Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:36][CH2:37][S:38][C:39]2[N:40]=[N:41][NH:42][CH:43]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:50](Cl)([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl.P(Cl)(Cl)(Cl)(Cl)Cl.C(O)CC(O)C>ClCCl.O>[C:8]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:36][CH:37]([C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[S:38][C:39]2[N:40]=[N:41][NH:42][CH:43]=2)=[O:16])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCSc3c[nH]nn3)CS[C@H]12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(O)CCO
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 7β-phenylacetamido-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (10.0 g: 15.9 mMol.) in dichloromethane (100 ml) under ice cooling are added pyridine (1.54 ml: 19.1 mMol.) and trityl chloride (5.32 g: 19.1 mMol.), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is mixed with 10% hydrochloric acid (2 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated. To a solution of the residue in dichloromethane (50 ml) under ice cooling are added pyridine (2.57 ml: 31.8 mMol.) and phosphorus pentachloride (5.96 g: 28.6 mMol.), and the mixture is stirred for 30 minutes. The reaction mixture is added dropwise to a solution of 1.3-butanediol (8.6 ml: 95.9 mMol.) in dichloromethane (25 ml) at -30° C., and the mixture is stirred at - 20° to -30° C. for 10 minutes and under ice cooling for 40 minutes. The reaction mixture is mixed with water, diluted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated. The residue is pulverized with ether, washed with ether, dissolved in dichloromethane, washed with 5% aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=2:1) to give 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (6.70 g: pale yellow foam, Yield: 56%,
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:16]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])=[N:17][CH:18]=[CH:19][N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH:12][C:22](=[O:23])[C:21]([C:16]2[C:15]([Cl:14])=[N:20][CH:19]=[CH:18][N:17]=2)([CH3:26])[CH3:25])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](NC(=O)C(C)(C)c2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottomed flask was added tert-butyl(cis-3-aminocyclobutyl)carbamate (0.4903 g, 2.63 mmol), 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (Intermediate 29, 0.634 g, 3.16 mmol), HATU (1.301 g, 3.42 mmol, GenScript Corp), and triethylamine (1.465 ml, 10.53 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (5.26 ml) to stir at room temperature for 24 h. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.8210 g, 2.226 mmol, 85% yield). LCMS showed product peak at 1.86 min (m+1=313.0, product-tbutyl group). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 7 H) 1.49 (s, 5 H) 1.82 (qd, J=9.00, 2.35 Hz, 2 H) 2.34-2.47 (m, 2 H) 2.69 (s, 3 H) 3.48-3.65 (m, 1 H) 3.72-3.87 (m, 1 H) 7.04 (d, J=6.85 Hz, 1 H) 7.63 (d, J=6.46 Hz, 1 H) 8.42 (d, J=2.54 Hz, 1 H) 8.65 (d, J=2.35 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][NH:9][C:10]([C@@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][N:13]1[C:14](=[O:28])[N:15]2[O:20]CC1C=CC=CC=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][NH:9][C:10]([C@@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][N:13]1[C:14](=[O:28])[N:15]2[OH:20])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 89.4 %

Procedure:
To a solution of tert-butyl[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetate 89 (0.23 g, 0.57 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetate 90 (0.16 g. 89%) as a clear thick oil.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH3:16])=[O:14])[C@@H:9]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[F:25])[CH2:8]2)[O:4][NH:3]1.[O:26]=[C:27]1[CH:31]=[C:30]([C@@H:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH3:41])=[O:39])[C@@H:34]([C:42]3[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=3[F:50])[CH2:33]2)[O:29][NH:28]1.CCCCCCC.CC(O)C>C(#N)C>[O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH3:16])=[O:14])[C@@H:9]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[F:25])[CH2:8]2)[O:4][NH:3]1.[O:26]=[C:27]1[CH:31]=[C:30]([C@H:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH3:41])=[O:39])[C@H:34]([C:42]3[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=3[F:50])[CH2:33]2)[O:29][NH:28]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)cc1F
Agent: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)cc1F
Solvent: CC(C)O
Solvent: CC#N
Solvent: CCCCCCC
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1c1cc(F)c(F)cc1F
Yield: 20 %

Procedure:
The mixture of cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)-piperidine-1-carboxylate and trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (1.027 g, 2.88 mmol) was subjected to chiral preparative HPLC (Column: CelluCoat (250×20), 5 μm particle size, mobile phase: Heptane/IPA 80/20, flow rate 18 mL/min) to yield (2R,4S)-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (259 mg, 25%), Chiral purity A % 99.9, Optical rotation [α]D20=+50.3 (acetonitrile, c=1), and (2S,4S)-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (203 mg, 20%), Chiral purity A %: 99.9, Optical rotation [α]D20=+4.5 (acetonitrile, c=1)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]=1[C:20]1[O:21][CH:22]=[CH:23][N:24]=1.[CH3:25][N:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[N:27]1>>[O:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:4]1[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31]([C:29]1[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=1)=[O:32])=[CH:10][CH:9]=[CH:8][N:7]=2
Reactant: Cn1cc(C(=O)O)cn1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Product: Cn1cc(C(=O)NCc2c(-c3ncco3)n(-c3ccccc3)c3ncccc3c2=O)cn1

Procedure:
Methyl-1H-pyrazole-4-carboxylic acid (2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridin-3-ylmethyl)-amide was prepared starting from intermediate B and 1-methyl-1H-pyrazole-4-carboxylic acid. MS calcd. for C23H19N6O3 [(M+H)+] 427.1, obsd. 427.2.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][CH2:6][C:5](=[O:8])[N:4]1[CH2:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:15][C:16]([C:21]([O:23]C)=[O:22])=[N:17]2)=[CH:12][CH:11]=1>C(O)(=O)C>[O:8]=[C:5]1[CH2:6][CH2:7][C:3](=[O:2])[N:4]1[CH2:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[CH:15][C:16]([C:21]([OH:23])=[O:22])=[N:17]2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)c(F)c2n1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)c(F)c2n1
Temperature: 120 °C
Yield: 85 %

Procedure:
6M HCl (2964 μl) was added to a solution of methyl 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate 7-11 (629 mg, 1.482 mmol) in Acetic Acid (2964 μl) and the reaction heated at 120° C. for 10 min in the microwave. The reaction was quenched with KH2PO4 (saturated) and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylic acid 7-12 (499 mg, 85% yield) as a white solid, 100% pure by LCMS, LRMS m/z (M+11)+ 397.2 found, 397.1 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[CH:5][CH:4]=1.B>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)NCCCN2CCCCC2)cc1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(CNCCCN2CCCCC2)cc1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
To a solution of 4-methoxy-N-(3-piperidin-1-ylpropyl)benzamide (1.9 g, 6.9 mmol) in THF (15 mL) was added borane*THF (1M in THF, 10 mL, 10 mmol) and the reaction mixture heated at reflux temperature for 18 h. The solution was cooled to room temperature and quenched with 4N HCl/dioxane (2 mL). The product mixture was washed with diethyl ether (2×50 mL) and basified with 40% (w/w) KOH (aq.). The aqueous layer was extracted with dichloromethane (3×50 mL) and the organic phase dried (Na2SO4) and concentrated in vacuo. The resultant oil was purified by chromatography on silica gel with methanol:dichloromethane (1:9, v/v) as eluent to afford N-(4-methoxybenzyl)-3-piperidin-1-ylpropan-1-amine (INTERMEDIATE IX.1) (400 mg, 1.5 mmol, 22%).
Reaction SMILES: Cl.[C:2]([OH:10])(=[O:9])[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19].Cl>O.ClCCl>[CH2:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][C:3]([C:2]([OH:10])=[O:9])=[CH:4][CH2:5]1)=[O:19])[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)C1=CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)N1CC=C(C(=O)O)CC1
Reaction time: 5 h
Yield: 102.4 %

Procedure:
1,2,5,6-Tetrahydroisonicotinic acid hydrochloride (150 g, 0.92 mol) is added to an aqueous solution of sodium carbonate (194 g, 1.83 mol) in water (920 ml), and thereto is added dropwise 2-propenyl chloroformate (116 g, 0.96 mol) under ice-cooling over a period of one hour. After the addition, the mixture is further stirred under icecooling for five hours. Separately, conc. hydrochloric acid (191 g) and dichloromethane (1000 ml) are cooled, and thereto is added dropwise the above reaction mixture in portions. The mixture is separated, and the aqueous layer is extracted twice with dichloromethane. The organic layers are combined, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent to give 1-(2-propenyloxycarbonyl)-1,2,5,6-tetrahydro-isonicotinic acid (198.9 g, quant.) as a white solid.
Reaction SMILES: N1C=C(CCN)N=C1.[CH:9]1[N:13]=[CH:12][N:11]([C:14]([N:16]2C=N[CH:18]=[CH:17]2)=[O:15])[CH:10]=1>CN(C=O)C>[CH:9]1[N:13]=[CH:12][N:11]2[C:10]=1[CH2:18][CH2:17][NH:16][C:14]2=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: NCCc1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C1NCCc2cncn21
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 2-(1H-imidazol-4-yl)ethanamine (26.8 g; 240.9 mmol; 1 eq) and CDI (39.1 g; 240.9 mmol; 1 eq) in DMF (401.7 ml) is stirred at 50° C. for two days. The mixture is concentrated to 100 ml and acetonitrile (200 ml) is added. The resulting precipitate is filtered, washed with acetonitrile (2×50 ml) and dried under vacuum, affording the title compound that is used in the next step without further purification (28.3 g; 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:10][OH:11])[CH:5]=[C:6]([I:8])[CH:7]=1.[ClH:20].O1CCOCC1>C(Cl)Cl>[ClH:20].[NH2:12][C@@H:9]([C:4]1[CH:5]=[C:6]([I:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cc(F)cc(I)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H](CO)c1cc(F)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-butyl (1-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)carbamate (2.507 g, 6.58 mmol) was dissolved in DCM (60 mL) and treated with 4 N HCl in dioxane (4.93 mL, 19.73 mmol). The mixture was stirred overnight at room temperature. After the majority of the solvent was evaporated carefully in vacuo, the slurry was triturated with Et2O to afford 1.525 g of a fine white HCl salt of (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethanol (72%), which was isolated by suction filtration. LCMS (m/z): 282.4 (MH+), 0.46 min.
Reaction SMILES: [CH2:1]1[C@@:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[C:17]2=[O:27])=[CH:12][CH:11]=1.Br[CH2:29][CH2:30][CH2:31][F:32]>>[F:32][CH2:31][CH2:30][CH2:29][N:7]1[CH2:8][CH2:9][C@@:5]2([CH2:1][N:2]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=5)[C:17]4=[O:27])=[CH:12][CH:11]=3)[CH2:3][CH2:4]2)[CH2:6]1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@]3(CCNC3)C2)cc1
Reactant: FCCCBr
Product: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@]3(CCN(CCCF)C3)C2)cc1

Procedure:
According to Method X, 2-[(S)-4-(2,7-diaza-spiro[4.4]non-2-yl)-phenyl]-6-hydroxy-2H-isoquinolin-1-one was reacted with 1-bromo-3-fluoro-propane. In this way the product was obtained with molecular weight 421.52 (C25H28FN3O2); MS (ESI): 422 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C@@H:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH:22]=2)=[CH:12][CH:11]=1)(C)(C)C.[ClH:45].C(O)C>ClCCl>[ClH:45].[ClH:45].[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C@@H:28]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:29][CH2:30][N:31]([CH:32]([CH3:33])[CH3:34])[CH:35]([CH3:37])[CH3:36])[CH:22]=2)=[CH:14][CH:15]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1O)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCN)cc2)ccc1O)C(C)C
Reaction time: 72 h

Procedure:
tert-butyl{2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}carbamate (Preparation 12, 450 mg, 0.75 mmol) was dissolved in dichloromethane (10 ml), hydrogen chloride (2M in diethyl ether, 6 ml, 12 mmol) was added followed by ethanol (1 ml). After 3 days, solvents removed in vacuo to furnish the title compound as a yellow foam, 420 mg.
Reaction SMILES: [ClH:1].C(O)C.C([N:12]1[CH2:19][C:16]2([CH2:18][CH2:17]2)[N:15]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[ClH:1].[F:24][C:21]([F:22])([F:23])[C:20]([N:15]1[CH2:14][CH2:13][NH:12][CH2:19][C:16]21[CH2:18][CH2:17]2)=[O:25]
Reactant: [H][H]
Reactant: O=C(N1CCN(Cc2ccccc2)CC12CC2)C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(N1CCNCC12CC2)C(F)(F)F
Yield: 82.6 %

Procedure:
1 N Hydrochloric acid-ethanol (105 ml, 105 mmol) and 5% palladium carbon (3 g) were added to an ethanol (250 ml) solution of the compound (15.5 g, 51 mmol) obtained in Step 4 above and contact reduction was performed for 15 hours in a hydrogen atmosphere. The catalyst was filtrated through celite, then the filtrate was concentrated under reduced pressure, an ethanol-diethyl ether mixed solvent was added to the resulting residue, and the precipitated solid was collected by filtration to give the title compound (10.3 g, 83%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][CH:14]=[C:13]([CH3:17])[C:12]2=[O:18])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN1CCCC1=O>[CH2:30]([O:18][C:12]1[C:11]2[C:16](=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:2]=3[Cl:1])[CH:8]=[CH:9][CH:10]=2)[N:15]=[CH:14][C:13]=1[CH3:17])[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCC=Cc1ccccc1
Reactant: Cc1c[nH]c2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1OCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
To a suspension of 8-(2,6-dichlorobenzoylamino)-1,4-dihydro-3-methyl-4-oxoquinoline (130 mg), potassium carbonate (155 mg) and N-methylpyrrolidone (3 ml) was added cinnamyl bromide (81.2 mg), and the mixture was stirred for 2.5 hours at ambient temperature. The mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from ethanol to give 4-cinnamyloxy-8-(2,6-dichlorobenzoylamino)-3-methylquinoline (125 mg) as white crystal.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:18])[NH:11][C:12]=2[CH2:13]CCCN)=[CH:4][CH:3]=1.ClC1[N:25]=[CH:24][C:23](C2N=C(C)NC=2CCCCN2C(=O)C3C(=CC=CC=3)C2=O)=[CH:22]C=1.NN>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:18][CH2:22][CH2:23][CH2:24][NH2:25])[NH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)nc2)c(CCCCN)[nH]1
Reactant: Cc1nc(-c2ccc(Cl)nc2)c(CCCCN2C(=O)c3ccccc3C2=O)[nH]1
Agent: NN
Solvent: CCO
Product: Cc1[nH]c(CCCCN)nc1-c1ccc(Cl)nc1
Temperature: 80 °C
Yield: 75 %

Procedure:
4-[4-(6-chloro(3-pyridyl))-2-methylimidazolyl]butylamine. To a solution of 2-{4-[4-(6-chloro(3-pyridyl))-2-methylimidazolyl]butyl}-isoindole-1,3-dione (1.0 g, 2.54 mmoles) in ethanol (25 ml) was added hydrazine (0.24 ml, 7.6 mmoles). After heating the reaction mixture in a 80° C. oil bath for 3 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (100 ml) and was washed with 1M NaOH (15 ml). The aqueous layer was extracted further with dichloromethane (2×100 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-chloro(3-pyridyl))-5-methylimidazolyl]butylamine (500 mg, 75%). MH+(265).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:25])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]([OH:7])[CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:25])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CCC(N2Cc3ccccc3NC2=O)CC1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2ccccc2CN1C1CCN(CC(O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
In this example, 2.70 g of 1-(4-chlorobenzoylmethyl)-4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine and 150 ml of methanol are mixed and stirred at room temperature. To the stirred mixture, 2.0 g of sodium borohydride is added over a period of 5 hours. Then, the resultant mixture is stirred overnight at room temperature. The white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 2.07 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 1.59 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>ClCCl.C(OCC)(=O)C>[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
To a solution of 4-fluoroaniline (0.2 g) in dichloromethane (10 ml) were added in turn pyridine (0.19 ml) and diphenylcarbamoyl chloride (0.417 g) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 10 hours, and to the mixture was added N,N-dimethylaminopyridine (0.22 g), and the mixture was allowed to stir for another 1 hour. The reaction mixture was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give N,N-diphenyl-N′-4-fluorophenylurea (0.384 g).
Reaction SMILES: [O:1]=[C:2]([P:5](=[O:10])([O:8]C)[O:6][CH3:7])[CH2:3][CH3:4].[I-].[Na+:12]>CC(CC)=O>[O:1]=[C:2]([P:5](=[O:8])([O-:10])[O:6][CH3:7])[CH2:3][CH3:4].[Na+:12]
Reactant: CCC(=O)P(=O)(OC)OC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCC(=O)P(=O)([O-])OC

Procedure:
Dimethyl (1-oxopropyl)phosphonate (10.0 g, 0.060 mol) and sodium iodide (9.0 g, 0.060 mol) were dissolved in ethyl methyl ketone (160 ml) and the solution stirred and refluxed for 16 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)C(OC(C)(C)C)=O)[CH3:2]>CC(O)=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:14]=1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(Br)cc(OCc2ccccc2)c1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(Br)cc(OCc2ccccc2)c1
Yield: 97 %

Procedure:
2-(3-Benzyloxy-5-bromophenyl)malonic acid tert-butyl ester ethyl ester (7.2 g, contains 1.4 equivalent malonic acid tert-butyl ester ethyl ester, 10 mmol) was dissolved in glacial AcOH (50 ml) and heated to reflux for 12 h. The AcOH was removed under reduced pressure. The residue was poured into Na2CO3 solution (sat aq) and the mixture was extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure to give (3-benzyloxy-5-bromo-phenyl-)acetic acid ethyl ester (6.8 g, 9.7 mmol) as a yellow liquid in 97% yield. 1H NMR (CDCl3) δ 7.44-7.30 (m, 5H), 7.07-7.03 (m, 2H), 6.87-6.84 (m, 1H), 5.03 (s, 2H), 4.15 (q, 2H), 3.54 (s, 2H), 1.26 (t, 3H).