Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)=[O:4].[C:17]([O:21][C:22](=[O:38])[NH:23]/[C:24](/N1C=CC=N1)=[N:25]/[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:28]([O:27][C:26]([NH:25]/[C:24](/[NH:16][C:13]1[CH:12]=[CH:11][C:10]([N:6]2[CH2:7][CH2:8][CH2:9][C@@H:5]2[C:3]([NH:2][CH3:1])=[O:4])=[CH:15][CH:14]=1)=[N:23]/[C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:38])=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CNC(=O)[C@H]1CCCN1c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Solvent: ClCCl
Product: CNC(=O)[C@H]1CCCN1c1ccc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
To (R)-1-(4-amino-phenyl)-pyrrolidine-2-carboxylic acid methylamide (Method 57; 1.0 g, 4.5 mmol) in DCM (60 ml) was added di-tert-butyl[(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (1.7 g, 5.5 mmol) in one portion. The reaction was stirred overnight before removal of the solvent in vacuo. The residue was purified via column chromatography eluting with 20% EtOAc/isohexane, 50% EtOAc/iso-hexne and finally 100% EtOAc. The title compound was obtained as a white foam (1.9 g, 91%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:20](O)(=[O:23])[CH2:21][CH3:22].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:20](=[O:23])[CH2:21][CH3:22])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CCC(=O)O
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a stirred solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (480 mg, 1.93 mmol) and propionic acid (158 μL, 2.12 mmol) in CH2Cl2 (10 mL) at 0° C. under Argon was added EDCI (406 mg, 2.12 mmol). Stirring was continued over night and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was poured into aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, aq. sat. NaHCO3 and with aq. sat. NaCl solution. The combined organic phases were dried over Na2SO4, filtered and evaporated to afford the title compound (558 mg, 95%) as light brown solid. MS: 306.2 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([OH:19])[N:9]=1.Br[CH2:21][CH2:22][CH3:23]>O>[Cl:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([O:19][CH2:21][CH2:22][CH3:23])[N:9]=1
Reactant: CCCBr
Reactant: Oc1cc2c(Cl)cccc2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCOc1cc2c(Cl)cccc2c(Cl)n1
Temperature: 50 °C
Yield: 91.9 %

Procedure:
Potassium carbonate (646 mg, 4.67 mmol) was added to a solution of 1,5-dichloroisoquinolin-3-ol (500 mg, 2.336 mmol) and 1-bromopropane (0.234 mL, 2.57 mmol) and heated to 50° C. for 3 hrs. After 3 hours the reaction was diluted with water and extracted with EtOAc (2×). The organic layer was washed with water followed by brine, dried over MgSO4, filtered and evaporated to give the crude product 1,5-dichloro-3-propoxyisoquinoline (550 mg, 92% yield), which was used as is in the next step. MS: MS m/z 256.1(M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1.[Cl:19][C:20]1[CH:21]=[N:22][N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32]B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:19][C:20]1[CH:21]=[N:22][N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=4)[N:3]=3)=[CH:28][CH:27]=2)[CH:24]=1
Reactant: CC1(C)OB(Cc2ccc(Cn3cc(Cl)cn3)cc2)OC1(C)C
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1cc(Cc2ccc(Cn3cc(Cl)cn3)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine (0.076 g, 0.26 mmol), 4-chloro-1-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)benzyl)-1H-pyrazole (0.129 g, 0.39 mmol), Pd(dppf)Cl2 (0.021 g, 0.03 mmol), and powdered Na2CO3 (0.082 g, 0.77 mmol) in dioxane (2 mL) and water (1 mL) was stirred under an argon atmosphere at 90° C. for 3 h. After this time, the mixture was cooled and filtered through celite with ethyl acetate washes. The filtrate was washed with brine (3×15 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, hexane/ethyl acetate) to afford the title compound (0.073 g, 98%) as an off-white solid. MW=463.28. 1H NMR (DMSO-d6, 300 MHz) δ 8.37-8.30 (m, 2H), 8.07 (s, 1H), 7.96 (s, 1H), 7.72-7.66 (m, 1H), 7.65-7.58 (m, 1H), 7.54 (s, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 5.26 (s, 2H), 4.31 (s, 2H); APCI MS m/z 463 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:36]1[N:37]=[C:38]([NH:41]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:39][CH:40]=1)[C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:19])=[C:13]([CH2:16]I)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].[OH:61][C:62]1[CH:63]=[C:64]([C:69]2[O:73][C:72]([SH:74])=[N:71][CH:70]=2)[CH:65]=[CH:66][C:67]=1[OH:68].C(=O)([O-])O.[Na+:79]>O>[NH2:41][C:38]1[S:39][CH:40]=[C:36]([C:5](=[N:4][O:3][CH2:1][CH3:2])[C:6]([NH:8][C@@H:9]2[C:34](=[O:35])[N:11]3[C:12]([C:18]([O-:20])=[O:19])=[C:13]([CH2:16][S:74][C:72]4[O:73][C:69]([C:64]5[CH:65]=[CH:66][C:67]([OH:68])=[C:62]([OH:61])[CH:63]=5)=[CH:70][N:71]=4)[CH2:14][S:15][C@H:10]23)=[O:7])[N:37]=1.[Na+:79]
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Oc1ccc(-c2cnc(S)o2)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3ncc(-c4ccc(O)c(O)c4)o3)CS[C@H]12)c1csc(N)n1

Procedure:
A trifluoroacetate obtained by the same operation as in EXAMPLE 1 by using 1.0 g (1.06 mmol) of benzhydryl 7β-[2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (syn-isomer) and 0.260 g (1.2 mmol) of 5-(3,4-dihydroxyphenyl)-2mercaptooxazole, was suspended in water and adjusted to pH6.5 with a saturated sodium hydrogencarbonate aqueous solution. Insoluble substances were filtered off and the filtrate was subjected to reversed phase column chromatography (LC-Sorb RP-18, manufactured by Kemco Co.). The fraction (elution with a 20% methanol aqueous solution) containing the desired compound was collected, concentrated and freeze-dried to obtain 70 mg (yield: 10.2%) of the above identified compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]2[NH:10][C:9]([CH2:11][CH2:12][CH2:13][CH3:14])=[N:8][C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CO>C1COCC1.CCCCC.[Cl-].[Na+].O>[CH2:11]([C:9]1[NH:10][C:4]2[C:5]([N:8]=1)=[N:6][CH:7]=[CH:2][C:3]=2[CH3:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nc2ncc(Br)c(C)c2[nH]1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCc1nc2nccc(C)c2[nH]1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
To a cooled (-78° C.) stirred solution of 6-bromo-2-butyl-7-methylimidazo[4,5-b]pyridine (98 mg, 0.366 mmol) in THF (4 mL) was added tert-butyl-lithium (0.86 mL of a 1.7M solution in pentane, 1.46 mmol). After 15 minutes, MeOH (0.5 mL and brine were added the mixture was warmed to room temperature and extracted with EtOAc (4×10 mL). Drying (K2CO3), concentration, and purification (SiO2, 100% EtOAc) gave 60 mg (87%) of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ8.18 (d, 1H, J=5 Hz), 7.08 (d, 1H, J=5 Hz), 3.05 (t, 2H, J=7.6 Hz), 2.72 (s, 3H), 2.03-1.89 (m, 2H), 1.62-1.43 (m, 2H), 0.96 (t, 3H, J=7.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([F:16])=[CH:14][CH:15]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[I:23]I.O>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([F:16])=[CH:14][C:15]=1[I:23])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(F)nc1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
Add a solution of [1-(6-fluoro-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (9.3 g, 38.8 mmol) in dry THF (90 mL) into tert-butyllithium (68.4 mL, 116.3 mmol, 1.7 M solution in pentane) in dry THF (70 mL) over 15 min under N2 at −78° C. Stir at −78° C. for 1 hour. Add a solution of iodine (14.8 g, 58.2 mmol) in dry THF (90 mL) over 15 min. Stir at −78° C. for 2 hours. Warm up to 0° C. Add water. Warm up to room temperature. Extract with ethyl acetate. Wash the organic layer with Na2CO3 solution, water and saturated aqueous sodium chloride, and dry over MgSO4. After filtration, concentrate and purify the crude by flash chromatography (5% to 20% ethyl acetate/hexane). Afford the desired product [1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (2.8 g, 20%), MS (ES) m/z 367 [M+1]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][N:12]2C(OC(C)(C)C)=O.CCOCC.[ClH:34]>>[ClH:34].[O:28]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][NH:12]2
Reactant: COC(=O)c1cc2c(c(N3CCCCS3(=O)=O)c1)CCN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1cc2c(c(N3CCCCS3(=O)=O)c1)CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1-(1,1-Dimethylethyl) 6-methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2,3-dihydro-1H-indole-1,6-dicarboxylate (D233) (500 mg, 1.2 mmol, 1 equiv) was dissolved in a 4N HCl solution in Et2O (10 ml, 40 mmol, excess) and the resulting solution was stirred at room temperature for 1 h then concentrated in vacuo. Trituration of the residue with Et2O gave methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2,3-dihydro-1H-indole-6-carboxylate hydrochloride salt (D234) (430 mg, 100%) as a white solid which was used in the next step without further purification. [M+H]+=311.0, RT=2.16 min.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6])[CH3:3]>CO.[Pd]>[OH:1][C@H:2]([C@H:4]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6])[CH3:3]
Reactant: COC(=O)[C@@H](CC=C(C)C)[C@H](C)O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](CCC(C)C)[C@H](C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.4 %

Procedure:
To a well stirred solution of (S)-methyl 2-((S)-1-hydroxyethyl)-5-methylhex-4-enoate (9.5 g, 51.0 mmol) in MeOH (51 mL) was added 10% Pd/C (0.543 g, 5.10 mmol). The reaction was put under a hydrogen atmosphere (balloon) and stirred at room temperature for 20 h. The mixture was filtered through a plug of Celite® and the plug was washed with MeOH (20 mL). The filtrate and washes were combined, the solvent was removed under reduced pressure, and the residue was dissolved in DCM (50 mL). The solution was passed through a phase separator to remove residual water (H2O), and the solvent was removed under reduced pressure to afford the title compound (9.45 g, 50.2 mmol, 98%) as a slightly yellow oil: IR (thin film) 3451, 2954, 2871, 1736, 1719, 1169 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.91 (p, J=6.4 Hz, 1H), 3.72 (s, 3H), 2.77 (s, 1H), 2.36 (ddd, J=9.2, 6.3, 5.0 Hz, 1H), 1.72-1.45 (m, 3H), 1.28-1.05 (m, 5H), 0.88 (dd, J=6.6, 3.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 176.13, 68.55, 53.29, 51.67, 36.55, 28.16, 27.37, 22.74, 22.44, 21.68.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][CH:19]=[CH:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1>CN(C)C=O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][C:19]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(-c2ccc3c(c2)C=CCCO3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(S(=O)(=O)Cl)CCO3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under ice-cooling, to dimethylformamide (0.2 ml) was added dropwise sulfuryl chloride (0.17 ml), and the mixture was stirred, under nitrogen atmosphere, at room temperature for 10 minutes. To the mixture was added 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine (0.3 g), and the mixture was stirred, under nitrogen atmosphere, at 90° C. for 3 hours. To the mixture was added ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-sulfonylchloride (0.36 g) as pale yellow crystals.
Reaction SMILES: [I:1]I.C([Sn](CCCC)(CCCC)[C:8]1[CH:9]=[C:10](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][F:23])CCC.C(Cl)Cl>C1COCC1>[I:1][C:8]1[CH:9]=[C:10](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][F:23]
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(/C=C/c2ccc(N(C)C)cc2)cnc1OCCOCCOCCF
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)c1ccc(/C=C/c2cnc(OCCOCCOCCF)c(I)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of iodine (I2, 0.063 g, 0.24 mmol) in THF (2 mL) was added dropwise to an ice bath cooled solution of 12a (0.114 g, 0.172 mmol) in THF (3 mL). After the addition, the reaction was stirred at 0° C. for 1 h. Following standard workup with CH2Cl2, the crude product was purified by FC (EtOAc/Hexanes, 25/75) to give a light yellow solid 13a (0.037 g, 48%). 1H NMR δ8.22 (d, 1H, J=2.1 Hz), 8.10 (d, 1H, J=2.1 Hz), 7.38 (d, 2H, J=8.8 Hz), 6.92 (d, 1H, J=16.3 Hz), 6.72 (d, 1H, J=16.3 Hz), 6.71 (d, 2H, J=8.8 Hz), 4.72-4.67 (m, 1H), 4.54-4.44 (m, 3H), 3.93-3.69 (m, 8H), 3.00 (s, 6H). 13C NMR δ160.4, 150.5, 144.6, 144.55, 129.8, 129.5, 127.8, 125.3, 118.8, 112.6, 85.1, 81.7, 80.6, 71.3, 71.1, 70.8, 70.5, 69.6, 67.1, 40.6. HRMS calcd for C21H26FIN2O3 (M+), 500.0972; found, 500.0959.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[Br-].O1CCC[CH2:28]1>>[CH3:28][C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:6][CH2:7]1
Reactant: C1CCOC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: [Br-]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C)(O)CC3)c(F)c2)C(=O)O1
Yield: 71 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.2 mmol) with methylmagnecium bromide (1.32 mmol) in tetrahydrofuran (20 ml) at a temperature 0° C. to 25° C. for twelve hours and by purifying the compound by silica gel column chromatography in 71% yield.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:32]C(=O)C)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].[OH-].[Na+]>CO>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: COC(=O)CCCCCCC(CCCC(COc1cccc(C(F)(F)F)c1)OC(C)=O)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(O)COc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A mixture of methyl 8-methylsulfonyl-12-acetoxy-13-(3-trifluoromethylphenoxy)tridecanoate (9.90 g., 0.019 mole), 20% aqueous sodium hydroxide (30 ml.) and methanol (30 ml.) is stirred at room temperature overnight. Then the reaction mixture is concentrated in vacuo on a steam bath. The concentrate is dissolved in water and extracted with ether. The basic aqueous solution is acidified with 6N hydrochloric acid and extracted with ether. These ether extracts are washed with water until neutral, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (5.55 g., 0.0118 mole, 62%) in analytical purity.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13]1(C)C=CC=C[CH:14]=1>>[CH:10]1[C:9]2[NH:8][C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1
Reactant: c1ccc(-c2ccccn2)nc1
Product: c1ccc2c(c1)[nH]c1ccccc12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To an ampoule, Cu(I)Br (1 mmol), 2,2′-bipyridine (1 mmol), norbornene methylene bromide(NBMBr)(1 mmol) and styrene(St) (100 mmol) were added in 10 mL toluene. The heterogeneous mixture was placed under vacuum and degassed via a freeze-pump-thaw cycle thrice. After degassing, the reaction mixture in ampoule was stirred at 100° C. for 12 hrs. The macromonomer containing polystyrene segments (NBMPStBr) was precipitated from methanol. Polymer was dissolved in THF and reprecipitated from methanol three times. Number average molecular weight of (NBMPStBr) is 160000 and PDI is 1.28(by GPC).
Reaction SMILES: [OH-].[Na+].[O:3]([CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[C:58]([CH3:84])=[C:59]([C:66]([C:68]3[CH:69]=[C:70]4[C:75](=[CH:76][CH:77]=3)[NH:74][C:73](=[O:78])[N:72]([CH2:79][C:80]([O-:82])=[O:81])[C:71]4=[O:83])=[O:67])[N:60]3[C:65]=2[CH:64]=[CH:63][CH:62]=[CH:61]3)=[CH:53][CH:52]=1)[CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([CH3:44])=[C:18]([C:25]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[NH:33][C:32](=[O:37])[N:31]([CH2:38][C:39]([O:41]C)=[O:40])[C:30]4=[O:43])=[O:26])[N:19]3[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:12][CH:11]=1.Cl>CN1C(=O)CCC1>[O:3]([CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[C:58]([CH3:84])=[C:59]([C:66]([C:68]3[CH:69]=[C:70]4[C:75](=[CH:76][CH:77]=3)[NH:74][C:73](=[O:78])[N:72]([CH2:79][C:80]([OH:82])=[O:81])[C:71]4=[O:83])=[O:67])[N:60]3[C:65]=2[CH:64]=[CH:63][CH:62]=[CH:61]3)=[CH:53][CH:52]=1)[CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([CH3:44])=[C:18]([C:25]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[NH:33][C:32](=[O:37])[N:31]([CH2:38][C:39]([OH:41])=[O:40])[C:30]4=[O:43])=[O:26])[N:19]3[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:12][CH:11]=1
Reactant: COC(=O)Cn1c(=O)[nH]c2ccc(C(=O)c3c(C)c(-c4ccc(OCCOCCOCCOCCOc5ccc(-c6c(C)c(C(=O)c7ccc8[nH]c(=O)n(CC(=O)[O-])c(=O)c8c7)n7ccccc67)cc5)cc4)c4ccccn34)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccc(OCCOCCOCCOCCOc3ccc(-c4c(C)c(C(=O)c5ccc6[nH]c(=O)n(CC(=O)O)c(=O)c6c5)n5ccccc45)cc3)cc2)c2ccccn2c1C(=O)c1ccc2[nH]c(=O)n(CC(=O)O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.1 %

Procedure:
A molar solution of sodium hydroxide (0.15 mL; 0.15 mmol) is added to a solution of methyl 2,2′-{oxybis[ethane-2,1-diyloxyethane-2,1-diyloxybenzene-4,1-diyl(2-methylindolizine-1,3-diyl)carbonyl(2,4-dioxo-1,4-dihydroquinazoline-6,3(2H)-diyl)]}diacetate (107 mg; 0.10 mmol) in 4 mL of NMP. The solution is stirred at ambient temperature for 24 h and then run into a hydrochloric acid solution (0.1 M). The precipitate obtained is filtered off, washed with water and dried under vacuum to give 101 mg (97%) of a yellow-orange powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][N:21]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:22]=4[CH:23]([CH3:25])[CH3:24])[C:14]3=[O:33])[N:9]=[C:10]([C:11]#[N:12])[C:3]=12.CCO.[CH2:37](N)[CH2:38][NH2:39]>CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][N:21]([C:26]5[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=5)[C:22]=4[CH:23]([CH3:24])[CH3:25])[C:14]3=[O:33])[N:9]=[C:10]([C:11]3[NH:39][CH2:38][CH2:37][N:12]=3)[C:3]=12
Reactant: NCCN
Reactant: CC(C)c1c(N2CCC(n3nc(C#N)c4c(N)ncnc43)C2=O)cnn1-c1ccc(F)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1c(N2CCC(n3nc(C4=NCCN4)c4c(N)ncnc43)C2=O)cnn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
A mixture of 4-amino-1-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carbonitrile (0.055 g, 0.12 mmol) in ethane-1,2-diamine (1.5 mL), HOAc (0.23 mL), and EtOH (2.0 mL) was stirred at 100° C. for 45 min. The mixture was then cooled to room temperature, quenched with sat. aq. NaHCO3 (50 mL), and extracted with IPA:CHCl3 (1:2 v/v, 100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-[4-amino-3-(4,5-dihydro-1H-imidazol-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.057 g, 97%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[NH:10][CH:9]=[CH:8][C:7]=2[N:6]=1)=[O:4]>C1COCC1.CO>[O:15]=[C:11]1[NH:10][CH:9]=[CH:8][C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:12]1=2
Reactant: COC(=O)c1ccc2c(=O)[nH]ccc2n1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(=O)[nH]ccc2n1
Reaction time: 1 h
Yield: 85.1 %

Procedure:
Stir a solution of 5-oxo-5,6-dihydro-[1,6]naphthyridine-2-carboxylic acid methyl ester (920 mg, 4.51 mmol) in a solution of THF/MeOH/1N LiOH (3:1:1) (30 mL) at rt for 18 h. Concentrate the solution and suspend the residue in water. Treat the solution with AcOH (1 mL) and let sit 1 h until a solid forms. Collect this by filtration to give desired product 5-oxo-5,6-dihydro-[1,6]naphthyridine-2-carboxylic acid (730 mg, 3.84 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([CH2:15][CH3:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][C:5]3([CH2:15][CH3:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]3=[O:14])[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCC1(CCCCl)C(=O)Nc2ccccc21
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCC1(CCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(3-chloropropyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-chlorophenyl)-piperazine.