Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[Br:15]Br.S([O-])(O)=O.[Na+]>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[Br:15][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)Cc1ccccc1-2
Reaction time: 5 h
Yield: 78.6 %

Procedure:
In a three-liter flask having four openings equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser, respectively, 237 g (1.4 mol) of fluorene, 1 L of water, three drops of a surfactant, and five drops of sulfuric acid were placed and stirred to mix. By adding 230 g (1.4 mol) of bromine into the mixture, a reaction was started. After the reaction had been conducted at room temperature for 5 hours, unreacted bromine was decomposed with an aqueous solution of sodium hydrogen sulfite. The reaction product, which was a light yellow solid, was filtered and thus 334 g of a crude product was obtained. The crude product was dissolved in toluene and was subsequently washed with water and a sodium hydrogencarbonate aqueous solution. The resulting organic liquid was dried using anhydrous magnesium sulfate. After filtration, the liquid was concentrated and then allowed to stand at 0° C., so that a white solid was precipitated. The precipitate was filtered and subsequently washed with toluene, followed by drying. Thus, 287 g (1.1 mol, yield of 82%) of a white solid product was obtained. This product was subjected to gas chromatography and the purity of the product was 98.8%.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][C:13]=1[CH3:20].[B:21](OC)([O:24]C)[O:22]C>C(OCC)C>[CH3:20][C:13]1[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:12]=1[B:21]([OH:24])[OH:22]
Reactant: CSc1ccc(Br)c(C)c1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CSc1ccc(B(O)O)c(C)c1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 50 %

Procedure:
1.7M tert-Butyllithium in pentane (6.70 mL, 11.39 mmol) was added dropwise to a solution of 1-bromo-2-methyl-4-(methylthio)benzene (1.2 g, 5.53 mmol) in diethyl ether (120 mL) at −78° C. over 15 min. The mixture was stirred at −78° C. for 2 min, then charged with trimethyl borate (0.661 mL, 5.91 mmol) dropwise over 2 min at −78° C., stirred at −78° C. for 15 min, then brought to ambient temperature. The mixture was quenched with saturated aqueous NH4Cl (14 mL), stirred at ambient temperature for 15 min, charged with 1M HCl (12 mL), stirred at ambient temperature for 2 min, and the organics were separated. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 20 to 100% EtOAc/hexane to give 503 mg (50%) of [2-methyl-4-(methylthio)phenyl]boronic acid as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, 1H, J=7.8 Hz), 7.09-7.00 (m, 2H), 2.61 (s, 3H), 2.46 (s, 3H); LRMS (ESI), m/z 183 (M+H).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[O:42])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[C:43]([Mg]Br)#[CH:44].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]([OH:42])[C:43]#[CH:44])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: C#C[Mg]Br
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To 25 ml of tetrahydrofuran solution containing 1.01 g (1.62 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 15-(a) was added dropwise 3.6 ml of tetrahydrofuran solution containing 0.5M ethynyl magnesium bromide at 60° C., and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into a saturated ammonium chloride solution, and extracted with toluene. The organic layer after separation was washed successively with water, and then, with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.11 g of the title compound as a yellowish oil. (Yield: 96%)
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:34]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:33][C:32]3[C:27](=[CH:28][C:29]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:10]1)=O)(C)(C)C.[ClH:52]>O1CCOCC1.CO>[NH2:8][C@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:34]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:33][C:32]3[C:27](=[CH:28][C:29]([N:46]4[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:10]1.[ClH:52]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the amide intermediate, 1 mL of 4 M HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure to give the sub-title compound as a HCl salt. LCMS calc. for C33H38N7O4 [M+H]+: m/z=596.3. found: 596.3.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]Br.[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: ClCCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCCCN1CCOCC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A solution of 1-chloro-3-bromopropane in dry tetrahydrofuran (2 mL) was added to a cold suspension of morpholine (200 mg, 2.29 mmol) and sodium carbonate (0.63 g, 4.56 mmol) in dry tetrahydrofuran (8 mL). at 0° C. The mixture was stirred at 45° C. overnight. The mixture was allowed to cool to rt, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a mixture of ethyl acetate and n-heptane (70:30), afforded 3-chloro-1-morpholin-4-yl-propane (156 mg, 42%).
Reaction SMILES: C(O[CH2:5][C@@H:6]([C@@H:12]1[CH2:16][O:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C(=O)C)[C:18]=2[CH3:27])=[N:13]1)[O:7]S(C)(=O)=O)(=O)C.CO.[C:30]([NH:34][C:35]([C@@H:37]1[CH2:46][C@H:45]2[C@H:40]([CH2:41][CH2:42][CH2:43][CH2:44]2)[CH2:39][NH:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>O>[C:30]([NH:34][C:35]([C@@H:37]1[CH2:46][C@H:45]2[C@H:40]([CH2:41][CH2:42][CH2:43][CH2:44]2)[CH2:39][N:38]1[CH2:5][C@H:6]([C@@H:12]1[CH2:16][O:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:18]=2[CH3:27])=[N:13]1)[OH:7])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(=O)OC[C@H](OS(C)(=O)=O)[C@@H]1COC(c2cccc(OC(C)=O)c2C)=N1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(O)cccc1C1=N[C@H]([C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)CO1
Temperature: 50 °C
Reaction time: 5.5 h

Procedure:
The crude product of Example 3, (2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)-2methanesulfonyloxyethane, 18′ (1.98 kg, 3.30 mol) was suspended in a mixed solvent of methanol (6.50 L) and water (6.50 L), and (3S, 4aS, 8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide, 642 g, 2.62 mol) and potassium carbonate (1.36 kg, 9.81 mol) were successively added, which was followed by stirring at 50° C. for 5.5 hours. Water (6.50 L) was added to cool the reaction mixture to room temperature and the resulting crystals were collected by filtration. These crude crystals were again suspended in water (6.50 L), stirred, washed and collected by filtration. The obtained crystals were re-suspended in methyl isobutyl ketone (10.0 L) and the suspension was subjected to azeotropic dehydration. The resulting slurry was cooled to room temperature and crystals were collected by filtration to give 902 g (1.07 mol) of the title compound, as colorless crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[C:13](=[CH2:29])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Yield: 66 %

Procedure:
1.0 g of 21-acetoxy-17α-hydroxy-4-pregnene-3,20-dione is reacted, using 2.0 g of p-toluenesulfonic acid, analogously to Example 42 and purified, thus obtaining 680 mg of 21-acetoxy-17α-hydroxy-6-methylene-4-pregnene-3,20-dione, mp 194°-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Br[C:11]#[N:12]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:11]#[N:12]
Reactant: N#CBr
Reactant: Nc1cc(Cl)ccc1Cl
Solvent: O
Product: N#CNc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a heterogeneous slurry of 2,5-dichloroaniline (3.0 g, 18.5 mmol) in 60 mL of water at 4° C. was added solid BrCN (1.22 g, 11.3 mmol) slowly. After 5 minutes the cooling bath was removed and the heterogeneous reaction mixture was stirred at room temperature for 24 hours to yield the product in water suspension. The product was collected by filtration, washed with water (100 mL), and dried under vacuum to yield the pure product (2 g, 60% yield).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:11][C:12]1[N:13]=[CH:14][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1Br>C1(C)C=CC=CC=1.C(OCC)(=O)C.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.Cl[Pd]Cl>[Br:11][C:12]1[N:13]=[CH:14][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Br)c1Br
Reactant: C[Sn](C)(C)c1cccnc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(Br)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
To a solution of 71 (0.82 g, 3.4 mmol) in anhydrous toluene (50 ml) were added 0.9 eq (1.10 g) of 4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (compound 72, LCMS (method A): Rt: 3.60 min, ([M+H]+=357)) and the resulting mixture was stirred for 2 hours under N2 (room temperature). To this reaction mixture were added 10 mol % of PdCl2(PPH3)2 (240 mg). After the addition, the temperature was raised to 100° C. and the resulting solution was stirred for 18 hours under N2. The reaction mixture was cooled, diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether followed by ethyl acetate) to afford 3-[5-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine (73) as an oil (385 mg, 36%). LCMS (method A): Rt: 3.40 min, ([M+H]+=355). 1H-NMR (400 MHz, CDCl3 and HMBC): δ 8.79 (d, J=2 Hz, 1H), 8.66 (dd, J=5 Hz, 2 Hz, 1H), 7.91 (dt, J=8 Hz, 2 Hz, 1H), 7.66 (s, 1H), 7.44-7.40 (m, 1H), 5.17 (s, 2H), 3.56-3.50 (m, 2H), 0.94-0.87 (m, 2H), 0.0 (s, 9H).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[S:19][CH:20]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+].Cl>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[S:19][CH:20]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.2 %

Procedure:
To a solution of methyl 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (97 mg) obtained in Step E of Example 12 in a mixed solvent of THF (10 mL)/methanol (10 mL) was added 1N aqueous sodium hydroxide solution (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 96 hr. To the reaction mixture was added 1N hydrochloric acid (2 mL) under ice-cooling, and the mixture was stirred, and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (83 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[CH:7]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[N:6]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:30][CH:31]([CH3:34])[CH2:32]I>CN(C)C=O>[CH3:4][C:2]([C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:30][CH:31]([CH3:34])[CH3:32])[C:8](=[O:16])[CH:7]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[N:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)CI
Reactant: CC(C)(C)C1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
A solution of 1,3-dihydro-5-(1,1-dimethylethyl)-3(R,S) -[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one (500 mg, 1.4 mmol) in dimethylformamide (10 ml) under an atmosphere of nitrogen, was treated with sodium hydride (54 mg of a 57% dispersion in mineral oil, 1.4 mol) in one portion at 0° C. After 1 h, 2-methylpropyl iodide (0.17 ml, 1.45 mmol) was added and the resulting mixture stirred at room temperature for 16 h. The solvent was then evaporated and the crude residue partitioned between water (15 ml) and dichloromethane (2×20 ml). The combined organic phases were washed with brine (2×20 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica using 2:1 petrol:ethyl acetate as eluent, to afford the title compound as a colourless solid (320 mg, 56%). 1H NMR (250 MHz, D6 -DMSO) δ 0.63 (3H, d, J=7 Hz), 0.77 (3H, d, J=7 Hz), 1.26 (9H, s), 1.49 (1H, m), 3.56 (1H, dd, J=4 Hz, 14 Hz), 4.10 (1H, dd, J=4 Hz, 14 Hz), 4.88 (1H, m), 5.02 (2H, m), 7.20-7.40 (5H, m), 7.58 (1H, t, J=8 Hz), 7.66 (1H, d, J=9 Hz), 7.77 (1H, d, J=8 Hz), 8.18 (1H, d, J=9 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([OH:18])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:17][CH2:16][CH2:15][CH2:14]2.C(N(CC)CC)C.[Cl:26][C:27]([Cl:34])([Cl:33])[CH2:28][O:29][C:30](Cl)=[O:31]>C(Cl)Cl>[OH:18][C:4]1([CH2:3][CH2:2][NH:1][C:30](=[O:31])[O:29][CH2:28][C:27]([Cl:34])([Cl:33])[Cl:26])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:14][CH2:15][CH2:16][CH2:17]2
Reactant: NCCC1(O)CCc2ccccc2C12CCCC2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCC1(O)CCc2ccccc2C12CCCC2)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A solution of the product from Example 9 (0.88 g, 3.59 mmol) and triethylamine (0.40 g, 3.78 mmol) in 10 mL of CH2Cl2 was cooled to 0° C. and treated dropwise with 2,2,2-trichloroethylchloroformate (0.80 g, 3.78 mmol) in 2 mL CH2Cl2. The resulting solution was stirred at 0° C. for 30 minutes and warmed to room temperature. The reaction mixture was washed with saturated aq. NaHCO3 solution (10 mL). The aqueous phase was extracted with CH2Cl2 (10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 10:1 heptane/ethyl acetate) to give the title compound (1.18 g, 78%) as a viscous oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccncc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and isonicotinoyl chloride, there is obtained ethyl N-(isonicotinoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 120°-122° C.;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (0.65 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.44 g, 2.20 mmol) according to the general procedure IVb. Obtained as a white solid (0.66 g, 73%). MS (EI) 446.0 [(M)+]; mp 134° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]2[N:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6]2.[N:17]([O-])=[O:18].[Na+].[OH-].[Na+]>CC(O)=O.O>[CH3:1][NH:2][C:3]1[C:4]([N:17]=[O:18])=[C:5]2[N:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: O=N[O-]
Reactant: CCOC(=O)c1c(NC)cc2ccccn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(NC)c(N=O)c2ccccn12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ethyl 2-(methylamino)-3-indolizinecarboxylate 6 (4.45 g, 20.4 mmol) was dissolved in CH3COOH (40 mL) and cooled to 0° C., before a solution of sodium nitrite (1.7 g, 24.0 mmol) in water (10 mL) was added. After being stirred at 0° C. for 3 h, the reaction mixture was basified with a 2 M solution of NaOH (pH=8-9) and extracted with CH2Cl2 (3×50 mL). The combined extracts were dried over anhydrous magnesium sulphate, filtered and then concentrated under vacuum. The residue was chromatographed on silica gel with an elution gradient of 1/1 to 4/1 of ethyl acetate/petroleum ether, to give, following removal of the solvents, 3.89 g of green microcrystals of ethyl 2-(methylamino)-1-nitroso-3-indolizinecarboxylate 7, m.p.: 156-157° C. 1H NMR (DMSO-d6): δ 1.40 (t, J=7.0 Hz, 3H), 3.47 (d, J=5.4 Hz, 3H), 4.38 (q, J=7.0 Hz, 2H), 7.35 (t, J=7.0 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.79 (br s, 1H), 8.38 (d, J=8.1 Hz, 1H), 9.27 (br s, 1H). 13C NMR (DMSO-d6): δ 14.5, 34.5, 59.7, 98.8, 116.2, 120.0, 123.5, 128.1, 135.2, 149.4, 149.8, 160.9.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:5][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22].P(Cl)(Cl)([Cl:30])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:30][C:2]1[C:3]([CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(C(=O)OC)c1c(-c2ccccc2)nc(N2CCCCC2)[nH]c1=O
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1-c1ccccc1

Procedure:
To a suspension of methyl 2-(6-oxo-4-phenyl-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoate (1.74 g; 4,71 mmol) in dry toluene (10 mL) under nitrogen atmosphere were carefully added phosphorus oxychloride (4.38 mL; 47.1 mmol) and dimethylaniline (0.476 mL; 3.77 mmol) and the reaction mixture was heated to reflux for 3 h. The volatiles were removed under reduced pressure (while the reaction mixture was still at elevated temperature), the residue was cooled in an ice-bath and quenched by adding crushed ice and a saturated solution of sodium hydrogen carbonate until neutralization. The aqueous layer was extracted with ethyl acetate, the organics were collected, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.040 g (1.6%, over 3 last steps) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: C1COCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCOCC3)cc21

Procedure:
6,7-Dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (4.3 g) and morpholine (10 cm3) in DMSO (45 cm3) were heated for 3 hours at 110° C. under the same conditions as in Example 6. The reaction product crystallised on cooling. It was filtered off and recrystallised from 40 cm3 of a mixture of DMF (dimethylformamide; 1 volume) and methyl cellosolve (1 volume). 3.3 g of 6-chloro-1-ethyl-7-morpholino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 266° C., were obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C)C=O.O>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH:24]=[CH2:23])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(O)c2c1CCC(=O)N2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OC(C)=O)c2c1NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
65 Grams of 5-acetoxy-3,4-dihydro-8-hydroxy-2(1H)-quinolinone was dissolved in 500 ml of dimethylformamide (DMF), to this solution were added 52 g of potassium carbonate powder and 50 ml of allyl bromide, the mixture thus obtained was stirred at room temperature for 8 hours. To this reaction mixture was diluted with 500 ml of water, extracted with 2 liter of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, then concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol, there was obtained 70 g of 5-acetoxy-8-allyloxy-3,4-dihydro-2(1H)-quinolinone as brown needle-like crystals.