Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])=O)(C)(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([NH:38][C:39](OC2C=CC=CC=2)=[O:40])[C:25](=[CH:36][CH:37]=1)[C:26](OCC1C=CC=CC=1)=[O:27]>>[NH2:8][C:9]1[CH:10]=[C:11]([S:17]([N:20]2[C:26](=[O:27])[C:25]3[C:24](=[CH:23][C:22]([Cl:21])=[CH:37][CH:36]=3)[NH:38][C:39]2=[O:40])(=[O:18])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(S(N)(=O)=O)cc1NC(=O)OC(C)(C)C
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: COc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1N
Yield: 16 %

Procedure:
400 mg (1.40 mmol) of 3-t-butoxycarbonylamino-4-methoxybenzenesulfonamide and 533 mg (1.40 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 17 to obtain 86 mg (yield 16%: 4 steps) of the above-identified compound.
Reaction SMILES: [O:1]1[CH2:5][CH:2]1[CH2:3]Cl.[OH:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].O>C(O)C>[O:1]1[CH2:5][CH:2]1[CH2:3][O:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(-c2ccccc2)oc2c(O)cccc2c1=O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(OCC3CO3)cccc2c1=O
Reaction time: 6 h

Procedure:
7 ml of 2,3-epoxypropyl chloride was added dropwise at 20°-25° C. to a stirred mixture of 5 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.7 ml of 2N aqueous sodium hydroxide solution in 10 ml of ethanol. After 6 hours at 20°-25° C., the reaction mixture was poured into 100 ml of water and the precipitate which formed was collected by suction filtration. After drying and purifying by flash chromatography on silica gel (eluant petroleum ether: ethyl acetate (65:35), there was obtained 4.45 g of the title compound, m.p. 128°-129° C.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C[S:7][CH2:8][C:9]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:20]([NH:22][C:23]([NH2:25])=[NH:24])=[O:21])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[CH:26](OC(C)C)(C)C>CO>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:26][C:8]([C:9]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:20]([NH:22][C:23]([NH2:25])=[NH:24])=[O:21])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[S:7]
Reactant: CSCc1cccc2c1OCCC(C(=O)NC(=N)N)=C2
Reactant: CC(C)OC(C)C
Agent: CS(=O)(=O)O
Solvent: CO
Product: CC(=S)c1cccc2c1OCCC(C(=O)NC(=N)N)=C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonic acid (0.04 ml) was added to the mixture of (2,3-dihydro-9-methylthiomethyl-1-benzoxepin-4-carbonyl)guanidine (0.15 g) in methanol (1.5 ml) and the mixture was stirred at ambient temperature for 30 minutes. To the mixture was added diisopropyl ether (3 ml). The isolated crystalline was collected by filtration and recrystallized from a mixture of methanol and diisopropyl ether to give (2,3-dihydro-9-methylthiocarbonyl-1-benzoxepin-4-carbonyl)guanidine methanesulfonate (0.12 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23].C([Mg]Cl)(C)C.[CH3:31][N:32]1[C:36]([C:37]([C:39]2[N:43]([CH3:44])[N:42]=[N:41][CH:40]=2)=[O:38])=[CH:35][N:34]=[N:33]1>C1COCC1>[CH3:44][N:43]1[C:39]([C:37]([C:36]2[N:32]([CH3:31])[N:33]=[N:34][CH:35]=2)([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]3[C:22]([F:25])([F:24])[F:23])[OH:38])=[CH:40][N:41]=[N:42]1
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Reactant: Cn1nncc1C(=O)c1cnnn1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cn1nncc1C(O)(c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(C(F)(F)F)c2c1)c1cnnn1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A ˜−70° C. solution of 6-iodo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (152 mg, 0.326 mmol; Intermediate 8, step d) in THF (0.322 mL) was treated with iPrMgCl (2.06 M in THF; 0.158 mL, 0.326 mmol) dropwise via syringe under argon over the course of 30 sec to provide an amber solution that became a yellow opaque slurry within 2 min. After 2 additional min the dark yellow opaque slurry was removed from the cold bath and immediately treated rapidly dropwise with a pre-formed solution of bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone (74.2 mg, 0.386 mmol; Intermediate 57) in THF (2.6 mL) over 45 sec. The reaction was stirred at room temperature for 3 hours and was then quenched with 5 M NH4Cl (1 mL). The aqueous layer was extracted with MTBE (1×3 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was dry load flash chromatographed with a heptane to 80% EtOAc/heptane gradient to provide the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J=8.59 Hz, 1H), 8.29 (br. s., 1H), 8.21 (s, 1H), 7.87 (d, J=9.09 Hz, 1H), 7.40-7.56 (m, 5H), 7.29 (s, 2H), 3.87 (s, 6H). MS m/e 534.2 [M+H]+.
Reaction SMILES: [O-:1]Cl.[Na+].[CH3:4][O:5][CH:6]([O:21][CH3:22])[C@:7]1([CH3:20])[CH:12]=[CH:11][C:10]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=2[O:8]1>C(Cl)Cl>[CH3:22][O:21][CH:6]([O:5][CH3:4])[C@:7]1([CH3:20])[C@@H:12]2[O:1][C@@H:11]2[C:10]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=2[O:8]1
Reactant: COC(OC)[C@]1(C)C=Cc2cc([N+](=O)[O-])ccc2O1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To the pre-cooled solution of 0.55 M NaOCl (110 mL, 60.0 mmol) and 0.05 M Na2HPO4 (43 mL) at 0° C., was added (2S)-2-dimethoxymethyl-2-methyl-6-nitro-2H-1-benzopyran (4 g, 15 mmol) and (R,R) Jacobson's catalyst (477.5 mg, 0.75 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred at rt for 8 hr and then filtered through Celite to remove the jacobson's catalyst. The layer was separated and the organic layer was washed with brine, dried (Na2SO4), filtered, then concentrated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=4:1) to give the desired compound (3.24 g, 77%) as a light yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][C:10]([CH2:15][N:16]4[C:24](=[O:25])[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]4=[O:26])([CH3:14])[C:9]=3[O:27][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[F:43][C:44]1[CH:45]=[C:46]([SH:50])[CH:47]=[CH:48][CH:49]=1>[Cu]I>[F:43][C:44]1[CH:45]=[C:46]([S:50][C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[CH2:13][CH2:12][NH:11][C:10]([CH2:15][N:16]5[C:24](=[O:25])[C:23]6[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=6)[C:17]5=[O:26])([CH3:14])[C:9]=4[O:27][C:4]=3[CH:3]=2)[CH:47]=[CH:48][CH:49]=1
Reactant: Fc1cccc(S)c1
Reactant: CC1(CN2C(=O)c3ccccc3C2=O)NCCc2c1oc1cc(I)ccc21
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: OCCO
Product: CC1(CN2C(=O)c3ccccc3C2=O)NCCc2c1oc1cc(Sc3cccc(F)c3)ccc21
Temperature: 120 °C
Reaction time: 72 h

Procedure:
To 2-(7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl)-isoindole-1,3-dione (0.192 g, 0.406 mmol) was added sodium tert-butoxide (117 mg, 1.22 mmol), copper (I) iodide (7.74 mg, 0.0406 mmol), 1,2-ethanediol (45.3 μL, 0.812 mmol), N,N-dimethylformamide (4.00 mL, 51.6 mmol), and finally 3-fluorobenzenethiol (36.0 μL, 0.427 mmol). The reaction mixture was flushed with N2 and heated at 120° C. under a N2 atmosphere. After 72 h, the reaction was cooled to room temperature and concentrated. The residual solid was partially dissolved into a 5% MeOH in DCM solution and flushed through a plug of Celite. The concentrated filtrate was chromatographed on silica gel using DCM-MeOH—NH4OH to afford a brownish yellow gum. MS m/z 473 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Yield: 78.5 %

Procedure:
A solution of methyl 4-benzyloxybenzoate (4.2 g, 17.3 mmole) and sodium hydroxide (15 mL of 2N) in methanol (200 mL) was heated at reflux for 24 hours. The methanol was removed under vacuum and water (200 mL) was added to the resulting residue. The mixture was acidified to pH 3 by the dropwise addition of concentrated hydrochloric acid. The resulting precipitate was isolated by filtration, washed with cold water and dried to provide 3.1 g of 4-benzyloxybenzoic acid as a white powder, m.p. 186°-187° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:21][CH2:22][OH:23]>O>[CH2:1]([N:3]([CH2:21][CH2:22][OH:23])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: OCCBr
Reactant: CCNc1ccc(Br)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCO)c1ccc(Br)cc1
Temperature: 125 °C
Yield: 69.5 %

Procedure:
17.3 g (86.7 mmols) of N-ethyl-4-bromoaniline, 22.7 ml (1.5-fold equivalent weight) of N,N-diisopropylethylamine and 9.64 ml (1.5-fold equivalent weight) of 2-bromoethanol were mixed, and the mixture obtained was heated at 125° C. for 2 hours in an atmosphere of argon. Next, to the reaction solution obtained, 1.5 ml (0.1-fold equivalent weight) of diisopropylethylamine and 0.64 ml (0.1-fold equivalent weight) of 2-bromoethanol were added, and the mixture obtained was heated at 125° C. for 3 hours in an atmosphere of argon. Water was added to the reaction solution obtained, which was then extracted with ethyl acetate. The organic layer obtained was dried with anhydrous magnesium sulfate and then concentrated. The residue thus obtained was purified by silica gel column chromatography developing system (chloroform) to obtain 14.7 g of N-ethyl-N-(2-hydroxyethyl)-4-bromoaniline (yield: 69.5%; a colorless oily liquid).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]1=[O:21].[CH2:22]([O:24][C:25](=[O:48])[C@H:26](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:23].CN1CCOCC1>C(OCC)(=O)C.CCCCCC>[CH2:22]([O:24][C:25]([C@@H:26]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:3]1=[O:21])[CH2:27][CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:48])[CH3:23]
Reactant: Cc1ccc(CN2C(=O)C(N)CCc3ccccc32)cc1
Reactant: CCOC(=O)[C@@H](CCC1CCCCC1)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)[C@H](CCC1CCCCC1)N[C@@H]1CCc2ccccc2N(Cc2ccc(C)cc2)C1=O

Procedure:
The reaction of 5.4 g of 3-amino-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one with 8.84 g of (R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-cyclohexylbutyric acid ethyl ester and 2.6 ml of N-methylmorpholine yields the two diastereoisomeric esters 3-(S)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and 3-(R)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one, Rf values (eluant ethyl acetate/hexane 1:2) non-polar component 0.58, polar component 0.39.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:46])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:45]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:46])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: Cc1ccccc1COC(=O)Cl
Product: Cc1ccccc1COC(=O)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc(C#N)cc2)C1

Procedure:
2-Methylbenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.20 mmol) and 2-methylbenzyl carbonochloridate (63.5 mg, 0.22 mmol) according to General Procedure H to give 25 mg (27.8%) of white solid. Anal. Calcd. for C27H34N4O2 m/z 446.3, found: 447.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.45 (d, J=8.7 Hz, 2H), 7.26 (d, J=7.3 Hz, 1H), 7.19 (m, 1H), 7.14 (m, 2H), 6.98 (m, 2H), 5.05 (m, 2H), 3.7 (m, 1H), 3.55 (m, 1H), 3.28 (m, 1H), 2.97 (m, 1H), 2.74 (m, 1H), 2.68 (m, 1H), 2.50 (m, 1H), 2.31 (s, 3H), 2.04 (m, 1H), 1.91 (m, 2H), 1.78 (m, 3H), 1.61 (m, 1H), 1.33 (m, 5H), 1.21 (m, 1H).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1

Procedure:
A solution of 2-[4-(2,3-epoxypropoxy)phenyl]trifluoromethylimidazole (2.5 g.) in tert. butylamine (20 ml.) is heated 6 hours at reflux. The excess tert. butylamine is removed by distillation at atmospheric pressure over steam. The residue is triturated with nitromethane (5 ml.) and the resulting solid removed by filtration. After recrystallation from acetonitrile, (1.2 g.) of 2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 185.5°-186.5° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:23]3[CH:24]=[C:25]4[O:30][CH2:29][O:28][C:26]4=[CH:27][C:22]=3[CH2:21][C:20]([CH3:31])=[N:19][N:18]=2)=[CH:13][CH:12]=1>CN(C)C=O.C(OCC)C>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:23]4[CH:24]=[C:25]5[O:30][CH2:29][O:28][C:26]5=[CH:27][C:22]=4[CH2:21][C:20]([CH3:31])=[N:19][N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1=NN=C(c2ccc(NC(=O)Nc3ccccc3)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
0.22 ml (2.04 mmol) of phenyl isocyanate was added to a solution of 0.50 g (1.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 4 ml of dimethylformamide and the reaction mixture was stirred at 25° C. for one hour. Then it was diluted with 20 ml of diethyl ether and filtered at 5° C. The crystals were washed with 2×5 ml of diethyl ether and dried at 60°-100° C. The resulting 0.70 g of raw product, m.p. 239°-240° C. (sintering at 180° C. was refluxed in 15 ml of ethanol, filtered after cooling, washed with 3×1 ml of ethanol and dried at 100° C. to yield 0.55 g (78.6%) of the aimed product, m.p. 240°-241° C. (decomp.).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][CH2:16][CH:17]([OH:19])[CH3:18]>>[C@H:17]([O:19][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH2:16][CH3:15])[CH3:18]
Reactant: CCC(C)O
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Product: CC[C@@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example B4(c) from 2-Fluoro-5-methanesulfonyl-benzoic acid (example B4(b)) and R-(−)-2-butanol. White solid. MS (m/e): 271.1 ([M−H], 100%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:21]Br.Cl>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:21])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: BrBr
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of methyl 3-acetyl-4-hydroxybenzoate (240 g, 1236 mmol) in DCM (2 L) was added pyridine (0.400 L, 4944 mmol) followed by a dropwise addition of dibromine (0.070 L, 1360 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h then cooled to 5° C. and HCl 4N (0.927 L, 3708 mmol) was added dropwise. The organic phase was separated, dried over MgSO4, filtered and concentrated to afford a brown solid which was stirred in ether/petroleum ether (1:1, 1 L) for 1 hr. The solid was collected by filtration and dried to afford methyl 3-acetyl-5-bromo-4-hydroxybenzoate (270 g, 80%) as a beige powder. Mass Spectrum: m/z [M+H]+=273.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[CH:19]=[N:20][CH:21]=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Cl:10])[C:7]=1[O:8]C.[Cl-].[Li+].N1CCNCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[CH:19]=[N:20][CH:21]=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Cl:10])[C:7]=1[OH:8]
Reactant: COc1c(Cl)cc(C(=O)N2CCOc3cnccc32)cc1Cl
Agent: C1CNCCN1
Agent: [Cl-]
Agent: [Li+]
Product: O=C(c1cc(Cl)c(O)c(Cl)c1)N1CCOc2cnccc21
Yield: 42.4 %

Procedure:
By the same method as in Example 39, (3,5-dichloro-4-methoxy-phenyl)-(2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-methanone (100 mg, 0.29 mmol), lithium chloride (124 mg, 2.9 mmol) and piperazine (38 mg, 0.44 mmol) were reacted. The resulting solid was purified by recrystallizing from methanol to obtain the target compound 41 as pale-brown solid (40 mg, 47%).
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(OCC)(=O)C>O1CCCC1.CCO.CCCCCC>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:50]2[CH2:51][CH2:52][N:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=3)[CH2:48][CH2:49]2)=[O:7])=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCN(c4ccccn4)CC3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 63 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and 1-(2-pyridyl)piperazine (1.21 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a earth orange compound CC-49. Mol. Wt.: 559.6145 (C33H29N5O4); Rf: 0.28 (ethyl acetate:n-hexane=1:2); Yield: 63%; Mp.: 258-259° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 559.2220 (C33H29N5O4+). Found, 559.2224. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 2.16 (s, 3H, —CH3), 3.05 (br, 8H, —CH2—), 3.22 (s, 2H, —CH2N—), 6.54 (d, J=8.4 Hz, 1H, Ar—H), 6.66 (t, J=6.3 Hz, 1H, Ar—H), 7.08 (d, J=7.8 Hz, 2H, Ar—H), 7.52 (td, J=7.7 Hz, J=2.1 Hz, 1H, Ar—H), 7.87-7.91 (m, 2H, Ar—H), 7.97 (d, J=8.1 Hz, 2H, Ar—H), 8.07-8.19 (m, 2H, Ar—H), 8.29 (d, =8.7 Hz, 1H, Ar—H), 8.82 (d, J=9.0 Hz, 1H, Ar—H), 10.16 (s, 1H, Ar—NH—), 10.51 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.88, 44.21, 52.56, 61.54, 107.00, 113.11, 124.91, 126.42, 126.89, 126.99, 127.63, 128.03, 128.21, 129.01, 129.29, 132.26, 133.39, 134.19, 134.52, 134.58, 137.30, 140.73, 142.51, 147.49, 159.15, 166.26, 166.31 (NCO), 169.23 (NCO), 181.54 (CO), 183.63 (CO).
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[CH2:28][S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[S:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:52]/[O:53][C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)/[C:49](O)=[O:50])[N:47]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl.Cl>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:49](=[O:50])/[C:48](/[C:46]4[N:47]=[C:43]([NH:42][C:40]([O:39][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:41])[S:44][CH:45]=4)=[N:52]\[O:53][C:54]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)[C@H:22]3[S:21][CH2:20][C:19]=2[CH2:28][S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[S:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Reactant: N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CSc3c[nH]nn3)CS[C@H]12
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a suspension of 7β-amino-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (110 mg: 0.2 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (122 mg: 0.23 mMol.) in dichloromethane (3 ml) are added N-methylmorpholine (72 μl: 0.66 mMol.) and phenyl dichlorophosphate (33 μl: 0.22 mMol.) at -30° C. After stirring for 2 hours, the reaction mixture is diluted with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, purified by silica gel chromatography, and crystallized from toluene to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (110 mg). m.p. 190°-200° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=1[CH3:22].B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[CH3:22]
Reactant: CCCn1nc(-c2ccc(OC)cc2C)c2cccc(Cl)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCn1nc(-c2ccc(O)cc2C)c2cccc(Cl)c21
Yield: 80.9 %

Procedure:
Prepared according to Method D step C from 7-chloro-3-(4-methoxy-2-methylphenyl)-1-propyl-1H-indazole (0.90 g, 0.3 mmol), boron tribromide (0.113 mL, 1.20 mmol) and 1.0 mL of cyclohexene to give the product (0.073 g) as a white solid.