Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]([N:13]=[C:14]=[S:15])([CH3:12])[CH3:11].[H-].[Na+].CCOCC>CN(C=O)C>[Cl:9][C:4]1[N:3]=[C:2]2[S:15][C:14]([NH:13][CH:10]([CH3:12])[CH3:11])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: Nc1ccc(Cl)nc1Cl
Reactant: CC(C)N=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Nc1nc2ccc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of 2,6-dichloropyridin-3-amine (3.71 g, 22.8 mmol, 1.0 eq.) and isopropyl isothiocyanate (2.5 mL, 23.5 mmol, 1.0 eq.) in DMF (57 mL) under nitrogen at 0° C. was added NaH (95% in mineral oil, 0.77 g, 30.5 mmol, 1.3 eq.). After 10 min., the cold bath was removed, and the reaction mixture was stirred to room temperature for 10 min. It was then heated at 68° C. overnight. After cooling to 0° C., isopropyl isothiocyanate (1.5 mL) and NaH (0.44 g) were added, and heating was resumed. After 7.25 h, the reaction was cooled to room temperature. At 0° C., aqueous HCl (1 N), water and EtOAc were added, and the reaction mixture was stirred. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Trituration with Et2O afforded 5-chloro-N-isopropylthiazolo[5,4-b]pyridin-2-amine as a white solid (3.43 g, 66% yield).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.CCO>[ClH:1].[OH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:13]([C:12]([O:16][CH2:17][CH3:18])=[O:15])[NH:2][CH2:3][CH2:4]2
Reactant: NCCc1cccc(O)c1
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1NCCc2cc(O)ccc21
Yield: 90.1 %

Procedure:
A solution of 3-(2-aminoethyl)phenol hydrochloride (4.60 g, 26.49 mmol) and 47% ethyl glyoxylate/toluene solution (polymer form) (6.15 mL, 29.14 mmol) in a mixed solvent of toluene/EtOH (50 mL) was heated under reflux for 18 hr. The reaction mixture was concentrated under reduced pressure. The precipitate was collected by filtration, and washed with ethyl acetate/diethyl ether to give ethyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate hydrochloride (6.15 g, 23.86 mmol, 90%) as a white powder.
Reaction SMILES: Cl.[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:4]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][N:15]([CH3:20])[CH2:14]2)[N:4]=1
Reactant: Nc1ncnc2c1c(I)nn2C1CCNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1CCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 170.3 %

Procedure:
To a solution of rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrochloride (0.400 g, 1.09 mmol) in dichloroethane (10 mL) was added formaldehyde (37% in water, 0.12 mL, 1.63 mmol), sodium triacetoxyborohydride (0.578 g, 2.73 mmol), and acetic acid (0.37 mL, 6.55 mmol). The reaction mixture was stirred at room temperature for 3 days and then additional formaldehyde (37% in water, 0.12 mL, 1.63 mmol), sodium triacetoxyborohydride (0.578 g, 2.73 mmol), and acetic acid (0.37 mL, 6.55 mmol) were added. The reaction mixture stirred for an additional 3 h and was then concentrated to afford rac-3-iodo-1-(1-methyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a pale yellow solid (0.639 g) which was used in subsequent reactions without further purification. RP-HPLC Rt 4.226 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 345 (MH+).
Reaction SMILES: [Li][CH3:2].C[Si](Cl)(C)C.[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12](/[C:19](/[CH3:26])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=[CH:14][CH:15]=2)[N:10]=1>CCOCC.C(Cl)Cl>[CH3:26][C:19]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[C:9]([CH3:8])[CH:18]=[CH:17]2)([CH3:2])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)/C=C(/C)c1cccc2ccc(C)nc12
Reactant: [Li]C
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC(C)(C)c1cccc2ccc(C)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a mixture of Cu(I)I (2.42 g, 12.7 mmol) in ether (5 mL) was added a solution of 1.6 M MeLi (15.9 ml, 25.4 mmol) in ether at 0° C. and the mixture was stirred at 0° C. for 10 minutes. The solvent was removed under reduced pressure and cold DCM (10 mL) was added. The solvent was removed under reduced pressure. Cold DCM (40 mL) was added and the mixture was cooled to −78° C. TMSCl (1.54 mL, 12.7 mmol) was added, followed by a solution of (Z)-ethyl 3-(2-methylquinolin-8-yl)but-2-enoate (0.81 g, 3.17 mmol) in DCM (10 mL). The reaction mixture was warmed to 0° C. and stirred at 0° C. for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution. The organic layers was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1 hexane/ethyl acetate) to give ethyl 3-methyl-3-(2-methylquinolin-8-yl)butanoate (0.66 g, 76.8%) as an oil.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:27][CH:26]=1>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:27][CH:26]=3)=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCOC(=O)CCc1ccc(O)c2ccccc12
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c3ccccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting from (3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate following Step 5 and 6 using ethyl 3-(4-hydroxynaphthalen-1-yl)propanoate as coupling agent to afford the desired product as an off-white solid. 1H-NMR (300 MHz, CDCl3) δ 8.22 (d, J=8.1 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.58 (t, J=7.5 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.22 (d, J=8.1 Hz, 3H), 6.77 (d, J=7.8 Hz, 1H), 5.22 (s, 2H), 3.39 (t, J=7.8 Hz, 2H), 2.82 (t, J=8.1 Hz, 2H), 2.65 (q, J1=15.5 Hz, J2=7.5 Hz, 2H), 1.20 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C26H22F3NO3S, 486.1 (M+H). found 486.1.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:1]([C:4]1[CH:10]=[C:9]([C:14]2[CH:13]=[CH:12][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(-c2ccc3ccccc3c2)cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
A suspension of 2-nitro-4-bromoaniline (5 g, 23 mmol) in toluene is admixed with 3.27 g (23 mmol) of 2-naphthylboronic acid, 9.5 g (0.069 mol) of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium. The mixture is heated to reflux for 4 hours and the reaction is stopped by adding 100 ml of water. The mixture is extracted with ethyl acetate and dried over sodium sulphate, and the solvent is removed under reduced pressure. Purification by column chromatography gives 4.1 g (68% yield).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([F:14])[CH:3]=1.[CH2:15]([O:17][C:18](=[O:22])[CH:19](Cl)[CH3:20])[CH3:16].FC(F)(F)C(O)=O.Cl>CN(C)C=O.[Mn]>[F:14][C:4]1[CH:3]=[C:2]([CH:19]([CH3:20])[C:18]([O:17][CH2:15][CH3:16])=[O:22])[CH:13]=[CH:12][C:5]=1[CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)NCc1ccc(Br)cc1F
Reactant: CCOC(=O)C(C)Cl
Agent: [Mn]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc(CNS(C)(=O)=O)c(F)c1
Temperature: 65 °C
Reaction time: 36 h
Yield: 39.3 %

Procedure:
N-(4-bromo-2-fluorobenzyl)methanesulfonamide (29 g, 102.8 mmol) and ethyl-2-chloropropionate (18.26 g, 133.6 mmol) were dissolved in dimethylformamide (155 mL) in a protective gas atmosphere at room temperature. Subsequently, manganese (11.29 g, 205.6 mmol), (2,2′-bipyridine)nickel(II) dibromide (2.69 g, 7.2 mmol) and trifluoroacetic acid (1.48 mL) were added and the mixture was stirred at 65° C. for 36 h. The reaction mixture was cooled to room temperature, hydrolysed using 1 N HCl (50 mL) and extracted with diethyl ether (4×100 mL). The combined organic layer were washed with water (40 mL) and brine solution (40 mL) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (eluent: diethyl ether/n-hexane 9:1) to afford ethyl 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoate (12.27 g, 39%).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([CH:21]([OH:29])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=1.O>CN(C)C=O>[Si:6]([O:29][CH:21]([C:19]1[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CCC(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(O[Si](C)(C)C(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
Imidazole (5.4 g) and tert-butyldimethylsilyl chloride (3.98 g) were added to a solution of ethyl 4-(5-chloro-2-nitrophenyl)-4-hydroxybutanoate (3.8 g) in anhydrous dimethylformamide (25 mL), and stirred at room temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water three times and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=20:1→10:1) to obtain 5.3 g of ethyl 4-(tert-butyldimethylsilyloxy)-4-(5-chloro-2-nitrophenyl)butanoate with a quantitive yield.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CO.[CH3:34][N:35]([CH3:61])[CH2:36][CH2:37][CH2:38][C:39]#[C:40][C:41]1[CH:42]=[N:43][C:44]([NH:47][S:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)(=[O:50])=[O:49])=[N:45][CH:46]=1>C1COCC1>[CH3:61][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][C:39]#[C:40][C:41]1[CH:42]=[N:43][C:44]([N:47]([CH3:1])[S:48]([C:51]2[CH:52]=[CH:53][C:54]([C:57]([F:60])([F:58])[F:59])=[CH:55][CH:56]=2)(=[O:49])=[O:50])=[N:45][CH:46]=1
Reactant: CN(C)CCCC#Cc1cnc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)nc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCCC#Cc1cnc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Yield: 23.4 %

Procedure:
A solution of 127 mg (0.485 mmol) triphenylphosphine in 0.5 ml THF was treated at 0° C. with 0.075 ml (0.485 mmol) DEAD, then with 0.016 ml (0.388 mmol) methanol and finally with 80 mg (0.19 mmol) of N-[5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-yl]-4-trifluoromethyl-benzenesulfonamide in 0.3 ml THF. The reaction mixture was stirred over night at RT, evaporated and extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were dried over Na2SO4, evaporated and purified by flash column chromatography on silica gel with CH2Cl2/MeOH (99:1 to 95:5) to yield 19 mg (23%) of N-[5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-yl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 427 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[C:32](=S)=[S:33].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:20]1([CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][N:9]3[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]=[C:32]3[SH:33])[CH2:18][CH2:17]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: S=C=S
Reactant: Nc1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Sc1nc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4.37 parts of N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine hydrochloride, 38 parts of carbon disulfide, 2 parts of sodium carbonate and 40 parts of ethanol is stirred and refluxed for 20 hours. The reaction mixture is evaporated and water is added to the residue. The precipitated product is filtered off, washed with water and dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1H-benzimidazole-2-thiol; mp 181.8° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15]CCCC>C1COCC1>[CH3:15][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCC
Solvent: C1CCOC1
Product: C[C@H](CN(C)C(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of N-Boc-α-(R,S)-methyl-β-alanine (1.33 g, 6.5 mmol) in THF (80 ml)was added pentane washed sodium hydride(1.2 g, 60% in oil dispersion) followed by methyl iodide (2 ml, exess). The reaction mixture was stirred overnight and then poured into an iced solution of citric acid (0.5N). The aqueous THF solution was extracted into ethyl acetate. Then the required acid was back extracted between ethyl acetate, sodium hydrogen carbonate and potassium hydrogen sulphate solutions. The organic extracts were dried (MgSO4) and evaporated to afford the title compound. (1.00 g, 71%), Anal: C10H19NO4.0.3H2O, Calc: C, 53.94; H, 8.87; N, 6.29. Found, C, 54.02; H, 8.56; N, 6.63.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][N:10]1[CH3:18].[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]3[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[N:33]=3)[CH:30]=2)=[C:22]([F:42])[CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:20]([NH:19][C:15]([C:12]5[C:13](=[O:14])[N:9]([C:3]6[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=6[Cl:1])[N:10]([CH3:18])[CH:11]=5)=[O:17])=[CH:21][C:22]=4[F:42])=[CH:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1c(Cl)cccc1Cl
Yield: 72 %

Procedure:
In the same manner as in Example 46 and using 2-(2,6-dichlorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (370 mg, 1.3 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.77 mmol), HATU (490 mg, 1.3 mmol), N,N-diisopropylethylamine (340 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) as starting materials, the title compound (330 mg, 72%) was obtained as a white solid.
Reaction SMILES: C[O-].[Na+].Cl[CH2:5][C:6]12OC(=O)C(=O)[N:7]1[CH2:8][CH2:9][C:10]1[C:15]2=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1.C[CH2:24][O:25]C(C)=O.O>CO>[CH2:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][N:7]=[C:6]2[CH2:5][O:25][CH3:24])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCc1ccc2c(c1)C1(CCl)OC(=O)C(=O)N1CC2
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1ccc2c(c1)C(COC)=NCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium methoxide (9.46 g) was added to a suspension of 10b-(chloromethyl)-9-ethyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione (14.0 mL) in MeOH (140 mL) under ice-cooling. The mixture was stirred at room temperature for 0.5 hours and then heated under reflux for 3 hours. EtOAc and water were added to the mixture, followed by filtration. The organic layer of the filtrate was collected, washed with saturated brine, and dried over magnesium sulfate. Activated carbon and silica gel were added thereto, followed by filtration. The filtrate was concentrated under reduced pressure to obtain 7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline (4.75 g).
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[N:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[N:53][CH:52]=1>CN(C)C=O>[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:57][C:54]3[CH:55]=[CH:56][N:51]=[CH:52][N:53]=3)=[O:22])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Nc1ccncn1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccncn2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
1-Methylimidazole (0.53 ml, 6.7 mmol) was added into a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (1.2 g, 2.23 mmol) in N,N-dimethylformamide (DMF) (15.9 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (0.18 ml, 2.34 mmol) was added dropwise at 0° C. Then 4-pyrimidinamine (0.255 g, 2.68 mmol) was added, and the reaction mixture was stirred for 1 h at room temperature. The reaction solution was purified via reverse phase HPLC (Gilson) to yield phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[(4-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (1.21 g, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][NH2:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([CH2:18][C@H:19]([CH2:23][N:24]([CH:32]=[O:33])[O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:20](O)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[N:5]=[C:6]([NH:9][NH:10][C:20](=[O:21])[C@H:19]([CH2:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:23][N:24]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:32]=[O:33])[C:7]=1[F:8]
Reactant: CSc1nc(Cl)c(F)c(NN)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CSc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 4-chloro-5-fluoro-6-hydrazino-2-(methylthio)pyrimidine (9.70 g, 46.5 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (19.9 g, 46.5 mmol), HOAt (6.96 g, 51.2 mmol), EDCI (9.82 g, 51.2 mmol) and N-methyl morpholine (25.6 mL, 232.5 mmol) in DMF (300 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate/hexanes (3:2, 1 L) and washed with water (3×500 mL), and the organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by Gilson RP-HPLC (35-95% acetonitrile/water, 8 min gradient time) to afford [(2R)-3-{2-[6-chloro-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a red glass (12.89 g, 56.0%). LCMS: (M+H)+: 490.4.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11](=[O:16])[CH2:12][C:13](=O)[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[N:27]=[CH:26][C:25]([I:28])=[CH:24][C:21]=1[CH:22]=O.N1CCCCC1>CO>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11]([C:12]2[C:13]([CH3:14])=[N:19][C:20]3[C:21]([CH:22]=2)=[CH:24][C:25]([I:28])=[CH:26][N:27]=3)=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ncc(I)cc1C=O
Reactant: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1nc2ncc(I)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 120 °C
Yield: 63 %

Procedure:
In a screw cap pressure tube were N-(4-tert-butylbenzyl)-3-oxobutanamide (104.2 mg, 0.42 mmol) and 2-amino-5-iodonicotinaldehyde (95.0 mg, 0.38 mmol) suspended in piperidine (151.0 μl, 1.53 mmol). The tube was sealed and the mixture heated to 120° C. for 2 h. The mixture was allowed to cool, diluted with MeOH, adsorbed in silica and purified by flash chromatography (CH2Cl2/MeOH 99:1→97:3) yielding 110 mg of the title compound (63%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:17]1([C:2]2[CH:3]=[C:4]([N:8]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10][CH2:9]3)[CH:5]=[N:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cncc(N2CCN3CCC2CC3)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: c1ccc(-c2cncc(N3CCN4CCC3CC4)c2)cc1

Procedure:
0.87 g (3.1 mmol) of 4-(5-bromo-3-pyridyl)-1,4-diazabicyclo[3.2.2]nonane is introduced into a 50 ml three-necked round-bottomed flask, 0.39 g (3.15 mmol) of phenylboronic acid, 0.11 g (0.095 mmol) of tetrakis(triphenylphosphine)palladium, 3.3 ml of aqueous 2 M sodium carbonate solution, 6.5 ml of benzene and 0.15 ml of ethanol are added and the mixture is refluxed for 16 h.