Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[N:12]([O-])=O.[Na+].[F:16][B-:17]([F:20])([F:19])[F:18].[Na+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Cl:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[N+:4]#[N:12]
Reactant: Cc1c(F)ccc(N)c1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: Cc1c(F)ccc([N+]#N)c1Cl
Temperature: 5 °C
Yield: 83.6 %

Procedure:
2-chloro-4-fluoro-3-methylaniline (73 g) was added dropwise, with vigorous stirring to 50% hydrochloric acid (256 ml). The resulting white suspension was cooled to 5° C. and with stirring, sodium nitrite (34.5 g) in water (50 ml), added dropwise. The resultant yellow solution after filtration was cooled to 0° C. and with stirring sodium tetrafluoroborate (71 g) in water (140 ml), added dropwise. The yellow solid formed was filtered off and washed with petroleum ether (6.p 60°-80°) and combined with further similarly washed solid obtained by treating the filtrate, maintained at 0° C., with sodium tetrafluroborate (71 g) in water (140 ml). The solid was dried overnight over phosphorus pentoxide in vacuo, giving a yield of 98.8 g 2-chloro-4-fluoro-3-methylbenzenediazonium tetrafluoroborate. This was divided into three protions each being placed in a round-bottomed flask (250 ml). The flasks were in turn heated with a naked bunsen flame until decomposition set in and an orange vapor was emitted, which was condensed and collected in a cooled receiver. The orange oil obtained from the three batches was dissolved in diethyl ether (200 ml) and washed with aqueous sodium hydroxide solution (10%, 300 ml) then saturated brine (200 ml). After drying the ethereal solution over anhydrous magnesium sulphate, filtering and evaporating at atmospheric pressure, the residual oil was distilled to give 2-chloro-3,6-difluorotoluene (45 g)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][CH3:16].[Br:17]Br.CCOC(C)=O>C(O)(=O)C>[Br:17][C:9]1[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:7]([O:15][CH3:16])[CH:8]=1
Reactant: COCCNc1c(OC)cccc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCNc1c(OC)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a solution of ca. 20 g (contains 15.65 g, 58.9 mmol) (2-methoxy-ethyl)-(2-methoxy-6-nitro-phenyl)-amine in 150 ml glacial acetic acid, 3.0 ml (58.9 mmol) bromine is slowly added at room temperature. The reaction mixture is stirred at room temperature for 3 h. 600 ml EtOAc are added and this solution is washed with 4n NaOH (2×), water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallized from diethyl ether/hexane to afford 13 g of the pure title compound as orange crystals and 6.6 g of an orange oil which contained 50% of the starting material.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([CH:22]([CH3:24])[CH3:23])[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[Na])(C)(C)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:23][CH:22]([C:4]1[CH:3]=[C:2]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH3:24]
Reactant: CC(C)c1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc(N2CCCC2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
A 50 mL round-bottom flask was charged with tert-butyl 4-[[4-bromo-2-(propan-2-yl)phenyl]methyl]piperazine-1-carboxylate (50.0 mg, 0.130 mmol, 1.00 equiv), pyrrolidine (11.0 mg, 0.150 mmol, 1.20 equiv), t-BuONa (17.5 mg, 0.180 mmol, 1.45 equiv), Pd2(dba)3 (6.00 mg, 0.010 mmol, 0.050 equiv), BINAP (12.0 mg, 0.020 mmol, 0.15 equiv), toluene (2 mL). The resulting solution was stirred overnight at 80° C. with an inert atmosphere of nitrogen and then diluted with water (5 mL). The resulting solution was extracted with dichloromethane (3×5 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 31.0 mg (61% yield) of tert-butyl 4-[[2-(propan-2-yl)-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 338 [M+H]+.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14]([C:26]#[N:27])=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[Cl:37][C:38]1[CH:39]=[N:40][C:41](I)=[N:42][CH:43]=1.CCOC(C)=O>CN1C(=O)CCC1>[Cl:37][C:38]1[CH:39]=[N:40][C:41]([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:15]3[C:14]([C:26]#[N:27])=[N:13][N:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=4)[C:17](=[O:18])[CH:16]=3)[CH2:21][CH2:22]2)=[N:42][CH:43]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1
Reactant: Clc1cnc(I)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-n2nc(C#N)c(OC3CCN(c4ncc(Cl)cn4)CC3)cc2=O)cc1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
To a stirring solution of 1-(4-(methylsulfonyl)phenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl (124 mg, 0.33 mmol) in NMP (3 mL) at room temperature under argon was added DIPEA (128 mg, 0.99 mmol) and 5-chloro-2-iodopyrimidine (159 mg, 0.66 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜3 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 121 mg (75%) of 4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile was obtained as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.75-2.27 (m, 4H) 3.08 (s, 3H) 3.66-3.97 (m, 2H) 3.97-4.24 (m, 2H) 4.54-4.95 (m, 1H) 6.34 (s, 1H) 7.84 (d, J=8.79 Hz, 2H) 8.07 (d, J=8.79 Hz, 2H) 8.24 (s, 2H). MS (ESI) 487 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]=O)[CH:9]=[CH:8]2.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27](=[O:29])[CH3:28]>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]=[CH:28][C:27]([C:18]1[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=1)=[O:29])[CH:9]=[CH:8]2
Reactant: COCOc1ccc2cc(C=O)ccc2c1
Reactant: CC(=O)c1ccc2ccccc2c1
Product: COCOc1ccc2cc(C=CC(=O)c3ccc4ccccc4c3)ccc2c1

Procedure:
Synthesised according to example 1.59.1 using 6-(methoxymethoxy)-2-naphthaldehyde (2.0 g, 9.25 mmol) and 1-(naphthalen-2-yl)ethanone (1.57 g, 9.25 mmol); yellow solid; yield: 1.90 g (56%);
Reaction SMILES: Cl[C:2]1C=C(C)C(C)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19].[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH2:25]Cl>>[Cl:19][C:12]1[C:11]2[O:10][C:3]([CH3:2])([CH3:4])[CH2:25][C:16]=2[C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=1
Reactant: Cc1cc(Cl)c(Oc2cc(C)c(C)cc2Cl)cc1C
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(Cl)c2c(c1C)CC(C)(C)O2
Temperature: 25 °C

Procedure:
To a solution of 23.8 g of the methally 2-chloro-4,5-dimethylphenyl ether in 200 ml absolute dichloromethane at -70° C. was added 10 g of AlCl3 under a current of nitrogen gas. After stirring and warming to the room temperature over a period of 1 hour, the reaction mixture was added 200 ml of ice-water and the aqueous layer was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 20 g of 7-chloro-2,3-dihydro-2,2,4,5-tetramethylbenzofuran as yellow oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCC>COCCOC.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]1([C:20]#[C:21][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1nccs1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C(#Cc1nccs1)c1ccccc1
Reaction time: 16 h
Yield: 58.5 %

Procedure:
2-Bromo-1,3-thiazole (2.0 g, 12 mmol) and CuI (460 mg, 2.4 mmol) were combined in DME (40 mL), and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (8.6 mL, 62 mmol) and PdCl2(PPh3)2 (856 mg, 1.22 mmol) were added and then phenylacetylene (3.7g, 36.5 mmol) was added dropwise. The reaction was heated to reflux at which point the reaction mixture solidified. Additional DME (20 mL) was added to dissolve the solids and the reaction mixture was allowed to stir for 16 h at reflux, at which time GC/MS showed no remaining 2-bromothiazole. After cooling, the mixture was diluted with 200 mL ethyl acetate, and filtered through Celite™. The pad was then washed thoroughly with ethyl acetate and the combined filtrates were washed with water (200 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with hexane, then 97:3 hexane:ethyl acetate) to afford 2-(phenylethynyl)-1,3-thiazole (1.3 g, 60% yield) as a yellowish oil. 1H NMR (CDCl3, 300 MHz) δ 7.86 (d, J=3.2 Hz, 1H), 7.61–7.57 (m, 2H), 7.42–7.26 (m, 4H). MS (ESI) 185.2 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9](O)=[O:10])([O-:3])=[O:2].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([Cl:23])=[O:10])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1

Procedure:
To a solution of 3-nitrocinnamic acid (5.0 g) in dry Toluene (100 ml), oxalyl chloride (11.33 ml) was carefully added, followed by dry DMF (0.1 mL). The resulting yellow solution was refluxed for 3 hrs and then evaporated to dryness, to get the 3-nitro cinnamoyl chloride as a solid residue, This solid residue was dissolved in THF, the resulting solution was cooled at 0° C., and 2M methylamine (13 ml) was added to the reaction mixture, the reaction mixture was stirred for 30 min. Solvents were evaporated under vacuum, the crude material was re-crystallised from diethylether to afford the title compound (4 gm).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:9]([OH:11])[CH3:10]>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:11][CH2:9][CH3:10])[CH:7]=1
Reactant: CCO
Reactant: Brc1cncc(Br)c1
Product: CCOc1cncc(Br)c1
Yield: 69 %

Procedure:
Ethanol and 3,5-dibromopyridine were processed as described in Example 7A to provide the title compound (69% yield). MS (DCI/NH3) m/z 202/204 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].O[CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1)[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: OC1CCOC1
Product: Fc1ccc2c(c1)c(I)nn2C1CCOC1
Yield: 56 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 3-hydroxytetrahydrofuran in 56% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.47-2.52 (2H, m), 3.95-4.00 (1H, m), 4.12-4.19 (2H, m), 4.19-4.28 (1H, m), 5.24-5.30 (1H, m), 7.12 (1H, dd, J=2.0, 8.4 Hz), 7.21 (1H, td, J=1.6, 8.8 Hz), 7.45 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[C@@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]4.[CH:23]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24]1.C1(CBr)CC1>>[ClH:1].[CH:23]1([CH2:27][N:20]2[CH2:19][CH2:18][C@@:15]34[C:16]5[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@@H:10]3[C@@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]4)[CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Reactant: BrCC1CCC1
Agent: BrCC1CC1
Agent: Cl
Product: COc1ccc2c(c1)[C@]13CCN(CC4CCC4)[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Yield: 34 %

Procedure:
A sample of 3-methoxy-8β-methylmorphinan-6-one hydrochloride (prepared in Example 1C) was treated as in Example 1D, except that cyclobutylmethyl bromide (1.5 eq) was substituted for the cyclopropylmethyl bromide. The product was isolated as in Example 1D and converted to the hydrochloride salt, yield 34%, mp 217°-220° C.
Reaction SMILES: O=O.[CH3:3][C:4](=[CH:6][CH2:7][CH2:8]/[C:9](=[CH:11]/[CH2:12][OH:13])/[CH3:10])[CH3:5]>CO>[CH3:3][C:4](=[CH:6][CH2:7][CH2:8][C@H:9]([CH2:11][CH2:12][OH:13])[CH3:10])[CH3:5]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=O
Solvent: CO
Product: CC(C)=CCC[C@@H](C)CCO
Reaction time: 23 h
Yield: 96.5 %

Procedure:
A 500 ml autoclave was charged in a glove box (O2 content <1 ppm) with 27.0 g (175.0 mmol) of geraniol, 136 ml of methanol and 3.6 mg of Ru(CF3COO)2 [(S)-(MeO)3BIPHEP] as the catalyst. The hydrogenation was effected at 20° C. and 60 bar. The conversion after 23 hours amounted to 89.4%. The hydrogenation solution was evaporated at 45° C./17 mbar and the crude product was distilled at 60°-65° C./0.03 mbar. There were obtained 26.4 g of (R)-citronellol, which still contained 10.6% of unreacted geraniol, as a colourless oil; e.e. 98.9%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34]([NH2:36])=[O:35])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:25])[C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:3]=[C:2]([N:27]3[CH2:32][CH2:31][CH:30]([NH:33][C:34]([NH2:36])=[O:35])[CH2:29][CH2:28]3)[N:7]2[N:8]=1
Reactant: NC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc(N3CCC(NC(N)=O)CC3)n2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
An orange solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(trifluoromethoxy)benzamide (14A, 69 mg, 0.186 mmol), 1-(piperidin-4-yl)urea hydrochloride (40 mg, 0.279 mmol), and N,N-diisopropylethylamine (72 mg, 0.558 mmol) in DMF (1.8 mL) was stirred at 100° C. for 2 h, cooled to 80° C., and stirred overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, filtered, and then purified by preparatory HPLC (45-60% (1:1 MeOH/MeCN)/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (26.9 mg, 39%). 1H NMR (DMSO-d6) δ: 10.98 (s, 1H), 8.06-8.11 (m, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.25 (s, 1H), 6.09 (s, 1H), 6.02 (d, J=8.1 Hz, 1H), 5.34 (br. s., 2H), 4.23 (d, J=12.1 Hz, 2H), 3.62 (br. s., 1H), 3.15 (t, J=10.7 Hz, 2H), 2.31 (s, 3H), 1.87 (d, J=11.1 Hz, 2H), 1.39-1.51 (m, 2H); ESI-MS: m/z 478.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6]([CH2:9][CH2:10][C:11]1([CH3:16])[O:15][CH2:14][CH2:13][O:12]1)(=[O:8])=[O:7])[CH3:2].[F:18][C:19]([S:22][CH2:23][CH2:24]OS(C(F)(F)F)(=O)=O)([F:21])[F:20]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([S:6]([CH2:9][CH2:10][C:11]1([CH3:16])[O:15][CH2:14][CH2:13][O:12]1)(=[O:7])=[O:8])[CH2:24][CH2:23][S:22][C:19]([F:21])([F:20])[F:18])[CH3:2]
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)CS(=O)(=O)CCC1(C)OCCO1
Product: CCOC(=O)C(CCSC(F)(F)F)S(=O)(=O)CCC1(C)OCCO1

Procedure:
Compound II-27 was prepared from [2-(2-methyl-[1,3]dioxolan-2-yl)-ethanesulfonyl]-acetic acid ethyl ester and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:10]1[C:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:35]([O:34][C@@H:9]([C:10]1[C:11]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 50 °C
Yield: 79 %

Procedure:
To the solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pivalate (15 mg) in THF/MeOH (1 mL/1 mL) was added sodium hydroxide solution (1.0 N, 1 mL). The mixture was heated at 50° C. for 16 hours and was diluted with water. The aqueous was extracted with ethyl acetate, and the organic phase was washed with brine, and dried over sodium sulfate. Concentration under reduced pressure gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol (10 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H32ClN2O3: 454.2. Found: 455.3.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:28]([OH:33])/[CH:29]=[CH:30]\[CH2:31][OH:32].CCOC(C)=O.CCCCCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[C:1]([O:32][CH2:31][CH:30]=[CH:29][CH2:28][OH:33])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC/C=C\CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: OCC=CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
Trityl chloride (557 mg; 2 mmol) Et3N (0.306 ml; 2.2 mmol) and DMAP (10 mg; 0.08 mmol) were added to a emulsion of cis-2-buten-1,4-diol (1.76 g; 20 mmol) in DCM (10 ml). The mixture was stirred at room temperature under atmosphere of nitrogen for 24 hours. After such period of time the complete disappearance of trityl chloride was observed by TLC (EtOAc/Hexane 50:50). DCM (20 ml) and water (10 ml) were added to the mixture. The phases were separated and the organic layer was washed with water (10 ml) and brine (10 ml). The solvent was dried over MgSO4 and evaporated under reduced pressure affording a residue (white oil) which was purified by flash chromatography using Hexane/EtOAc 70:30→40:60 as gradient which gave the title product as a colourless oil (563 mg, 81%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[O:1]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[CH2:4][CH2:3]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OC1CCN(c2nc(-c3ccccc3)nc3ccccc23)CC1
Reactant: Fc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OC2CCN(c3nc(-c4ccccc4)nc4ccccc34)CC2)cc1

Procedure:
Equimolar quantities of 4-(4-hydroxypiperidinyl-2-phenylquinazoline, sodium hydride, and fluorobenzene are heated in dimethylformamide to prepare the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[CH:42][CH:41]=3)[C:23]2=[CH:22][N:21]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc(N5CCN(C)CC5)cc4)n[nH]c3n2)c1F

Procedure:
This compound was prepared as a TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine. LCMS (M+H)+=467.0.
Reaction SMILES: [NH2:1][C:2]1[N:3](CC2C=CC=CC=2)[C:4](=[O:11])[C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc2cc[nH]c2c(=O)n1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1nc2cc[nH]c2c(=O)[nH]1
Temperature: 75 °C
Yield: 103.2 %

Procedure:
To a mixture of 2-amino-3-benzyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (10 g, 0.04 mol) in MeOH (334 mL) was added 10% Pd/C (2 g), ammonium formate (13.2 g, 0.21 mmol) and heated at 75° C. for 4 h. After completion of the reaction, the reaction mixture was cooled and filtered through a pad of Celite with hot 1:1 DMF/MeOH. The filtrate was concentrated in vacuo to provide the product as an off-white solid (6.2 g, 99%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH3:19])([CH3:18])[C:12](=[O:17])[N:13]2[CH3:16])=[CH:9][C:8]=1[NH:20][C:21]([C:23]1[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[N:25]([CH3:31])[CH:24]=1)=O)[CH3:5]>C(O)(=O)C>[CH3:31][N:25]1[C:26](=[O:30])[C:27]([CH3:29])=[CH:28][C:23]([C:21]2[N:6]([C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[C:7]3[C:8]([N:20]=2)=[CH:9][C:10]2[C:11]([CH3:19])([CH3:18])[C:12](=[O:17])[N:13]([CH3:16])[C:14]=2[CH:15]=3)=[CH:24]1
Reactant: COC[C@H](C)Nc1cc2c(cc1NC(=O)c1cc(C)c(=O)n(C)c1)C(C)(C)C(=O)N2C
Solvent: CC(=O)O
Product: COC[C@H](C)n1c(-c2cc(C)c(=O)n(C)c2)nc2cc3c(cc21)N(C)C(=O)C3(C)C
Temperature: 150 °C
Reaction time: 1 h

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid [6-((S)-2-methoxy-1-methyl-ethylamino)-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl]-amide I-1′ (110 mg; 0.26 mmol) is dissolved in 2 ml acetic acid and stirred at 150° C. for 1 h. The solvent is evaporated and the crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](CO)Cc1ccccc1
Yield: 22 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with D-phenylalaninol to provide the title compound in 22% yield as yellow needles (recrystallization from EtOH).