Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Mg]Cl>C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].C1COCC1>[C:10]1([CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[Mg]Cl
Reactant: COc1ccc(Cl)cc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Solvent: C1=CCCC=CCC1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
In a drybox, 50 mg (0.303 mmol) of (Me3C)2PH(O) from Experiment 2, 83.4 mg (0.303 mmol) of Ni(COD)2 (COD=1,5-cyclooctadiene) and 5.0 mL of THF were loaded into a reactor (100 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature over 10 min. Next, 1.43 g (10.0 mmol) of 4-chloroanisole was added into the mixture above, followed by adding 15 mL (15.0 mmol, 1.0 M solution in THF) of o-tolylmagnesium chloride, and 15 mL of THF into the reactor. The resulting mixture was stirred at room temperature for 15 h. before the reaction mixture was quenched with 10 mL of H2O. The mixture above was extracted with 3×50 mL of diethyl ether. The combined ether extracts were dried over mgSO4, filtered, and the ether and THF removed from the filtrate by rotary evaporation. The resulting residues were chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 1.85 g (93% yield) of 4-o-tolylanisole. It was >95% pure by 1H NMR. 1H NMR (500 MHz, CDCl3): δ7.47-7.19 (m, 8H), 4.03 (s, 3H), 2.53 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ158.5, 141.5, 135.3, 134.3, 130.2, 130.1, 129.8, 126.8, 125.7, 113.4, 55.0, 20.4. ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12]([NH:14][CH:15]1[CH:23]=[CH:22][CH2:21][CH:20]2[CH:16]1[C:17](=O)[NH:18][C:19]2=O)=O)(C)(C)C.O.[OH-].[Na+]>O1CCCC1>[CH3:12][NH:14][CH:15]1[CH:23]=[CH:22][CH2:21][CH:20]2[CH:16]1[CH2:17][NH:18][CH2:19]2
Reactant: CC(C)(C)OC(=O)NC1C=CCC2C(=O)NC(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1C=CCC2CNCC21

Procedure:
Under nitrogen, 27.1 g (0.71 mol) of lithium aluminium hydride are introduced into 300 ml of absolute tetrahydrofuran, and a solution of 57 g (0.21 mol) of 4-(tert.-butyloxycarbonylamino)-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisoindole in 570 ml of absolute tetrahydrofuran is added dropwise. The mixture is then refluxed overnight. 27.1 g of water in 82 ml of tetrahydrofuran, 27.1 g of 10% strength sodium hydroxide solution and 81.3 g of water are then added dropwise to the cold batch. The salts are filtered off with suction and washed with tetrahydrofuran, and the filtrate is concentrated in vacuo. The residue is distilled off under a high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][CH:29]=2)=[O:27])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26]([C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=[CH:30][CH:29]=4)=[O:27])[CH2:21][CH2:20]3)[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=CC[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccnc2ccccc12
Reaction time: 8 h

Procedure:
4-(4-fluorobenzoyl)piperidine (trifluoro-acetic acid salt) (0.020 g, 0.062 mmol) was solved in 1,2-dichloromethane (0.300 mL) and Quinoline-4-carboxylic acid trans-[4-(2-oxo-ethyl)-cyclohexyl]-amide (0.020 g, 0.067 mmol) was added. Methanol (0.200 mL) was added to the mixture and it was stirred overnight. Sodium triacetoxyborohydride (0.024, 0.11 mmol) was added to the clear solution that was stirred 10 hours at room temperature. The mixture was concentrated to dryness and the residue was taken up on methanol and purified with preparative HPLC on reversed phase eluting with acetonitrile/water. The combined producted fractions were evaporated under reduced pressure to yield 0.03 g of a white solid (0.06 mmol, 99%). MS (m/e): 488.3 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 63.9 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 45 mmol), K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H20 and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140°-142° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:14])[C:3]([C:5]1[C:9]([NH2:10])=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1nn(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)c1nn(C)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid dimethylamide (100 mg, 0.5 mmol) in ethanol (4 ml) was flushed with argon and treated with Pd/C5% (40 mg, 0.02 mmol). The reaction vessel was evacuated and flushed with hydrogen three times and the reaction was stirred at ambient temperature overnight. The reaction mixture was filtrated and the solvent was evaporated to yield an off-white solid material (83 mg, 98%) which was used without further purification.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH3:5])[CH2:2]1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([Mg]Br)[CH:11]=[CH:12][CH:13]=1>C1COCC1.[Cu]I>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:2][CH:3]([OH:1])[CH2:4][CH3:5])[CH:11]=[CH:12][CH:13]=1
Reactant: CCC1CO1
Reactant: COc1cccc([Mg]Br)c1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC(O)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirred suspension of CuI (0.40 g, 2.08 mmol) in 3-methoxyphenylmagnesium bromide in THF (31.2 mL, 1.0M THF solution, 31.2 mmol) at −20° C. was slowly added a solution of 1,2-epoxybutane (1.50 g, 20.8 mmol) in THF (1 mL). The mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was cooled in an ice bath and quenched with saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate (3×70 mL). The combined organic phase was washed with 1 N NaOH, brine, dried (Na2SO4) filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (4:1) to give 3.50 g (94%) of compound (51) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.00 (t, J=7.4 Hz, 3H), 1.50-1.65 (m, 2H), 2.62 (dd, J1=13.5 Hz, J2=8.6 Hz, 1H), 2.82 (dd, J1=13.5 Hz, J2=4.1 Hz, 1H), 3.74-3.79 (m, 1H), 3.80 (s, 3H), 6.75-6.85 (m, 3H), 7.20-7.25 (m, 1H).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)[NH2:2].[CH3:15][C:16]([CH3:23])([CH3:22])[C:17](=O)[CH2:18][C:19]#[N:20].Cl>CCO>[NH2:20][C:19]1[N:1]([C:3]2[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=2)[N:2]=[C:17]([C:16]([CH3:23])([CH3:22])[CH3:15])[CH:18]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CCOC(=O)Cc1cccc(NN)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 91.9 %

Procedure:
A solution of ethyl (3-hydrazinophenyl)acetate (15 g, 65 mmol) and 4,4-dimethyl-3-oxopentanenitrile (12.5 g, 0.1 mol) in EtOH (100 mL) containing conc. HCl (25 mL) was heated at reflux overnight. After removal of the solvent, the residue was washed with Et2O to afford ethyl 2-(3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl)acetate (18 g). MS (ESI) m/z: 302 (M+H+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=O)=O.O1CCOC[CH2:27]1.ClCCl.C[Zn]C.C1(C)C=CC=CC=1>C(OCC)(=O)C.O>[Cl:16][C:10]1[C:9]([CH3:17])=[C:8]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:7]([CH3:27])=[C:12]([C:13](=[O:15])[CH3:14])[CH:11]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(-c2ccncc2)c1OS(=O)(=O)C(F)(F)F
Reactant: C1COCCO1
Agent: C[Zn]C
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(C)c(-c2ccncc2)c1C
Temperature: 70 °C
Yield: 69.3 %

Procedure:
A solution of 6-acetyl-4-chloro-3-methyl-2-pyridin-4-ylphenyl trifluoromethanesulfonate (0.40 g, 1.0 mmol) in 1,4-dioxane (10 mL, 130 mmol) was degassed with nitrogen and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (41 mg, 0.051 mmol). The reaction mixture was degassed with nitrogen for 5 minutes, treated with 2.0 M dimethylzinc in toluene (0.76 mL, 1.5 mmol), and heated at 70° C. for 1.5 hours. The reaction mixture was cooled to room temperature diluted with ethyl acetate and water and filtered over celite to remove solids. The ethyl acetate layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude brown gum. Purification by flash column chromatography using ethyl acetate in hexanes (0%-20%) gave the desired product (0.18 g, 69%). LCMS for C15H15ClNO (M+H)+: m/z=260.1. Found: 260.1.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCOC(C)=O>C1COCC1>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:27][CH2:26]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(CCCOc2ccc(NC=C3C(=O)Nc4ccccc43)cc2)CC1
Temperature: 50 °C

Procedure:
A solution of 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one (66 mg, 0.157 mmol) in 1 mL THF is treated with 1-methylpiperazine (37.2 μL, 2.2 equiv.) and the resulting reaction mixture is heated at 50° C. for 4 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is partitioned between EtOAc and H2O. The organic layer is collected and washed with saturated aqueous NaHCO3, brine, and dried over anhydrous Na2SO4. The yellow solid residue obtained upon evaporation is broken up in 1:9 EtOAc:hexane and collected by filtration to give the named compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[N+:13]([O-])=O)[CH3:2].CC(=O)OCC>[Pd].CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:5][C:4]=1[NH2:13])[CH3:2]
Reactant: CCc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1ccc(S(C)(=O)=O)cc1N
Yield: 94.6 %

Procedure:
The title compound of step 1 (0.6 g, 2.6 mmol) and palladium on carbon (0.18 g) in CH3OH (20 mL) was hydrogenated at 1 atm. for 6 h. Silica gel chromatography (PE:EA=6:1) gave the title compound (0.49 g, 94%) as a brown liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]([NH:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[O:12])[N:10]=[C:4]2[CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[CH:45][CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:57][C:42]([F:41])([F:56])[C:43]1[CH:44]=[CH:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52]([O:1][C:2]3[CH:7]=[CH:6][N:5]4[CH:8]=[C:9]([C:11]([NH:13][CH:14]5[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]5)=[O:12])[N:10]=[C:4]4[CH:3]=3)[CH2:51][CH2:50]2)=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cn3ccc(O)cc3n2)CC1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cn3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a stirred solution of tert-butyl 4-(7-hydroxyimidazo[1,2-a]pyridine-2-carboxamido)piperidine-1-carboxylate (0.18 g, 0.50 mmol) in toluene (4 mL) at room temperature was added diisopropyl azodicarboxylate (0.12 g, 0.6 mmol), 1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.12 g, 0.5 mmol), and triphenylphosphine (0.16 g, 0.6 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, methylene chloride/methanol/30% ammonium hydroxide=20/1/0.01) to afford tert-butyl 4-(7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)imidazo[1,2-a]pyridine-2-carboxamido)piperidine-1-carboxylate as a off-white solid (0.13 g, 44%). 1H-NMR (CDC3, 300 MHz): δ 7.97 (m, 2H), 7.47 (m, 2H), 7.18 (m, 1H), 6.95 (m, 2H), 6.81 (s, 1H), 6.58 (m, 1H), 4.56 (m, 1H), 4.11 (m, 3H), 3.61 (m, 2H), 3.26 (m, 2H), 2.92 (m, 2H), 2.15 (m, 2H), 2.03 (m, 4H), 1.66 (m, 2H), 1.47 (s, 9H) ppm; MS (ESI): 588.4 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[N:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:19].O1CCOCC1>C(Cl)Cl>[ClH:19].[ClH:19].[Br:17][C:14]1[CH:15]=[N:16][C:11]([C:8]2([NH2:7])[CH2:9][CH2:10]2)=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ncc(Br)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ncc(Br)cn2)CC1
Reaction time: 2 h

Procedure:
[1-(5-Bromo-pyrimidin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (1.18 g, 3.76 mmol) is dissolved in CH2Cl2 (5 mL) at room temperature. A 4M solution of HCl in dioxane (9.4 mL, 38 mmol) is added. After 2 hours, solvents are removed by a stream of N2 to afford crude title compound as a solid, which is used without purification (ES+ m/z 216.3).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:11](Cl)=[O:12].[CH2:18]([O:20][C:21]([C@:23]1([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:28]([NH2:29])[CH2:27][C@@H:26]2[C@H:24]1[C@@:25]2([F:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22])[CH3:19]>C(Cl)(Cl)Cl>[CH2:18]([O:20][C:21]([C@:23]1([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@H:28]([NH:29][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:8]([Cl:7])[CH:9]=2)[CH2:27][C@@H:26]2[C@H:24]1[C@@:25]2([F:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22])[CH3:19]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](NC(=O)c3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
7.3 μL of pyridine and 14 mg of 3,4-dichlorobenzoyl chloride were added to 17 mg of (1R,2R,3R,5R,6R)-3-amino-2-t-butoxycarbonylamino-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 0.17 mL of chloroform, and the mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: chloroform-ethanol=100:1), thereby yielding 21 mg of (1R,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzoylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.Cl.NO.CC([C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])=O>C(O)C>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([F:21])[C:14]=1[CH:6]([NH2:3])[CH3:7]
Reactant: CC(=O)c1c(F)cccc1F
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC(N)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (2.37 mL) and hydroxylamine hydrochloride (634 mg) were added to a solution of 2,6-difluoroacetophenone (890 mg) in ethanol (30 mL), and the reaction solution was heated to reflux for 4 hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Zinc (1.86 g) was added to a solution of the resulting residue in trifluoroacetic acid (10 mL), and the reaction solution was stirred at room temperature overnight. The reaction solution was filtered on a celite, made basic with a 5 N aqueous solution of sodium hydroxide, and then extracted with chloroform. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 210 mg of a crude purified product containing the title compound (purity: 50 wt %). The physical properties of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=4)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=4)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH:11]=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CO)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Solvent: C1CCOC1
Product: Nc1ncnn2c(C=O)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 41.2 %

Procedure:
To a suspension of Example 105 (14.7 mg, 0.033 mmol) in THF (3 mL) was added 3,3,3-triacetoxy-3-iodophthalide (42.2 mg, 0.10 mmol). The mixture was stirred at rt under nitrogen for 4 d. The solvent was evaporated under reduced pressure. The residue was dissolved in DMF and purified by HPLC using a gradient of 20-90% MeCN in water to yield 6.0 mg (41%) of the title compound. 1H-NMR (DMSO-d6) 10.34 (s, 1H), 9.90 (bs, 1H), 9.75 (bs, 1H), 8.15 (s, 1H), 8.06-7.99 (m, 2H), 7.59 (d, J=8.6, 2H), 7.51 (dd, J=7.0, 1.1, Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.25 (s, 1H); MS [M+H]+=442.1; LCMS RT=3.29 min.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26]C4CCCCO4)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+]>CO>[C:1]1([C@H:7]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][OH:26])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](Nc1ncnc2cc(OCCOC3CCCCO3)c([N+](=O)[O-])cc12)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@@H](Nc1ncnc2cc(OCCO)c([N+](=O)[O-])cc12)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 7.70 g 4-[(R)-(1-phenyl-ethyl)amino]-7-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-6-nitro-quinazoline in 120 ml of methanol are added 2 ml of concentrated hydrochloric acid. The reaction mixture is stirred for 1.5 hours at 50° C. After cooling, the mixture is neutralized with solid sodium bicarbonate and concentrated in vacuo. The solid residue is dissolved in ethyl acetate, washed with concentrated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and concentrated. The residue is triturated with 30 ml of diethyl ether, filtered off with suction, and dried. Yield: 4,34 g (88% of theory), Melting point: 187-192° C. Mass spectrum (ESI*): m/z=355 [M+H]*
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([CH2:17][OH:18])[C@@H:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:14]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.OP(O)(O)=O.O>CS(C)=O>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([CH:17]=[O:18])[C@@H:15]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:14]([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](CO)[C@H]1OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CS(C)=O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](C=O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of methyl 2,4,6-tri-O-benzyl-3-deoxy-3-C-(hydroxymethyl)-α-D-galacto-hexopyranoside (5.13 g, 10.72 mmol) in 25 ml of dry DMSO, 5.0 g of DCC and 0.5 ml H3PO4 were added. The mixture was stirred overnight at room temperature. The reaction mixture was treated with water (100 ml), and extracted several times with ethyl acetate. The combined organic extracts were washed with a saturated sodium hydrogen carbonate solution, dried with MgSO4 and concentrated in vacua. Purification of the crude product by flash chromatography with petroleum ether/ethyl acetate (4:1) gave 4.9 g (94%) methyl 2,4,6-tri-O-benzyl-3-deoxy-3-C-(formyl)-α-D-galacto-hexopyranoside as a colorless oil. —TLC (petroleum ether/ethyl acetate, 4:1): Rf=0.36.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([NH:9][CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]([OH:28])[CH2:26]Br>O>[C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([N:9]([CH2:26][CH2:25][OH:28])[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NCCNS(C)(=O)=O)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(N(CCO)CCNS(C)(=O)=O)cc1
Reaction time: 48 h

Procedure:
0.037 mol (10 g) of 4-acetylamino-N-(β-mesylaminoethyl)-aniline is dissolved in 31 ml of boiling water. 7.4 g of sodium carbonate and 0.148 mol (18.5 g) of glycol bromohydrin are added, whilst stirring. After stirring for 4 hours in a boiling water bath, the reaction medium is filtered and the filtrate is then left to stand for 48 hours at 0° C. The 4-acetylamino-N-(β-hydroxyethyl)-N-(β-mesylaminoethyl)-aniline which has precipitated in crystalline form is filtered off. After recrystallisation from boiling water and drying in vacuo, the products melts at 118° C.