Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([N:11]2[CH2:14][CH:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23]CC3C=CC([N+]([O-])=O)=CC=3)=[O:22])[CH2:12]2)=[N:7]1>O1CCCC1.P([O-])([O-])([O-])=O.[Zn]>[CH3:1][O:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([N:11]2[CH2:12][CH:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:14]2)=[N:7]1
Reactant: COCOC[C@@H]1CSC(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)=N1
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: COCOC[C@@H]1CSC(N2CC(SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of 756 mg of Compound (30) obtained in Example 3 in 10 ml of tetrahydrofuran and 30 ml of 0.35 M phosphate buffer (pH 6.0) solution was added 6.0 g of zinc powder, and the reaction mixture was stirred for 2 hours at room temperature. After removal of the zinc powder by filtration, the filtrate was washed with ethyl acetate and the pH of the filtrate was adjusted to 5.5, then the filtrate was concentrated. The resulting residue was purified by using Diaion HP-40R column (10% isopropanol-water) to give 415 mg (71%) of (1R,5S,6S)-2-[1-((4R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylic acid [Compound (31)].
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][N:6]=1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[O:4][C:5]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][N:6]=2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[N:37][CH:36]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: FC(F)(F)c1ccnc(Oc2ccccc2Br)n1
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3nccc(C(F)(F)F)n3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)-4-(trifluoromethyl)pyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H13F4N5O, 427.11; m/z found, 428.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J=4.9, 1H), 8.41 (d, J=1.4, 2H), 7.69 (d, J=4.9, 1H), 7.60-7.57 (m, 1H), 7.55-7.50 (m, 2H), 7.46-7.38 (m, 2H), 7.35-7.29 (m, 2H), 6.88 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][C:12]([CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[H-].[Na+].CI.[CH3:25]CCCCC>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH3:25])[CH:9]2[CH2:10][CH2:11][C:12]([CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:3]=1
Reactant: CCCCCC
Reactant: CCOC(=O)C1(C)CCC(Nc2ncc(Br)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCC(N(C)c2ncc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To an ice-cold solution of ethyl 4-(5-bromopyrimidin-2-ylamino)-1-methylcyclohexanecarboxylate (0.30 g, 0.88 mmol) in THF (10 mL) was added NaH (0.053 g, 1.32 mmol, 60% dispersion in mineral oil) portion wise and the mixture stirred at 0° C. for 10 min followed by drop wise addition of MeI (0.066 ml, 1.06 mmol). The mixture was heated up to 65° C. for 6-8 h. After completion (by TLC), the reaction was cooled up to 0° C. and quenched with ice-cold water (20 mL), extracted with EtOAc (2×50 mL) and the combined organics washed with water, brine and dried over Na2SO4. The crude residue was purified over 100-200 M silica-gel using 2% EtOAc:hexane to obtain the desired product as a yellow liquid (0.074 g, 24% yield). 1H NMR (DMSO-d6): δ 8.42 (s, 2H), 4.51 (m, 1H), 4.15 (q, J=6.80 Hz, 2H), 2.85 (s, 3H), 2.15 (m, 2H), 1.52 (m, 4H), 1.36 (m, 2H), 1.29 (t, J=6.80 Hz, 3H) and 1.21 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(N(C(C)C)CC)(C)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:43]=[C:42]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[C:40]2[C:35]=1[CH2:36][N:37]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=1)[C:38](=[O:56])[N:39]2[C:48]1[C:53]([Cl:54])=[CH:52][CH:51]=[CH:50][C:49]=1[Cl:55]>C1COCC1>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:43]=[C:42]([S:44]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH:2]([CH3:1])[CH2:7]2)(=[O:46])=[O:45])[CH:41]=[C:40]2[C:35]=1[CH2:36][N:37]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=1)[C:38](=[O:56])[N:39]2[C:48]1[C:49]([Cl:55])=[CH:50][CH:51]=[CH:52][C:53]=1[Cl:54]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)Cl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: CC1CNCCN1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)N4CCN(C(=O)OCc5ccccc5)C(C)C4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Benzyl 2-methylpiperazine-1-carboxylate (34 mg, 0.144 mmol) and diisopropylethylamine (19 mg, 0.144 mmol) were added to a mixture of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-sulfonyl chloride (60 mg, 0.096 mmol) (COMPOUND CCC8) in 1 mL THF. The mixture was heated to 80° C. and stirred at this temperature for ca. 1 h. The reaction mixture was cooled to rt and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 50:50 hexanes-acetone to yield benzyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]sulfonyl}-2-methylpiperazine-1-carboxylate. Mass spectrum (ESI) 819.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=[O:13].[CH3:15][Si:16]([CH3:21])([CH3:20])[CH2:17][CH2:18]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C1COCC1.CN(C)C1C=CN=CC=1>[CH3:15][Si:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][O:13][C:12]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1])=[O:14]
Reactant: O=C(O)c1c(O)ccc2ccccc12
Reactant: C[Si](C)(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)c1c(O)ccc2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 2-hydroxynaphtoic acid (2.02 g, 10.7 mmol) in dichloromethane (45 mL) and THF (2 mL) were added 2-trimethylsilylethanol (4.6 mL, 32.2 mmol) and 4-dimethylaminopyridine (1.07 g, 8.9 mmol) under N2. The mixture was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (2.33 g, 11.3 mmol) was added. After removal of the ice bath, the mixture was stirred for 3 h at room temperature. 2N HCl was added to adjust the pH to 2, and the mixture was filtered to remove urea. After the separation of layers the organic phase was washed with water and brine, dried (Na2SO4), and concentrated to dryness. Purification by chromatography gave 2.92 g of 2-hydroxy-naphthalene-1-carboxylic acid 2-trimethylsilanyl-ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([O:16][CH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)=[CH:10][CH:9]=3.C[Li].C([Li])CCC.[CH3:29][C:30]1([O:33][CH2:32]1)[CH3:31].B(F)(F)F.CCOCC>C1COCC1>[CH:19]1([CH2:18][CH2:17][O:16][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[CH:6][C:5]2[CH:4]=[CH:3][C:2]([CH2:29][C:30]([CH3:32])([OH:33])[CH3:31])=[CH:15][C:14]3=2)[CH2:21][CH2:20]1
Reactant: CC1(C)CO1
Reactant: Brc1ccc2ccc3ccc(OCCC4CC4)cc3c2c1
Agent: FB(F)F
Agent: [Li]C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc2ccc3ccc(OCCC4CC4)cc3c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a solution of 3-bromo-6-(2-cyclopropylethoxy)phenanthrene (11 mmol) from Step 1 above in THF (75 mL) at −78° C. was successively added methyllithium (1.6 M in diethyl ether, 1 mL) and butyllithium (2.5 M in hexanes, 5.3 μL). The mixture was stirred at −78° C. for 30 minutes, after which isobutylene oxide (2.9 mL, 33 mmol) was added, followed by BF3.OEt2 (4.2 mL, 33 mmol). The reaction mixture was stirred at −78° C. for 1 h, then quenched with 1 M HCl. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The material was purified by flash chromatography on silica (10% ethyl acetate in hexanes) to afford 1-[6-(2-cyclopropylethoxy)-3-phenanthryl]-2-methylpropan-2-ol (1.33 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)[C@@H:8]([OH:24])[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:16][CH:17]=2)[C@@H:8]([O:24][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](O)C1
Reactant: COCCCOc1cc(C)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](OCc2ccc(C)cc2OCCCOC)C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A suspension of the title C compound, (3R,4R)-4-biphenyl-3-yl-3-hydroxy-piperidine-1-carboxylic acid ethyl ester (150 mg, 0.45 mmol) and sodium hydride (60% dispersion in mineral oil, 30 mg, 0.68 mmol) in 10 mL of dry DMF is stirred for 10 min at 60° C. under argon. After cooling to room temperature, 1-bromomethyl-2-(3-methoxy-propoxy)-4-methyl-benzene (252 mg, 0.9 mmol) is added and the mixture further stirred for 3 h at 60° C. After addition of H2O, the aqueous layer is extracted twice with ethyl acetate and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by preparative HPLC (Macherey-Nagel 250/4 nucleosil 100-10 C18 column, 20:80 CH3CN+0.1% TFA over 11 min, then 100% CH3CN+0.1% TFA for 5.5 min, 40 ml/min). To the combined fractions containing the desired product is added 1M aqueous sodium carbonate solution and the acetonitrile is removed under reduced pressure. The resulting aqueous suspension is extracted twice with ethyl acetate. The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound. MS 535.2 [M+18]; Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 7.29 min.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]([NH:8][CH:9](Br)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6]>C1COCC1>[C:5]([NH:8][CH:9]([CH:1]=[CH2:2])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6]
Reactant: C=C[Mg]Br
Reactant: CCOC(=O)C(Br)NC(C)=O
Solvent: C1CCOC1
Product: C=CC(NC(C)=O)C(=O)OCC
Temperature: -78 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
Vinyl magnesium bromide (10.9 mL, 1N, 10.9 mmol) was slowly added to a cooled (-78° C.) solution of ethyl 2-acetamido-2-bromoacetate (1.10 g, 4.91 mmol) in THF (50 mL). The reaction was stirred at -78° C. (2 h), and was then quenched with a 1N citric acid solution (7.0 mL). The mixture was allowed to warm to room temperature, and then the THF was removed in vacuo. The aqueous mixture was extracted with CHCl3 (3×100 mL), and the combined CHCl3 extracts were dried (Na2SO4) and concentrated to dryness. The residue was purified by flash chromatography using SiO2 gel and 2% MeOH/CHCl3 as the eluant to give 0.50 g (60%) of the desired product as a light yellow colored oil: Rf 0.51 (4% MeOH/CHCl3); 1H NMR (DMSO-d6) δ 1.17 (t, J=7.1 Hz, OCH2CH3), 1.88 (s, C(O)CH3), 4.09 (d, J=7.1 Hz, OCH2CH3), 4.80-4.86 (m, α-CH), 5.22-5.35 (m, CH=CH2), 5.82-5.92 (m, CH=CH2), 8.47 (d, J=7.4 Hz, NH); 13C NMR (DMSO-d6) 13.96 (OCH2CH3), 22.12 (C(O)CH3), 54.65 (α-CH), 60.71 (OCH2CH3), 117.89 (CH=CH2), 132.48 (CH=CH2), 169.16 (C(O)CH3), 170.26 (C(O)NH) ppm.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10](N3CCC(N4CCCC4)CC3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.Cl.[OH:68][CH2:69][C@H:70]1[N:74]([CH:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)[CH2:73][C@H:72]([NH:81][C:82](=[O:84])[CH3:83])[CH2:71]1>CN(C=O)C>[CH:1]1([C:4]2[C:9]([C:10]([N:78]3[CH2:77][CH2:76][CH:75]([N:74]4[C@H:70]([CH2:69][OH:68])[CH2:71][C@@H:72]([NH:81][C:82](=[O:84])[CH3:83])[CH2:73]4)[CH2:80][CH2:79]3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@@H]1C[C@@H](CO)N(C2CCNCC2)C1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)nc(C2CC2)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H]1C[C@@H](CO)N(C2CCN(C(=O)c3c(C)nc(-c4cccc(OC(F)(F)F)c4)nc3C3CC3)CC2)C1

Procedure:
In analogy to the procedure described for intermediate 2,4-cyclopropyl-6-methyl-2-(3-trifluoromethoxy-phenyl)-pyrimidine-5-carboxylic acid (example 36) was reacted with HATU, triethylamine and N-((3R,5S)-5-hydroxymethyl-1-piperidin-4-yl-pyrrolidin-3-yl)-acetamide dihydrochloride (intermediate 8) in DMF. Subsequent purification by preparative HPLC afforded the title compound as a gum. MS: 562.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of 24.4 g (200 mmol) of 4-hydroxybenzaldehyde in 100 ml of dimethylformamide is treated with 97.75 g (300 mmol) of caesium carbonate and stirred at 90° C. for 1 h. A solution of 66.93 g (300 mmol) of tert-butyl 2-bromisobutyrate in 100 ml of dimethylformamide is then added dropwise, and the mixture is stirred at 90° C. overnight. The dimethylformamide is distilled off under reduced pressure and the residue is then taken up in ethyl acetate, washed 2× with water, 2× with 1 N aqueous sodium hydroxide solution and 1× with sat. NaCl solution, dried over sodium sulphate and freed from the solvent under reduced pressure. This gives 16.6 g (31%) of tert-butyl 2-(4-formylphenoxy)-2-methylpropionate.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.[CH3:14][C:15](ON1C(=O)CCC1=O)=[O:16]>>[CH3:14][C:15]([NH:13][CH2:12][CH2:11][C:8]1[C:4]2[CH:5]=[C:6]([OH:7])[CH:1]=[CH:2][C:3]=2[NH:10][CH:9]=1)=[O:16]
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: CC(=O)ON1C(=O)CCC1=O
Product: CC(=O)NCCc1c[nH]c2ccc(O)cc12

Procedure:
Serotonin (compound 7 in Scheme 3) reacts with N-succinimidyl acetate (8) selectively on the primary alkyl amine, as shown below, to give N-acetylserotonin (9). The electroactive hydroxytryptamine ring system emerges from the reaction unchanged. In practice a biological sample of 1.0 ml volume (for example: cerebrospinal fluid) is degassed by bubbling argon and treated with 0.05 ml of a solution of N-succinimidyl acetate in dioxane (100 mg/ml). The reaction is carried out at a pH of 10-11 in a closed vessel under argon at 70° C. for a period as short as five minutes or as long as two hours. The reaction is then quenched with glycine, giving the non-electroactive sodium N-acetylglycinate (10). ##STR5##
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([F:14])=[CH:11][C:12]=2[F:13])=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[C:3]([OH:18])[CH:2]=1.[H-].[Na+].[C:21](=[O:29])([O:25][CH:26](Cl)[CH3:27])[O:22][CH2:23][CH3:24]>CN(C=O)C>[F:13][C:12]1[CH:11]=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:6]1[CH:5]=[C:4]([C:15]([O:17][CH:23]([O:22][C:21]([O:25][CH2:26][CH3:27])=[O:29])[CH3:24])=[O:16])[C:3]([OH:18])=[CH:2][CH:1]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CCOC(=O)OC(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diflunisal (5.0 g) in 40 ml DMF was added 0.8 g of sodium hydride (oil suspension containing 60% of NaH). The resultant mixture was stirred for 1.5 hours at room temperature before 3.0 ml of ethyl 1-chloroethyl carbonate was added dropwise. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The concentrate was partitioned between ether/ethyl acetate and acidified water. The organic layer was separated and the aqueous layer was extracted again with ether. The organic layers were combined, washed well with water, dried over anhydrous sodium sulfate and concentrated to 6.6 g of crude product. After further purification by chromatography (eluted through 120 g of silica gel with hexane, and then 5% ethyl acetate in hexane), the product was crystallized from hexane to afford 3.71 g of 1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][C@@H:32]([F:35])[CH2:31]3)[N:25]=[C:26](I)[C:13]=12>>[Cl:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][C@@H:32]([F:35])[CH2:31]3)[N:25]=[C:26]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:13]=12
Reactant: OB(O)c1ccc(F)cc1
Reactant: F[C@@H]1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)C1
Product: Fc1ccc(-c2nn(CCN3CC[C@@H](F)C3)c3nnc(-c4ccccc4)c(Cl)c23)cc1

Procedure:
Compound IIy was synthesized according to Example 1, but using 4-fluorophenylboronic acid instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-chloro-1-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazine instead of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine in Step 8.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6]OS(=O)(=O)[N:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[CH:24][NH:25]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C>[NH:25]1[C:26]2[C:22](=[C:21]([N:15]3[CH2:20][CH2:19][N:18]([CH2:6][C@@H:2]([CH3:1])[NH:3][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH2:17][CH2:16]3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: CC#N
Product: C[C@H](CN1CCN(c2cccc3[nH]ccc23)CC1)Nc1ccccn1
Temperature: 60 °C
Yield: 67.5 %

Procedure:
A solution of (R)-4-methyl-3-pyridin-2-yl-[1,2,3]-oxathiazolidine-2,2-dioxide (4.04 g 0.019 moles) and 4-piperazinoindole (3.80 g 0.019 moles) in acetonitrile (200 ml) was heated to 60° C. for 0.5 h then evaporated in vacuo. The residue was taken up into dilute HCl (100 ml), warmed to 60° C. for 0.5 h, cooled, washed with ethyl acetate (2×100 ml), made basic with potassium carbonate, extracted into dichioromethane (3×100 ml), dried (MgSO4) then evaporated in vacuo to give a brown glass. This was purified on a silica column eluting with 10% propan-2-ol in dichloromethane to give (R)-1-(4-indolyl)-4-[2-methyl-2-(2-pyridinylamino)ethyl]piperazine (4.3 g) as a clear glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:23]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4c(C)cccc4C)CC3)nc2c1
Yield: 87 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 2.33-2.36 (m, 6H), 3.14-3.22 (m, 4H), 3.70-3.90 (m, 6H), 4.09-4.15 (m, 4H), 6.67-7.32 (m, 6H), 7.50-7.65 (m, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7].Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl.O>[CH3:39][Si:2]([CH3:38])([CH3:1])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([N:27]=[C:41]=[O:43])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N=C=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid 2-trimethylsilanylethyl ester (from EXAMPLE 3.2B, 90 mg in a mixture of 1 mL chloroform and 1 mL water containing 47 mg calcium carbonate) at 0° C. was added 46 mg triphosgene and the mixture allowed to warm slowly to room temperature. After 2 hours, the reaction was quenched by the addition of 2N hydrochloric acid, extracted with methylene chloride and the organics dried over sodium sulfate to give the crude title compound (94 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)#[N:32].CCN(C(C)C)C(C)C>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: N#Cc1ccc(CC(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C#N)cc3)c2)c2cncnc21

Procedure:
Prepared according to the method described for Example 1 using (5-aminopyridin-3-yl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Preparation 38), and 4-cyanophenylacetic acid with DIPEA.