Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)=[O:6].C([C:28]1[C:29]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#N.NC1C=C(C=CC=1OC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:14][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:2]([NH:1][C:39]3[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:29]=4[N:35]=[CH:36][N:37]=3)[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(C(=O)Nc2cccc(Br)c2)ccc1Oc1ccc(O)cc1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Oc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3ccc(O)cc3)ncnc2n1
Yield: 75 %

Procedure:
The product of Example 39A was reacted with the product of Example 9B using the procedure of Example 37D substituting the product of Example 39A for the product of Example 37C and substituting the product of Example 9B for Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (32 mg, 75%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.67 (s, 3 H) 6.75 (d, J=8.82 Hz, 2 H) 6.82-6.98 (m, 3 H) 7.20-7.38 (m, 2 H) 7.54 (d, J=8.46 Hz, 1 H) 7.69-7.81 (m, 1 H) 7.87 (dd, J=8.64, 2.02 Hz, 1 H) 8.10 (s, 1 H) 8.19 (d, J=1.84 Hz, 1 H) 8.61 (s, 1 H) 8.78 (d, J=8.46 Hz, 1 H) 9.39 (s, 1 H) 10.01 (s, 1 H) 10.32 (s, 1 H); MS (ESI+) m/z 542/544 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CC(=O)CC(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]3[N:28]=[C:7]([CH3:6])[CH:2]=[C:3]([CH3:4])[N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCC(=N)N)CCC2c2ccc(F)cc2)cc1
Solvent: CC(=O)CC(C)=O
Product: Cc1ccc(S(=O)(=O)N2C(CCCc3nc(C)cc(C)n3)CCC2c2ccc(F)cc2)cc1
Yield: 73.7 %

Procedure:
A stirred solution of (2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-butyramidine (0.35 g, 0.87 mmol) in pentan-2,4-dione (7 ml) was heated for 3 h at 125° C. Evaporation and purification by column chromatography on silica gel (ethyl acetate) yielded the title compound (0.15 g, 38%) as a light yellow oil, MS: m/e=468.3 (M+H+).
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:21])([CH3:20])[C:12]1=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:34]1C=CC=C[CH:35]=1>C(OCC)(=O)C.CN>[CH3:20][C:13]1([CH3:21])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2][NH:34][CH3:35])[C:12]1=[O:22]
Reactant: c1ccncc1
Reactant: CC1(C)C(=O)N([C@@H](CCO)c2ccccc2)c2ccccc21
Agent: CN
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@@H](c1ccccc1)N1C(=O)C(C)(C)c2ccccc21
Reaction time: 16 h

Procedure:
1-[(1S)-3-hydroxy-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.15 g, 3.9 mmol) was dissolved in pyridine (5 mL) and toluenesufonyl chloride (0.89 g, 4.6 mmol) was added. Stirred for 16 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. A portion of the crude product (100 mg, 0.21 mmol) was immediately dissolved in methylamine (8M in ethanol, 10 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 0-15% methanol saturated with ammonia in chloroform) to give 3.3-dimethyl-1-[(1S)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one as a colorless oil. The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (1.0 equivalent). The white precipitate was collected and dried under vacuum to give 43 mg 3,3-dimethyl-1-[(1S)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH:9]1[C:19]([OH:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.[CH3:25]OS(OC)(=O)=O>C1COCC1>[OH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:19]([O:21][CH3:25])=[O:20])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][CH2:16]2
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1C(=O)O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1c2ccc(O)cc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (7.4 g, 25.3 mmol) in THF (40 mL) was added LiOH.H2O (1.06 g, 25.3 mmol). The reaction mixture was stirred at room temperature for 40 min. Me2SO4 (1.19 mL, 12.63 mmol) was added and the reaction was brought to reflux for 3 h. The reaction was cooled down to room temperature and THF was removed. The residue was diluted with CH2Cl2 (150 mL), washed with H2O (2×30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on ISCO (120 g) with 0-50% ethyl acetate in hexanes over 40 minutes to yield 2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a pale yellowish foam (3.56 g, 46%). This racemic mixture was separated by Chiral preparative HPLC using chiralpak OD 20μ column (5×50 cm, eluting with 5% (EtOH/MeOH (50:50))/Heptane with flow rate 50 mL/min). The later eluted peak is the desired (R)-2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a white foam (1.1 g, 31%). HPLC retention time (Method B)=3.04 min. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (d, 9H), 2.67-2.99 (m, 2H), 3.59-3.74 (m, 1H), 3.70 (s, 3H), 3.74-3.86 (m, 1H), 5.35 (s, 0.5H), 5.51 (s, 0.5H), 5.70 (s, 0.5H), 5.76 (s, 0.5H), 6.64 (s, 1H), 6.67-6.76 (m, 1H), 7.31 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][NH:3]1.[SH:6][CH2:7][C:8]([O:10]C)=O>>[CH3:1][C:2]1([CH3:5])[NH:3][C:8](=[O:10])[CH2:7][S:6][CH2:4]1
Reactant: COC(=O)CS
Reactant: CC1(C)CN1
Product: CC1(C)CSCC(=O)N1
Reaction time: 2 h

Procedure:
2,2-Dimethylaziridine (35.5 g) was added dropwise with stirring at 100° C. to methyl mercaptoacetate (53 g) during 1.5 hours. After a further 2 hours at 100° C., the mixture was cooled and crystallized from ethyl acetate. Melting point: 151-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[C:6]=2[CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)[C:6]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3ccc(Br)cc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc2ncn(C3CCNC3)c2c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate (crude) in DCM (9 mL) was added TFA (3 mL). After stirring for 2 h, the solution was concentrated to give the desired crude product which was used directly in the next step.
Reaction SMILES: [CH:1](=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[C:10](=O)[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][NH2:20]>C(O)C>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[C:10](=[O:9])[NH:20][N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=Cc2ccccc2)c2cc(Br)ccc21
Reactant: NN
Solvent: CCO
Product: O=c1[nH]nc(Cc2ccccc2)c2cc(Br)ccc12

Procedure:
To a solution of EXAMPLE 1D (778 mg, 2.58 mmol) in ethanol (10 mL) was added hydrazine (83 mg, 2.58 mmol) and the mixture was refluxed for 2 hours. After cooling, the precipitated solid was collected by filtration and dried under vacuum to yield the title compound. MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.CN(CCN(C)C)C.[CH3:27][C:28]([N:31]([CH3:43])[C:32]1[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=1[C:34]([NH:36][CH2:37][CH3:38])=[O:35])([CH3:30])[CH3:29].[Cl:44]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:44][C:39]1[CH:40]=[CH:41][CH:42]=[C:32]([N:31]([C:28]([CH3:29])([CH3:30])[CH3:27])[CH3:43])[C:33]=1[C:34]([NH:36][CH2:37][CH3:38])=[O:35]
Reactant: CCNC(=O)c1ccccc1N(C)C(C)(C)C
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1c(Cl)cccc1N(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (5.7 mL, 7.5 mmol) was added dropwise to a dry-ice/acetone cooled solution of TMEDA (0.5 mL, 3.6 mmol) in THF (10 mL), followed by the dropwise addition of a solution of the compound of Example 188 (0.7 g, 3.0 mmol) in THF (5 mL). The reaction mixture was stirred at -78° C. for 30 min, then hexachloroethane (2.1 g, 9.0 mmol) in THF (5 mL) was added. This mixture was stirred for 30 min at -78° C., then was warmed to -30° C., diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 3:17 EtOAc/cyclohexane to give 495 mg of the title compound as a yellow solid, an 61% yield. m.p. 106-108° C.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[C:6](O)(=O)C=C.C(O)(=O)C=C.C(O)(=O)C=C.C(C(CO)(CO)C)O.C(O)(=O)C=C.C(O)(=O)C=C.C(C(CO)(CO)CC)O.OCC(CO)(COCC(CO)(CO)CO)CO>>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[C:1]([O-:5])(=[O:4])[C:2]([CH3:6])=[CH2:3]
Reactant: C=CC(=O)O
Agent: C=CC(=O)[O-]
Agent: CC(CO)(CO)CO
Agent: CCC(CO)(CO)CO
Product: C=C(C)C(=O)[O-]

Procedure:
The monomer or oligomer used in the invention is preferably a monomer or oligomer which has two or more ethylenic unsaturated double bonds and which is addition-polymerized by irradiation with light. The monomer or oligomer may be a compound having at least one addition-polymerizable ethylenic unsaturated group therein and having a boiling point of 100° C. or higher at a normal pressure. Examples thereof include: a monofunctional acrylate and a monofunctional methacryalte such as polyethylene glycol mono(meth)acrylate, polypropylene glycol mono(meth)acryalte and phenoxyethyl(meth)acrylate; polyethylene glycol di(meth)acryalte, polypropylene glycol di(meth)acrylate, trimethylolethane triacrylate, trimethylolpropane tri(meth)acrylate, trimethylolpropane diacrylate, neopentyl glycol di(meth)acrylate, pentaerythritol tetra(meth)acryalte, pentaerythritol tri(meth)acrylate, dipentaerythritol hexa(meth)acryalte, dipentaerythritol penta(meth)acrylate, hexanediol di(meth)acrylate, trimethylolpropane tri(acryloyloxypropyl)ether, tri(acryloyloxyethyl)isocyanurate, tri(acryloyloxyethyl)cyanurate, glycerin tri(meth)acrylate; a polyfunctional acrylate or polyfunctional methacrylate which may be obtained by adding ethylene oxide or propylene oxide to a polyfunctional alcohol such as polymethylolpropane or glycerin and converting the adduct into a (meth)acrylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[C:26]([CH3:37])=[CH:27][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[N:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[N:29][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:27][C:26]=1[CH3:37])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(OC2CCOC2)ncc1Br
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: Cc1cc(OC2CCOC2)ncc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-5-bromo-4-methyl-2-(tetrahydro-furan-3-yloxy)-pyridine (Intermediate 22) in analogy to Example 1a): MS (ISN): 479.0 and 481.0 (M−H)−.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH2:15]I)[CH2:13][S:14][C@H:9]12)=[O:6].C(OC([NH:67][CH2:68][CH2:69][C:70]1[S:74][CH:73]=[N:72][C:71]=1[CH3:75])=O)(C)(C)C>C(Cl)Cl.CS(C)=O.C(OCC)(=O)C>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O-:19])=[O:18])=[C:12]([CH2:15][C:73]4[S:74][C:70]([CH2:69][CH2:68][NH2:67])=[C:71]([CH3:75])[NH+:72]=4)[CH2:13][S:14][C@H:9]23)=[O:6])[N:36]=1
Reactant: Cc1ncsc1CCNC(=O)OC(C)(C)C
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(Cc3[nH+]c(C)c(CCN)s3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 13.4 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (VII-1) 468 mg, 0.5 mmole) and 5-(2-t-butoxycarbonylaminoethyl)-4-methylthiazole (242 mg, 1 mmole) [prepared by t-butoxycarbonylation of 5-(2-aminoethyl)-4-methylthiazole; see K. M. Muraveva and M. N. Shchukina, Zh. Obshch. Khim., 33, 3723 (1963); CA, 60, 8012a (1964)] in a mixture of methylene chloride (2 mL) and DMSO (0.5 mL) was stirred for 6 hours at room temperature and diluted with ethyl acetate (100 mL). The mixture was washed with water and evaporated under reduced pressure. The residue was triturated with ether and 400 mg of the quaternary salt was collected by filtration and treated with TFA (5 mL) for 2 hours at room temperature. After removal of TFA under reduced pressure below 20° C., the mixtrue was triturated with ether and 310 mg of the TFA salt of the crude product was collected by filtration. The TFA salt was dissolved in a small amount of aqueous NaHCO3 and chromatographed on a column of HP-20 (1.8×20 cm) by eluting with water. The fractions containing the title compound were combined, concentrated under reduced pressure and freeze-dried to give 36 mg (yield 14%) of the title product [Ij]. Estimated purity 50% (by HPLC).
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[C:22]3=[C:23]4[N:18]([CH2:19][CH2:20][CH2:21]3)[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15](=[O:27])[C:14]4=[CH:13][CH:12]=2)(=O)=O)=CC=1.[F:29][C:30]([F:38])([F:37])[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CS(C)=O.Cl>O>[F:29][C:30]([F:38])([F:37])[N:31]1[CH2:36][CH2:35][N:34]([C:11]2[C:22]3=[C:23]4[N:18]([CH2:19][CH2:20][CH2:21]3)[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15](=[O:27])[C:14]4=[CH:13][CH:12]=2)[CH2:33][CH2:32]1
Reactant: FC(F)(F)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cn2c3c(c(N4CCN(C(F)(F)F)CC4)ccc3c1=O)CCC2
Yield: 52.4 %

Procedure:
A mixture of 3.4 g of 8-(p-toluenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoromethylpiperazine and 200 ml of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 150° to 160° C. for 18 hours under nitrogen gas flow at a pressure of 10 atms. After completion of the reaction, the solvent and excessive piperazine compound were removed by distillation under reduced pressure and a mixture of methanol and ethanol was added to the residue. The precipitates formed were collected by filtration and washed with ether. The crystals obtained were suspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous hydrochloric acid solution and insoluble substances were removed by filtration. The filtrate was rendered neutral with saturated aqueous solution of sodium bicarbonate and purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 1.7 g of 8-(4-trifluoromethyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13](=[O:28])[C@H:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>>[CH3:11][O:12][C:13](=[O:28])[C@H:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:8](=[O:10])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: O=C(O)CC1CCCCC1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CC1CCCCC1

Procedure:
Following General Procedure U and using cyclohexylacetic acid (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=156-158° C.). The reaction was monitored by tlc (Rf=0.25 in 1:1 EtOAc/hexanes).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[C:15]([CH3:16])=[N:14][NH:13][C:12]=3[NH2:17])=[N:8][C:7]=2[CH:18]=1.BrB(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH2:17][C:12]1[NH:13][N:14]=[C:15]([CH3:16])[C:11]=1[C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:18][C:7]=2[N:8]=1
Reactant: COc1ccc2sc(-c3c(C)n[nH]c3N)nc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1n[nH]c(N)c1-c1nc2cc(O)ccc2s1
Temperature: 4 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a suspension of 4-(5-methoxy-benzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine (60 mg, 0.23 mmol) in CH2Cl2 (5 mL) at 4° C. was slowly added tribromoborane (2.3 mL of a 1M solution in dichloromethane, 2.3 mmol). The reaction temperature was maintained at 4° C. and the solution was stirred overnight. The mixture was then neutralized with sodium carbonate solution. The resulting solids were isolated by filtration and were purified by flash chromatography eluting with CHCl3:MeOH=9:1 to yield 10 mg (19%) of the title compound as a cream coloured solid. MS (m/z, ES+): 247.1 (M+1,100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.BrC1C=CC(C(C)C)=C(F)C=1.[CH:21]1([C:26]([OH:39])([C:37]#[CH:38])[CH2:27][C:28]2[O:33]C(C)(C)O[C:30](=[O:36])[CH:29]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:26]2([CH2:37][CH2:38][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=3)[O:39][C:30](=[O:36])[CH2:29][C:28](=[O:33])[CH2:27]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Reactant: CCc1cccc(Br)c1
Agent: CC(C)c1ccc(Br)cc1F
Product: CCc1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1

Procedure:
The title compound was prepared analogously to Example A(64), where 1-Bromo-3-ethyl-benzene was substituted in place of 4-bromo-2-fluoro-1-isopropylbenzene of that example and Enantiomer B of 6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one was used in place of the racemic alkyne. 1H NMR (CDCl3): δ 1.23 (t, 3H, J=7.6 Hz), 1.50-1.83 (br m, 8H), 1.91-2.05 (m, 2H), 2.29 (m, 1H), 2.59-2.68 (m, 4H) 2.27, (s, 2H), 3.42 (s, 2H), 6.96 (m, 2H), 7.06 (d, 1H, J=7.01 Hz), 7.21 (t, 1H, J=8.0 Hz). ESIMS: MH+ 315.20, MH− 313.20.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C=O)C>>[C:21]1([S:27]([N:18]2[CH2:17][CH:16]=[C:15]([C:7]3[N:6]=[C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[N:9]4[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=34)[CH2:20][CH2:19]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCNCC3)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(S(=O)(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-cyclobutyl-1-(1,2,3,6-tetrahydropyridin-4-yl)-imidazo[1,5-a]pyrazin-8-ylamine (20.0 mg, 0.0742 mmol), benzenesulfonyl chloride (9.48 uL, 0.0742 mmol), DIEA (0.0647 mL, 0.371 mmol) and DMF (1 mL, 0.01 mol) was stirred at rt for 10 min. The reaction mixture was directly given for Gilson HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=2.03 (dt, J=8.84, 2.65 Hz, 1H) 2.09-2.24 (m, 1H) 239-2.59 (m, 4H) 2.81 (d, J=1.77 Hz, 2H) 3.50 (t, J=5.68 Hz, 2H) 3.72 (quin, J=8.53 Hz, 1H) 3.85 (t, J=2.91 Hz, 2H) 5.93 (t, J=1.52 Hz, 1H) 6.82 (d, J=5.56 Hz, 1H) 6.99 (d, J=5.56 Hz, 1H) 7.55-7.69 (m, 3H) 7.86-7.90 (m, 2H). MS (ES+): m/z 409.99 (100) [MH+]. HPLC: tR=2.29 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH2:9][C:8](=O)[CH2:7][CH2:6][S:5]1)[CH3:3].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:32]=1)[NH:29][CH:28]=[CH:27]2.C([SiH](CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:8]1[CH2:7][CH2:6][S:5][CH:4]([CH:2]([CH3:3])[CH3:1])[CH2:9]1
Reactant: CC(C)C1CC(=O)CCS1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCSC(C(C)C)C3)c[nH]c12

Procedure:
2-(1-methylethyl)tetrahydro-2H-thiopyran-4-one (1.185 g, 7.49 mmol) was dissolved in dry dichloromethane (DCM) (20 mL), cooled in an ice bath to ca 0° C., and stirred under argon. Trimethylsilyl trifluoromethanesulfonate (2.71 mL, 14.98 mmol) was added dropwise over 10 minutes, and dry DCM (5 mL) was used to wash in the last of the trimethylsilyltrifluoromethanesulfonate. To this mixture was added dropwise, a solution of ethyl 5-bromo-1H-indole-7-carboxylate (2.145 g, 8 mmol) in dry DCM (20 mL), and then an additional portion of dry DCM (5 mL) was used to wash the last of ethyl 5-bromo-1H-indole-7-carboxylate into the reaction. Triethylsilane (4.77 mL, 30.0 mmol) was added to the reaction in one portion. The resulting mixture was stirred 2 h at 0° C., and left stirring at 23° C. overnight. The reaction was diluted with saturated aqueous sodium bicarbonate, and the resulting biphasic mixture was extracted with DCM, dried (MgSO4) and the DCM was removed in vacuo to give the title compound as a dark yellow oil.