Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH:28]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17]2)=[O:10].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][C:27]1[CH:26]=[C:8]([CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]=2[F:1])[CH:28]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17]2)=[O:10]
Reactant: CCOC(=O)c1cc2cccc(NC(=O)c3cc(OCc4ccccc4F)cc(OCc4ccccc4F)c3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cccc2cc(C(=O)O)[nH]c12)c1cc(OCc2ccccc2F)cc(OCc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a mixed solution of ethyl 7-({3,5-bis[(2-fluorobenzyl)oxy]benzoyl}amino)-1H-indole-2-carboxylate (170 mg) in tetrahydrofuran (8 mL)-methanol (8 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (150 mg), and the mixture was stirred at room temperature for 18 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (147 mg, yield 91%) as colorless crystals. melting point 271-273° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9].[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:9])=[C:15]([CH:19]=1)[C:16]([O:18][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9])=[O:17]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1Cl)c1cc(Br)ccc1OCc1ccccc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
1-(Bromomethyl)-2-chlorobenzene (833 mg, 4.05 mmol) was added dropwise to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (400 mg, 1.84 mmol) and potassium carbonate (509 mg, 3.69 mmol) in acetone (50 ml) over 1 min under nitrogen. The reaction mixture was stirred at 55° C. for 16 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted by ethyl acetate (3×30 ml) and evaporated in vacuo to yield the title compound as a light yellow solid. 520 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][P:6](OCC)([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16].C(OC(=O)CP(OCC)(Cl)=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][PH:6]([O:8][CH2:9][CH2:10][Cl:16])=[O:7])[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: CCOC(=O)CP(=O)(Cl)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C[PH](=O)OCCCl

Procedure:
Ethyl(diethoxyphosphinyl)acetate (11.2 gm., 0.05 mol.) and phosphorus pentachloride (10.5 gm., 0.05 mol.) are dissolved in 200 ml. of benzene and refluxed overnight. The solvent is removed in vacuo, leaving yellow, oily, ethyl(ethoxychlorophosphinyl)acetate as residue (11.5 gm.).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[CH2:21]1[N:26]([C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=2)[CH2:25][CH2:24][N:23]2[CH2:34][CH2:35][CH2:36][CH:22]12>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:26]5[CH2:25][CH2:24][N:23]6[CH2:34][CH2:35][CH2:36][CH:22]6[CH2:21]5)=[CH:32][N:31]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2CCN3CCCC3C2)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCC5C4)cn3)nc2n1C1CCCC1
Yield: 37.2 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.34 mmole) was combined with 5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-amine (74.6 mg, 0.34 mmole) which gave 7-cyclopentyl-2-(5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (60 mg) in 37% yield. 1H NMR (400 MHz, DMSO) δ 9.30 (s, 1H). 8.77 (s, 1H), 8.18-8.12 (m, 1H), 8.02-7.98 (m, 1H), 7.48-7.40 (m, 1H), 6.59 (s, 1H), 4.78-4.68 (m, 1H), 3.77-3.72 (m, 1H), 3.62-3.55 (m, 1H), 3.08 (s, 3H), 3.04 (s, 3H), 2.77-2.63 (m, 2H), 2.51-2.31 (m, 4H), 2.30-2.21 (m, 1H), 2.13-1.91 (m, 6H), 1.88-1.58 (m, 5H), 1.43-1.33 (m, 1H) HR-MS m/z 475.2941 (M+H)+
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.C[O:18][C:19](=[O:31])[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[C:22]([NH2:30])[CH:21]=1>>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:30][C:22]3[CH:21]=[C:20]([CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=3)[C:19]([OH:31])=[O:18])[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: COC(=O)c1cc(N)cc(S(C)(=O)=O)c1
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(C(=O)O)cc(S(C)(=O)=O)c3)nc21

Procedure:
Starting from 2-chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (4.8 g; 0.05 mmol) and 3-amino-5-(methylsulfonyl)-benzoic acid methyl ester (5.5 g; 0.024 mmol), 6.4 g (15.27 mmol; 77% yield) of white powder were obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)(C)CC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(C)(C)CC(=O)Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
Crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3,3-dimethylbutanamide (55 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 16.9 mg of 173. MS (Q1) 451 (M)+
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C:8]1C=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:9]=1C(O)=O>CN(C=O)C.C(Cl)Cl>[CH3:7][C:8]1[CH:9]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Oxalyl chloride (0.31 g) was added dropwise to a stirred mixture of 2-methyl-5-nitrobenzoic acid (0.4 g), DMF (a few drops) and methylene chloride (25 ml) which had been cooled to 0° C. The mixture was allowed to warm to ambient temperature and was stirred for five hours. The mixture was evaporated to give 2-methyl-5-nitrobenzoyl chloride which was dissolved in methylene chloride (10 ml) and added dropwise to a stirred mixture of 3-(4-methylpiperazin-1-ylmethyl)aniline (0.44 g), triethylamine (0.49 g) and methylene chloride (10 ml). The mixture was stirred at ambient temperature for 16 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-methyl-5-nitrobenzamide(0.46 g); Mass Spectrum: M+H+ 369.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C)C=O>[Cl:24][C:14]([C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=1)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Temperature: 0 °C
Yield: 99.6 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c (3.00 g, 10.14 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by dropwise addition of oxalyl dichloride (4.50 g, 35.43 mmol, 3.00 equiv) with stirring at 0° C. To this was added N,N-dimethylformamide (1 drop). The resulting solution was stirred for 1.5 h at room temperature. The resulting mixture was concentrated under vacuum to yield 3.18 g (99%) of tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate as red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[NH2:30][C:31]1([CH2:36][OH:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:30][C:31]4([CH2:36][OH:37])[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: NC1(CO)CCCC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)NC3(CO)CCCC3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and 1-amino-1-cyclopentanemethanol gave 174. MS: (ESI+) 511.0
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[C@@H:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15])(=O)=O>CC#N>[C:18]1([C@@H:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](OS(C)(=O)=O)c1ccccc1
Reactant: Nc1ccccc1
Solvent: CC#N
Product: COC(=O)[C@H](Nc1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 91.4 %

Procedure:
Aniline (16.8 mL, 184 mmol) is added to a solution of (S)-methyl 2-(methylsulfonyloxy)-2-phenylacetate (I5) (22.4 g, 92.0 mmol) in CH3CN (50 mL). The mixture is heated under MW irradiation at 120° C. for 5 minutes (UPLC-MS monitoring: complete conversion). The resulting crude is partitioned between EtOAc (200 mL) and 1N HCl (200 mL) and the aqueous phase is extracted with EtOAc (3×200 mL). The combined organic layers are dried over Na2SO4, filtered and evaporated under vacuum to obtain 20.3 g of a pale yellow solid (92% yield), which is used in the next step without any additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:26]=[CH:25][C:24]2[O:23][CH2:22][O:21][C:20]=2[CH:19]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:17][C:18]3[CH:26]=[CH:25][C:24]4[O:23][CH2:22][O:21][C:20]=4[CH:19]=3)[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)c1nc2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nc2cc(Cl)ccc2n1Cc1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2.3 g of the 6-chloro-2-methanesulfonylbenzimidazole was dissolved in 30 ml of dimethylformamide, followed by the addition of 480 mg of 60% sodium hydride and 2.04 g of piperonyl chloride under cooling with ice. The obtained mixture was maintained at 80° C. by heating for 4 hours, allowed to stand overnight and filtered to remove insolubles. The filtrate was concentrated in a vacuum and subjected to silica gel column chromatography to give the title compound.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[CH2:24](O)[CH:25]=[CH2:26].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[O-].[Na+]>C(Cl)Cl.O>[C@@H:6]1([O:8][C@@H:9]2[C@@H:10]([CH2:18][OH:19])[O:11][CH:12]([O:17][CH2:26][CH:25]=[CH2:24])[C@H:13]([OH:16])[C@H:14]2[OH:15])[O:7][C@H:2]([CH2:1][OH:23])[C@@H:3]([OH:22])[C@H:4]([OH:21])[C@H:5]1[OH:20]
Reactant: C=CCO
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: C[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCOC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
α-D-cellobiose octacetate (48.59 g, 71.6 mmol) was dissolved in methylene chloride (600 mL), and allyl alcohol (29 mL, 0.43 mol) and trimethylsilyl trifluoromethanesulfonate (16 mL, 86.0 mmol) were added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 1.5 hours. Water (200 mL) was added to the reaction mixture and the mixture was extracted with methylene chloride (200 mL). After the extract was washed with saturated brine (100 mL) and dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (300 mL) and sodium methoxide (28 mL, 0.14 mol) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 2 hours. After Dowex 50w×8 was added thereto until the reaction mixture became neutral and it was filtered, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 8:2:1, V/V) to obtain the desired title compound (24.8 g, yield 91%) as pale yellow amorphous matter.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[O:15]C>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Br)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
BBr3 (8.58 mL of 1.0M solution, 8.6 mmol) was added to the DCM (10 mL) solution of 1-bromo-2-methoxy-4-nitrobenzene (1.0 g, 4.3 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was quenched with water and extracted with ethyl acetate (3×20 mL). The combined extracts were dried and the crude was purified by flash column chromatography to get the desired compound as pale brown powder in 65% yield (600 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH:7]1([C:10]2[C:11]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4[CH:32]=[CH:31][C:30](I)=[CH:29][C:28]=4[F:34])=[O:26])[CH2:21][CH2:20]3)=[N:12][CH:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[CH2:9][CH2:8]1>>[CH:7]1([C:10]2[C:11]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[CH:29][C:28]=4[F:34])=[O:26])[CH2:23][CH2:24]3)=[N:12][CH:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[CH2:8][CH2:9]1
Reactant: O=C1CCCN1
Reactant: O=C(c1ccc(I)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: O=C(c1ccc(N2CCCC2=O)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 63 %

Procedure:
Using pyrrolidin-2-one (35 mg) and [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (200 mg) described in Preparation Example 164 and by the reaction and treatment in the same manner as in Example 1, the title compound (115 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13]
Reactant: CC(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
A mixture of 4-nitrobenylchloride (4.1 g, 23.90 mmol), N-isopropylpiperazine (3.6 g, 28.67 mmol, 1.2 eq.), potassium carbonate (6.5 g, 47.79, 2 equiv), and acetone (82 mL) is stirred for 16 h at reflux. The reaction mixture is allowed to cool to rt, filtered and concentrated. Purification of the residue by silica gel column chromatography (CH2Cl2/MeOH+1% NH3aq, 9:1) affords 6.2 g of the title compound as a yellow solid: to afford the title compound as a yellow solid: ESI-MS: 264.1 [M+H]+; tR=1.73 min (System 1); TLC: Rf=0.34 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:22][CH:23]=1)(=[O:29])[CH3:28]
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 69.5 %

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.200 g, 0.77 mmol), 1-bromo-4-acetylbenzene (0.147 g, 0.74 mmol), tetrakis(triphenylphosphine)palladium(O) (0.045 g, 0.039 mmol), and 2M aqueous sodium carbonate solution (2 mL) in 15 mL of tetrahydrofuran:methanol (1:1) to give the title compound (0.171 g, 70%) as an amorphous solid. FDMS m/e=348 (M+). EA calculated for C22H24N2O.¼ H2O: C, 78.19; H, 7.31; N, 8.29. Found: C, 78.00; H, 7.27; N, 7.93.
Reaction SMILES: [Na].[CH2:2]([C:9]1[N:13]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:12](=[S:22])[NH:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:23]I>CO>[CH2:2]([C:9]1[N:13]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:12]([S:22][CH3:23])=[N:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(Cn1c(Cc2ccccc2)n[nH]c1=S)OCC
Reactant: CI
Agent: [Na]
Solvent: CO
Product: CCOC(Cn1c(Cc2ccccc2)nnc1SC)OCC
Reaction time: 0.33 h

Procedure:
In 1 l of methanol was dissolved 11.0 g of sodium, followed by the addition of 134.4 g of 3-benzyl-4-(2,2-diethoxyethyl)-4H-1,2,4-triazole-5-thione. Then, 30.0 ml of methyl iodide was added dropwise and the mixture was stirred for 20 minutes. Thereafter, the reaction mixture was treated as in Reference Example 3 to obtain 140 g of 3-benzyl-4-(2,2-diethoxyethyl)-5-methylthio-1,2,4-triazole as an oil. This oil was gradually added to 430 ml of concentrated sulfuric acid previously cooled with ice-sodium chloride and, then at room temperature, the mixture was stirred for 30 minutes, after which it was poured into 5 l of ice-water. The mixture was neutralized with concentrated aqueous ammonia and the resultant crystals were collected by filtration. The crystalline 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine thus obtained was recrystallized from methanol. This procedure yielded colorless needles melting at 168°-169° C. Infrared absorption spectrum of this product was identical with that of the product obtained in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:12][CH2:13][OH:14])C(O)=O)=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:15])[CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](CCO)c1ccc(F)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@H](CCO)c1ccc(F)cc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (R)-2-(4fluorophenyl)-4-hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (R)-1-(4-fluorophenyl)-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: [C:1]1([C:7]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[C:15]4=[C:16]([C:21]5[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=5[N:14]4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=4)[CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:41]=[CH:40][C:39]([N:42]([C:58]2[CH:63]=[CH:62][C:61](Br)=[CH:60][CH:59]=2)[C:43]2[CH:55]=[CH:54][C:53]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:46]([CH3:57])([CH3:56])[C:45]=3[CH:44]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(C)C=CC=CC=1.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.O>[C:36]1([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:37]=[CH:38][C:39]([N:42]([C:43]2[CH:55]=[CH:54][C:53]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:46]([CH3:57])([CH3:56])[C:45]=3[CH:44]=2)[C:58]2[CH:63]=[CH:62][C:61]([C:23]3[CH:24]=[CH:25][C:26]4[N:14]5[C:13]6[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=6[C:7]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)[C:20]6[C:15]5=[C:16]([CH:17]=[CH:18][CH:19]=6)[C:21]=4[CH:22]=3)=[CH:60][CH:59]=2)=[CH:40][CH:41]=1
Reactant: CC1(C)c2ccccc2-c2ccc(N(c3ccc(Br)cc3)c3ccc(-c4ccccc4)cc3)cc21
Reactant: OB(O)c1ccc2c(c1)c1cccc3c1n2-c1ccccc1C3(c1ccccc1)c1ccccc1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccc5c(c4)c4cccc6c4n5-c4ccccc4C6(c4ccccc4)c4ccccc4)cc3)cc21

Procedure:
85 g (190 mmol) of 8,8-diphenyl-8H-indolo[3,2,1-de]acridine-3-boronic acid, 98 g (190 mmol) of biphenyl-4-yl-(4-bromophenyl)-(9,9-dimethyl-9H-fluoren-2-yl)amine and 13 g (123 mmol) of sodium carbonate are suspended in 180 ml of toluene, 180 ml of dioxane and 60 ml of water. 3.0 mg mmol) of Pd(PPh3)4 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness. The residue is recrystallised from toluene and from dichloromethane/isopropanol and finally sublimed in a high vacuum. The purity is 99.9%. The yield is 124 g (147 mmol), corresponding to 78% of theory.