Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H].CO.[C:17](OCC)(=O)C>[Pd]>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([O:8][CH3:17])=[O:7]
Reactant: CCOC(C)=O
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccccc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccccc1F

Procedure:
In a Parr® hydrogenation vessel is placed 2-fluorocinnamic acid (1h) (1.0 equiv) and palladium on carbon in a 1/1 methanol/ethyl acetate solution. The heterogeneous solution is placed on a Parr® shaker and treated with hydrogen (50 psi) until uptake has ceased. The mixture is filtered through Celite® and concentrated under reduced pressure. The residue is taken up in diethyl ether and is treated with diazomethane until the yellow color persists. The solution is concentrated under reduced pressure giving the crude methyl ester. Purification is effected by column chromatography on silica gel (hexane/ethyl acetate 5/1) to yield Methyl 3-(2-fluorophenyl)propionate (1i) in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:20]O>>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:20])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Reaction time: 18 h

Procedure:
To a mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (5 g, 21.3 mmol) in anhydrous methanol (100 mL) was added concentrated sulfuric acid (0.5 mL). The resulting solution was stirred for 18 h at reflux. Upon cooling, the mixture was concentrated under reduced pressure, dissolved in CH2Cl2 and washed with NaHCO3 solution and brine. The organic phase was dried over sodium sulfate and concentrated to afford methyl 2-chloro-4-(methylsulfonyl)benzoate as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[O-:10][C:11]#[N:12].[Na+]>C(O)(=O)C.O>[CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]([NH2:12])=[O:10])=[CH:5][CH:4]=1
Reactant: CSc1ccc(N)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(NC(N)=O)cc1
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of 30 g (170 mmol) of 4-(methylmercapto)aniline dissolved in 83 ml of acetic acid and 165 ml of water was heated to 40° C. Once warmed to 40° C. a solution of sodium cyanate (22.2 g; 340 mmol) in 150 ml of water was slowly added. The resulting suspension was stirred for 15 minutes and then allowed to sit for 2 hours. Filtration of the suspension provided 29.98 g of title compound. m.p. 155°-159° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12]Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=S(CCCCl)c1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCS(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 3-chloropropyl 4-fluorophenyl sulfoxide and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.64 (m, 2H), 7.53 (s, 1H), 7.24 (m, 5H), 6.94 (d, 1H, J=7.7 Hz), 2.89 (m, 4H), 2.45 (m, 4H ), 1.99 (m, 3H), 1.77 (m, 5H), 1.24 (d, 6H, J=6.8 Hz); Anal. Calcd for C24H31FN2O2S+0.6EtOAc: C, 65.5; H, 7.45; N, 5.79. Found: C, 65.4; H, 7.30; N, 5.73; ESMS m/e: 431.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[C:9](S(C)(=O)=O)[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(O)(CC)(C)C>[Cl:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[C:9]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1nc(Nc2ccc(C(F)(F)F)cc2)c2nc(Cc3c(Cl)cccc3Cl)sc2n1
Solvent: CCC(C)(C)O
Product: FC(F)(F)c1ccc(Nc2nc(N3CCOCC3)nc3sc(Cc4c(Cl)cccc4Cl)nc23)cc1
Temperature: 130 °C
Reaction time: 12 h
Yield: 68.5 %

Procedure:
To a mixture of [2-(2,6-dichloro-benzyl)-5-methanesulfonyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (49 mg, 0.1 mmol) in tert-amyl alcohol (2 mL) was added morpholine (24 mg, 0.3 mmol). The resulting mixture was heated to 130° C. in a sealed tube. After 12 h, the solution was cooled and purified by preparative reverse-phase HPLC to afford the title compound as a colorless solid (37 mg, 77%). MS (ESI): mass calcd. for C23H18Cl2F3N5OS, 539.0; m/z found, 540.0 [M+H]+. 1H NMR ((CD3)2SO): 10.14 (s, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.49-7.42 (m, 1H), 4.69 (s, 2H), 3.66 (s, 8H).
Reaction SMILES: [OH:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C:12](=[O:25])[N:6]2[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[N+](=[CH2:28])=[N-]>O1CCOCC1.CCOCC>[CH3:28][O:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C:12](=[O:25])[N:6]2[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)C1=C(O)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C1=C(OC)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-oxo-7-phthalimidocephem-4-carboxylate (b) thus prepared by above methods is dissolved in dioxane, mixed with a solution of diazomethane in ether, and stirred for 1 hour at room temperature. The reaction mixture is evaporated under reduced pressure to give methyl 3-methoxy-7-phthalimido-3-cephem-4-carboxylate in nearly quantitative yield. Recrystallization from a mixture of acetone and ether gives pure crystals, m.p. 225°-227° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 3 tR=1.106 min, m/z=460.2; 1H NMR (CD3OD) 1.54 (m, 3H), 1.95 (m, 1H), 2.16-2.29 (m, 4H), 2.40 (m, 2H), 2.44 (m, 1H), 3.10 (m, 1H), 3.99 (s, 3H), 5.56 (m, 1H), 6.94 (m, 1H), 7.03 (m, 2H), 7.28-7.39 (m, 8H), 7.93 (m, 1H), 8.28 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([CH:11]2[CH2:13][CH2:12]2)[N:3]=1.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:7])=[C:4]([CH:11]2[CH2:13][CH2:12]2)[N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1C1CC1
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1C1CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 79 %

Procedure:
A solution of 6-chloro-2-cyclopropylnicotinoyl chloride (PATENT WO2005/080342) (0.216 g, 1 mmol) in DCM (2.5 mL) was added drop wise to a stirred solution of cyclohexylamine (0.171 mL, 1.50 mmol) and N-ethyldiisopropylamine (0.606 mL, 3.50 mmol) in THF (5 mL) at 20° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (10 mL) and washed sequentially with 2M HCl (10 mL), saturated NaHCO3 (10 mL), and saturated brine (10 mL). The organic layer was collected from a phase separation cartridge (15 ml) and evaporated to afford crude product. This was triturated with Et2O to give a solid that was collected by filtration and dried under vacuum to give 6-chloro-N-cyclohexyl-2-cyclopropylnicotinamide (79%) as a white solid.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]3[C:18]([C:19]#N)=[CH:17][N:16]=[C:15]4[NH:21][CH:22]=[CH:23][C:14]=34)[CH2:3]1)[CH2:9]2.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl.[O:42]1CCCC1>>[OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]3[C:18]([CH:19]=[O:42])=[CH:17][N:16]=[C:15]4[NH:21][CH:22]=[CH:23][C:14]=34)[CH2:3]1)[CH2:9]2
Reactant: N#Cc1cnc2[nH]ccc2c1NC1C2CC3CC1CC(O)(C3)C2
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1cnc2[nH]ccc2c1NC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[(5-hydroxyadamantan-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (150 mg) in tetrahydrofuran (3 ml) was added 1.01M diisobutylaluminum hydride/toluene solution (1.93 ml) at 778° C. The reaction solution was stirred for 18 hours under ambient temperature. To the reaction solution was added 1M hydrochloric acid under ice cooling, and the mixture was stirred for 30 minutes. The mixture was extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 4-[(5-hydroxyadamantan-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (100 mg) as a pale yellow amorphous substance.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].[C:18]([C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH:26]([C:31](O)=[O:32])[CH2:25][CH2:24][C:23]=2[N:22]=1)(=[O:20])[CH3:19].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCCC1=O.C(N(CC)C(C)C)(C)C>CCOC(C)=O>[C:18]([C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH:26]([C:31]([NH:2][C@@H:3]([C:5]3[CH:6]=[C:7]([CH3:17])[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:10]=3[F:11])[CH3:4])=[O:32])[CH2:25][CH2:24][C:23]=2[N:22]=1)(=[O:20])[CH3:19]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: CC(=O)c1ccc2c(n1)CCC(C(=O)O)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc2c(n1)CCC(C(=O)N[C@H](C)c1cc(C)c(NS(C)(=O)=O)cc1F)C2
Temperature: 60 °C
Yield: 91.7 %

Procedure:
To a mixture of N-[4-((R)-1-Aminoethyl)-5-fluoro-2-methylphenyl]methanesulfonamide hydrochloride (55.3 mg, 0.195 mmol), 2-acetyl-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (45 mg, 0.20 mmol) and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (110 mg, 0.29 mmol) in N-Methylpyrrolidinone (192 uL, 1.99 mmol), N,N-Diisopropylethylamine (0.10 mL, 0.59 mmol) was added and the reaction was heated at 60° C. 4 h. The crude was diluted with EtOAc and washed with 1N HCl, 1M NaHCO3 and brine. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford the title product (80 mg, 90%) as a brown oil that was used without further purification into the next step. m/z=448.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([O:17][CH3:16])=[C:19]([N:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)[CH:20]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)c2ccccc12
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)Cc2ccc(Br)c3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 4-bromonaphth-1-ylacetic acid (J. Org. Chem., 1951, 16, 1588) and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) following a similar procedure to Example 1.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C(=O)=O.CC(C)=O.[Li]CCCC.[Si:22]([O:39][CH2:40]C(Cl)=O)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C1COCC1.C(OCC)C>[Si:22]([O:39][CH2:40][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])([C:35]([CH3:36])([CH3:37])[CH3:38])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](OCC(=O)Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOC(=O)CC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
To a 1-L round-bottom flask equipped with a magnetic stir-bar, addition funnel, low temperature thermometer with thermometer adapter and a N2inlet was added monoethyl malonate (14.53g, 0.11moles, 2eq) in dry THF (150ml, 0.73M) and 20mg of 2,2′-dipyridyl. After cooling the reaction mixture to −78° C. (dry ice/acetone), n-BuLi (2.5M in Hexanes, 88ml, 0.22moles, 4eq) was added at a rate to maintain the internal temperature below −10° C. Once the addition was complete the reaction was allowed to warm to −10° C. by removal of the cold bath. The reaction remained a light pink color; this designates that there was ample amount of n-BuLi to deprotonate the monoethyl malonate. (If the color had turned yellow the reaction would have had to have been re-cooled to −78° C. and additional n-BuLi would have had to have been added followed be re-warming to −10° C.) At this point the reaction mixture was cooled to −78° C. followed by the dropwise addition of neat {[tert-Butyl(diphenyl)silyl]oxy}acetyl chloride (18g, 54mmoles, 1eq) over a period of 15minutes maintaining the internal reaction temperature below 60° C. This was allowed to stir at −78° C. for 10minutes at which point the reaction was transferred to a separatory funnel containing diethyl ether (900ml) and 1N HCl (450ml). This was agitated and vented until further gas evolution ceased after which the phases were separated and the organic phase washed with saturated sodium bicarbonate, brine and dried over Na2SO4. This was then filtered, concentrated in vacuo and purified by silica gel chromatography (5% EtOAc/Hexanes to 20% EtOAc/Hexanes) to yield 12.2g (60%) of product.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O1CCOCC1.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>Cl.O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH2:16][C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])[OH:2]
Reactant: CC(=O)c1ccccc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(Cc1c(O)cccc1O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 550 g. of resorcinol in 1 l. of dioxane were added 600 g. of acetophenone and 0.5 ml. of 35% conc. hydrochloric acid as a catalyst. The resulting mixture was heated with stirring for 3 hours and then poured into 5 l. of a cold water to give a pale brown powdery resin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[C:44]1([C:50]2([C:56]([OH:58])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:53]3[CH2:52][CH2:51][C:50]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:56]([OH:58])=[O:57])[CH2:55][CH2:54]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: NC(=O)N1CCCC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid pyrrolidine-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.C(O)(=O)C.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1C=CC=CC=1>[C:23]([C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:1][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1cc(C(=O)OCC)c(=O)n2ccccc12)C(=O)OCC
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A 100 ml round-bottom flask equipped with a Dean-Stark trap was charged with 50 ml benzene, ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (8) (1.22 g, 5 mmol), acetic acid (5 g, 83 mmol), NH4OAc (5 g, 65 mmol), and diethyl malonate (2.3 g, 9 mmol). The reaction mixture was refluxed for 48 h. The reaction mixture was cooled to room temperature and washed three times with 50 ml water. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (ethyl acetate) to yield ethyl 1-(2,2-dicarboethoxyvinyl)-4-oxo-4H-quinolizine-3-carboxylate (12) as a yellow powder (1.58 g, 82%). M.p. 149-151° C. 1H NMR (δ, CDCl3): 1.31 (t, J=7 Hz, 3H), 1.36 (t, J=7 Hz, 3H), 1.42 (t, J=7 Hz, 3H), 4.34 (q, J=7 Hz, 2H), 4.36 (q, J=7 Hz, 2H), 4.41 (q, J=7 Hz, 2H), 7.34 (dd, J=7 Hz, J=7 Hz, 1H), 7.82 (dd, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 8.05 (s, 1H), 8.60 (s, 1H), 9.50 (d, J=7 Hz). MS: m/z 387.1331; required for C20H21NO7: 387.1318.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:36]2\[C:37](=[O:51])[N:38](C(=O)C)[C:39]3[C:44]\2=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)/[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3C(=O)C4=CC=CC=C4C3=O)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:36]2\[C:37](=[O:51])[NH:38][C:39]3[C:44]\2=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)/[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N1C(=O)/C(=C(\Nc2ccc(CNC(=O)OC(C)(C)C)cc2)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(CN)cc2)cc1

Procedure:
Prepared analogously to Example 139b from (Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone and hydrazine hydrate solution in ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[N:9]=[C:10]([I:11])[C:3]=12.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[I:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])[N:8]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:14][CH2:13]2)[N:9]=1
Reactant: Nc1ncnc2c1c(I)nn2C1CCC(=O)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A mixture of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-cyclohexanone (Intermediate AK) (1.32 g, 0.0037 mol), N-methylpiperazine (1.11 g, 0.011 mol) and acetic acid (0.66 g, 0.011 mol) in 1,2-dichloroethane (50 mL) was stirred for 10 min at 40° C. and sodium triacetoxyborohydride (1.09 g, 0.0052 mol) was added at once. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 24 hours and sodium triacetoxyborohydride (0.25 g, 0.0012 mol) was added. The mixture was stirred for another 48 hours , the solvent removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate solution (80 mL) and chloroform (50 mL). The organic layer was separated and the aqueous layer further extracted with chloroform (3×50 mL). The combined organic extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to yield a yellow oil. The compound was further purified by flash chromatography on silica gel using dichloromethane/triethylamine/methanol (88:11:1) as a mobile phase to yield cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.93 g, 0.0021 mol): 1H NMR (DMSO-d6, 400 MHz) 8.18 (s, 1H), 4.71 (m, 1H), 2.38-1.9 (m, 13H), 2.17 (s, 3H), 1.63-1.5 (m, 4H); TLC (dichloromethane/triethylamine=9:1) Rf 0.24 and trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.38 g, 0.00086 mol): 1H NMR (DMSO-d6, 400 MHz) 8.18 (s, 1H), 4.55 (m, 1H), 2.38-1.9 (m, 15H), 2.15 (s, 3H), 1.42 (m, 2H); TLC (dichloromethane/triethylamine=9:1) Rf 0.11.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([F:28])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(Cl)Cl>[F:28][C:20]1[CH:19]=[C:18]([CH:10]2[CH2:9][CH:8]([C:6]3[O:7][NH:32][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])[CH:23]=[CH:22][C:21]=1[C:24]([F:27])([F:26])[F:25]
Reactant: NO
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1c1ccc(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (2.19 g, 5.22 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.219 g, 5.48 mmol) dissolved in water (2.000 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.336 mL, 5.48 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (27.0 mL, 161.89 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.670 g, 33.0%) was yielded as a colorless solid. 1H NMR (400 MHz, cdcl3) δ 1.82-1.93 (m, 1H), 2.12-2.44 (m, 3H), 3.04-3.16 (m, 1H), 3.35-3.46 (m, 1H), 3.69 (s, 3H), 4.11-4.21 (m, 1H), 5.09-5.18 (m, 1H), 5.56 (s, 1H), 6.97-7.09 (m, 2H), 7.52 (t, 1H). MS m/z 387 (M−H)−