][C:30]([O:29][CH2:28][C:27]3[CH:47]=[CH:48][C:49]([O:50][CH3:51])=[C:25]([O:24][CH3:23])[CH:26]=3)=[O:31])=[N:41][C:40]1=2)[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)O)c(=O)[nH]2)cc1OC
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc(OC)c(OC)c3)nc21
Yield: 68.1 %

Procedure:
The title compound (2.48 g, 68%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [2-N-(3,4-dimethoxybenzyloxycarbonyl)-guanin-9-yl]-acetic acid (2.02 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 8.26 (dd, 1H), 8.14 (dd, 1H), 7.80 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (m, 2H), 7.04 (s, 1H), 6.95 (m, 2H), 5.15 (s, 2H), 5.09 (s, 1.2H), 4.90 (s, 0.8H), 4.42 (s, 0.8H), 4.16 (q, 0.8H), 4.06 (s, 1.2H), 4.03 (q, 1.2H), 3.74 (s, 3H), 3.73 (s, 3H), 3.62 (t, 1.2H), 3.43 (t, 1.2H), 3.39 (t, 0.8H), 3.20 (t, 0.8H), 1.21 (t, 1.2H), 1.13 (t, 1.8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12](=O)[CH3:13])[N:4]=1.Cl.[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24]N)[CH3:17]>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2[C:20]3[C:19](=[C:18]([CH2:16][CH3:17])[CH:23]=[CH:22][CH:21]=3)[NH:24][C:12]=2[CH3:13])[N:4]=1
Reactant: CCc1ccccc1NN
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCc1cccc2c(-c3nc(OC)cc(OC)n3)c(C)[nH]c12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
Into a reactor were fed 2.4 g (12.2 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone, 1.7 g (9.98 m moles) of 2-ethylphenylhydrazine hydrochloride, 1.4 g (10.2 m moles) of zinc chloride and 10 ml of toluene, followed by refluxing for 2 hours with heating. After the completion of the reaction, the reaction mixture was cooled to room temperature. Thereto were added water and ethyl acetate and phase separation was made. The ethyl acetate layer was concentrated. The concentrate was subjected to silica gel column chromatography separation (developing solvent: n-hexane/ethyl acetate) to obtain 2.38 g (8.01 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-ethylindole.
Reaction SMILES: [O:1]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=[N:26]O)=[CH:18][C:17]=1[CH3:28]>P(=O)(O)(O)O>[F:15][C:16]1[C:17]([CH3:28])=[CH:18][C:19]2=[CH:20][CH2:21][CH2:22][C:23](=[O:1])[N:26]=[C:24]2[CH:25]=1
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: Cc1cc2c(cc1F)C(=NO)CCC2
Agent: O=P(O)(O)O
Product: Cc1cc2c(cc1F)=NC(=O)CCC=2
Temperature: 0 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To 70 ml of 85% phosphoric acid, 100 g of phosphoric anhydride were added in portions. After the phosphoric anhydride was dissolved thoroughly, 10.0 g of 7-fluoro-6 -methyl-1-tetralone oxime were added to the resulting solution over 20 minutes at an external temperature of 90° C., followed by stirring for 4 hours under the same conditions. After the completion of the reaction, the reaction mixture was poured into ice water. The crystals so precipitated were collected by filtration. The crystals so obtained were recrystallized from chloroform-diethyl ether, whereby 8.3 g of the title compound was obtained.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34](O)=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34]([NH:1][N:2]2[C:7](=[O:8])[C:6]3[CH:9]=[CH:10][S:11][C:5]=3[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3]2)=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(-c2ccccc2)c2sccc2c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccccc2)c2sccc2c1=O
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A mixture of the product of Example 9B (31.6 mg, 0.13 mmol), triethylamine (0.028 mL, 0.20 mmol), 2-(3,5-difluorophenyl)acetic acid (25.4 mg, 0.15 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (49.8 mg, 0.16 mmol) in DMF (0.4 mL) was stirred overnight, diluted with EtOAc, washed with 1 N NaOH and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (12% EtOAc/CH2Cl2) to give the title compound as a white solid (6.2 mg, 0.016 mmol). 1H NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.24 (d, J=5.2 Hz, 1H), 7.87-7.77 (m, 3H), 7.64-7.55 (m, 3H), 7.22-7.08 (m, 3H), 3.78 (s, 2H); MS (ESI−) M/Z 396.1 (M−H)−.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1.CS(C)=O.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:35])[C:33]=1Cl>[Cl-].[Na+].O>[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:35])[C:33]=1[NH:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1
Reactant: Clc1cncc(Br)c1Cl
Reactant: COc1ccc2c(N)cc(=O)oc2c1OC1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Br)cc(=O)oc2c1OC1CCCC1
Reaction time: 0.17 h

Procedure:
Sodium hydride (7 mg, 60%, 0.18 mmol) was added to a solution of 4-amino-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (77 mg, 0.28 mmol, Example 3, Step 1) and anhydrous DMSO (3 mL) under N2. After 10 min, 3-bromo-4,5-dichloropyridine (69 mg, 0.31 mmol) was added, and the reaction was stirred for 20 h, poured into brine, and extracted with EtOAc. The organic extract was dried, filtered, concentrated, and purified by reverse-phase HPLC (20→100% MeCN/H2O) to give 4-(3-bromo-5-chloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.91 (s, 1H), 8.84 (s, 1H), 7.95 (d, 1H), 7.21 (d, 1H), 4.85 (m, 1H), 4.59 (s, 1H), 3.92 (s, 3H), 1.87-1.79 (m, 4H), 1.68-1.54 (m, 4H); MS (ESI): 464.7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>ClCCl>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:31](=[O:34])[CH2:32][CH3:33])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC
Reaction time: 15 h

Procedure:
To a solution of 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol), triethylamine (0.20 ml, 14.50 mmol) in dichloromethane (8.0 ml), propionyl chloride (134 mg, 1.45 mmol) was added at room temperature. The mixture was stirred for 15 hours. The solvent was removed under diminished pressure. After evaporation, the mixture was stirred in acetonitrile/methanol (1:2, 9.0 ml) with aqueous ammonia (3.0 ml) for 3 hours. Water (50 ml) was added and the mixture was extracted three times with ethyl acetate (3×50 ml). The combined organic layers were washed with aqueous hydrochloric acid (1N), brine, dried and evaporated to afford a residue purified by HPLC. The title compound was obtained as white powder (19 mg).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37]>N1C=CC=CC=1.C(Cl)Cl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:36]([O:1][C@@H:2]1[C@H:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:37]
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc(OC)c(OC)c2)cc1
Reaction time: 17 h
Yield: 90.7 %

Procedure:
To a solution of 2.0 g (0.0047 mol) of (-)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[ 1,2-b][1,4]thiazepin-4(5H)-one in 25 ml of dry pyridine was added dropwise 1.6 g (0.0082 mol) of 3,4-dimethoxybenzoyl chloride at ice-bath temperature. After the addition, the reaction mixture was kept at ice-bath temperatures for 17 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and cold 10% potassium carbonate. The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and the solvent was removed to give 3.3 g of crude product, which was dissolved in methylene chloride and chromatographed using 45 g of silica gel. The comumn was eluted with 50 ml portions of methylene chloride-acetone (80:20). Fractions 21-50 were collected and the solvent was removed to give 2.5 g (92%) of (-)-cis-2,3-dihydro-3-[(3,4-dimethoxybenzoyl)oxy]-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one as an amorphous solid, [α]D25 + 47.39° (C 0.928, MeOH).
Reaction SMILES: [C:1]1([CH2:17]P(=O)(OCC)OCC)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.C[O-].[Na+].C(O)(=O)C>CN(C)C=O.O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[CH:17][C:1]2[C:14]3[C:15]4=[C:16]5[C:11](=[CH:12][CH:13]=3)[CH:10]=[CH:9][CH:8]=[C:7]5[CH:6]=[CH:5][C:4]4=[CH:3][CH:2]=2)=[CH:29][CH:28]=1
Reactant: CCOP(=O)(Cc1ccc2ccc3cccc4ccc1c2c34)OCC
Reactant: O=Cc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(C=Cc2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.47 g (7 mmol) of diethyl 1-pyrenylmethylphosphonate and 0.99 g (7 mmol) of 4-chlorobenzaldehyde were dissolved with stirring in 25 ml of N,N-dimethylformamide. To this reaction mixture, 1.62 g (7×1.2 mmol) of sodium methylate (28 wt. % methanol solution of sodium methylate) was gradually added in such a manner that the temperature of the reaction mixture did not exceed 30° C. The reaction mixture was then stirred at room temperature for 1 hour, neutralized with acetic acid, and diluted with about 300 ml of water. Crystals separated out. The crystals were separated by filtration, washed with water, dried and then purified by column chromatography two times. In the first time, the purification was carried out on a column of silica gel, using a mixed solvent of toluene/n-hexane (1/1) as the developing solvent, and in the second time, the purification was carried out on a column of silica gel, using a mixed solvent of toluene/n-hexane (1/2) as the developing solvent, whereby yellow 1-(4-chlorostyryl)pyrene was obtained with a yield of 2.21 g (93.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([OH:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:31]([F:43])=[CH:32][C:33]([F:42])=[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:35]=2)[CH2:26][CH2:25]1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([OH:12])[C:9]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([C:30]3[C:31]([F:43])=[CH:32][C:33]([F:42])=[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:35]=3)[CH2:28][CH2:29]2)=[O:11])=[CH:14][CH:15]=1
Reactant: O=C(O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)c(F)cc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(F)cc1F

Procedure:
Example 160 was prepared from bis(4-fluoro phenyl) (hydroxy)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluoro phenyl}-2-methyl propanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 9.31 (s, br, 1 H), 8.44–8.33 (m, 1 H), 7.59–7.45 (m, 4 H), 7.39 (s, 1 H), 6.97 (t, 4 H, J=8.8 Hz), 6.80 (t, 1 H, J=9.6 Hz), 5.61–5.36 (br, 1 H), 3.57–3.43 (m, 2 H), 3.14–2.99 (m, 2 H), 2.99–2.84 (m, 1 H), 2.62–2.47 (m, 2 H), 2.47–2.29 (m, 1 H), 2.14–1.93 (m, 4 H), 1.81–1.59 (m, 4 H), 0.98 (apparent t, 6 H, J=6.8 Hz); ESMS m/e: 586.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.C1C=CC=CC=1>O>[CH3:2][C:1](=[N:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(N=C(C)c2ccccc2)cc1

Procedure:
A solution of acetophenone (64 ml), p-anisidine (65 mg), benzene (100 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(αmethyl-benzylidene)-p-anisidine (VII) (50 g). VII had a melting point of 81°-82° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.O=[C:14]([CH3:18])[C:15]([OH:17])=[O:16].N12CCN(CC1)CC2>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:14]([C:15]([OH:17])=[O:16])=[CH:18]2)=[O:12]
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Product: COC(=O)c1ccc2[nH]c(C(=O)O)cc2c1

Procedure:
A solution of 25 g 4-Amino-3-iodo-benzoic acid methyl ester, 19 ml 2-Oxo-propionic acid, 30.4 g 1,4-Diaza-bicyclo[2.2.2]octane and 1 g Pd(OAc)2 was heated under argon to 100° C. After 5 h the reaction mixture was concentrated under reduced pressure and the residue was partitioned between 300 ml ethyl acetate and 200 ml 1 M hydrochloric acid. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure to yield a yellow solid (6.4 g). From the aqueous layer additional product slowly precipitated as a white solid (7.9 g) which was collected by filtration. Both fractions were combined, dried in vacuo and used in the next reaction without further purification. Yield: 14.3 g MS (ES+): m/e=220.