Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1.[CH3:9][C:10]([O:13][C:14]([N:16]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:17]([C:25]1[C:30]([F:31])=[C:29](Cl)[N:28]=[C:27]([Cl:33])[N:26]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOCC>[CH3:12][C:10]([O:13][C:14]([N:16]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:17]([C:25]1[C:30]([F:31])=[C:29]([N:4]2[CH2:5][CH2:6][O:7][CH2:8][C@@H:3]2[CH3:2])[N:28]=[C:27]([Cl:33])[N:26]=1)[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:15])([CH3:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: C[C@H]1COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@H]1COCCN1c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of (3S)-3-methylmorpholine hydrochloride (0.2059 g, 1.496 mmol) in DMF (7.5 mL) was added tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.7451 g, 1.498 mmol), and N,N-diisopropylethylamine (0.575 mL, 3.301 mmol). The solution was stirred overnight, and then diluted with Et2O (150 mL). The mixture was washed with water (2×50 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (50 mL). This Et2O layer was washed with a fresh portion of water (50 mL), and the combined organic phase was diluted with DCM (50 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and azeotroped with EtOAc. The solid was collected by vacuum filtration and washed with hexanes. The supernatant was concentrated in vacuo, and purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N). The desired fractions were concentrated in vacuo, and the resulting solid was collected by vacuum filtration, washed with hexanes, and combined with the first crop of solid to give tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.6610 g, 79%) as a white solid. LCMS: (M+H)+: 562.2.
Reaction SMILES: [C@H:1]1([C:13]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH2:2]1.[C:19](O)(=[O:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:56][O:57][C:58]1[CH:59]=[C:60]([CH2:64][C:65]([OH:67])=O)[CH:61]=[CH:62][CH:63]=1>CN(C)C=O.O>[C:19]([NH:12][C:10]1[S:11][C:7]([C@H:3]2[CH2:4][CH2:5][CH2:6][C@H:1]([C:13]3[S:17][C:16]([NH:18][C:65](=[O:67])[CH2:64][C:60]4[CH:61]=[CH:62][CH:63]=[C:58]([O:57][CH3:56])[CH:59]=4)=[N:15][N:14]=3)[CH2:2]2)=[N:8][N:9]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: COc1cccc(CC(=O)O)c1
Reactant: Nc1nnc([C@H]2CCC[C@H](c3nnc(N)s3)C2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc(CC(=O)Nc2nnc([C@H]3CCC[C@H](c4nnc(NC(C)=O)s4)C3)s2)c1
Temperature: 50 °C

Procedure:
A solution of 5,5′-((1S,3S)-cyclohexane-1,3-diyl)bis(1,3,4-thiadiazol-2-amine) (50 mg, 0.18 mmol), acetic acid (1 eq), HATU (202 mg, 0.53 mmol), and DIPEA (73 mg, 0.57 mmol) in N,N-dimethylformamide (2 ml) was heated to 50° C. for 2 h, then 3-methoxy-2-phenylacetic acid was added. The mixture was heated at 50° C. overnight and then poured into water (20 ml), the precipitate was filtered to give the crude product. The crude product was purified by a standard method to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(OCC)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To 2-chloro-5-nitroaniline (2 g, 11.59 mmol) in pyridine (5 mL) at room temperature was added 4-methylbenzoyl chloride (1.6 mL, 12.17 mmol), followed by pyridine (5 mL). The mixture was then stirred at room temperature for 16 h. Ethyl acetate was then added to the solution to give a precipitate, which was filtered off and washed twice with ethyl acetate, and then hexanes. The resulting solid was then washed with aqueous sodium bicarbonate, 1M aqueous sodium hydroxide, water and hexanes to afford (1.4 g, 42%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7]
Reactant: [I-]
Reactant: C=CCOC(=O)c1cccc(CCl)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOC(=O)c1cccc(CI)c1

Procedure:
A solution of allyl 3-(chloromethyl)-benzoate (54.5 g, 0.259 mmol) and sodium iodide (46.56 g, 0.311 mol) in acetone (500 mL) is stirred at room temp. for 6.5 hours, after which time the mixture is filtered. The filtrate is evaporated and the residue is dissolved in diethyl ether (500 mL), then washed with water (1×200 mL), 5% sodium sulfite solution (1×200 mL) and brine (1×200 mL), dried over magnesium sulfate, and evaporated to yield allyl 3-(iodomethyl)-benzoate as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([O:31]COC)=[CH:27][CH:26]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])\[CH2:16][CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.O1CCOCC1.O>[CH3:36][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])\[CH2:16][CH3:17])=[CH:10][CH:11]=1
Reactant: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1)c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 4a (75 mg, 0.153 mmol) in MeOH (2 ml) was added 4N HCl in 1,4-dioxane (0.4 ml) under ice cooling, and the mixture was stirred at room temperature for 2 h. A solution of NaHCO3 in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residual was crystallized with AcOEt to give 5a (74%). 5a: colorless powder; 1H-NMR (CD3OD) δ 0.97 (3H, t, J=7.5 Hz), 2.09 (3H, s), 2.37 (6H, s), 2.58 (2H, q, J=7.5 Hz), 2.80 (2H, t, J=5.5 Hz), 4.11 (2H, t, J=5.5 Hz), 6.47 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=9.1 Hz), 6.94 (2H, d, J=9.1 Hz), 7.05-7.15 (4H, m), 7.53 (2H, d, J=9.1 Hz). HRMS calcd for C28H33N2O3 [M+H]+: 445.2491. Found: 445.2497.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[NH2:22])=[CH:7][CH:6]=1.[C:24](=O)([O-])[O-].[K+].[K+].[C:30]1(C)[C:31]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=1.Cl>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[NH:22][S:36]([C:31]2[CH:30]=[CH:35][C:34]([CH3:24])=[CH:33][CH:32]=2)(=[O:37])=[O:38])=[CH:7][CH:6]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2N)cc1
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
[4-(2-Amino-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester (84 mg, 0.542 mmol) was added to a mixture of 150 mg (1.08 mmol) of potassium carbonate in 3 mL of ethyl acetate in presence of 0.5 mL of water. To the resulting mixture was added 155 mg (0.813 mmol) toluenesulfonyl chloride. The resulting mixture was allowed to stir at room temperature overnight. Upon completion, 20 mL of 2N HCl aqueous solution was added and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed to give 97 mg of {4-[2-(toluene-4-sulfonylamino)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester. 1H NMR (CDCl3): δ 7.93 (s, 1H), 7.65 (d, J=8.36 Hz, 2H), 7.15-7.28 (m, 5H), 6.68 (d, J=8.68 Hz, 1H), 6.63 9d, J=8.48 Hz, 2H), 3.72 (s, 3H), 3.61 9s, 2H), 2.39 9s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])[CH:27]=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:44][S:45]([CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:47])=[O:46]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:54]3[CH2:55][CH2:56][N:51]([CH2:50][CH2:49][CH2:48][S:45]([CH3:44])(=[O:46])=[O:47])[CH2:52][CH2:53]3)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])[CH:27]=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1ccc(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccc(S(=O)(=O)N2CCCC2)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-5-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H48N5O6S2Cl2 [(M+H)+] 804.2418, observed 804.2413
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:10](I)[C:3]=12.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CN(C=O)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:10]([C:22]3[CH:23]=[C:24]4[C:19]([CH2:18][CH2:17][N:16]4[CH3:15])=[CH:20][CH:21]=3)[C:3]=12
Reactant: CN1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(C)n1cc(I)c2c(Br)ccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)n1cc(-c2ccc3c(c2)N(C)CC3)c2c(Br)ccnc21
Temperature: 55 °C
Yield: 68.2 %

Procedure:
To a stirred suspension of 4-bromo-3-iodo-1-isopropyl-1H-pyrrolo[2,3-b]pyridine (D10) (2.5 g, 6.85 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (2.130 g, 8.22 mmol) in ACN (15 mL), DMF (15.00 mL) and DCM (7.50 mL) was added 2M sodium carbonate aq. solution (34.2 mL, 68.5 mmol). Bis(triphenylphosphine)palladium(II) chloride (0.577 g, 0.822 mmol) was then added to the solution and the resulting mixture was heated at 55° C. for ca. 1 hour. Temperature was raised to 65° C. and heated for another 1 hour. The reaction was allowed to cool to RT and diluted with DCM (70 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organics were dried and concentrated down. The residue obtained was purified on silica using 0-10% ethyl acetate/cyclohexane to afford the title compound (1.73 g). LCMS (A): m/z (M+H)+ 370/372, C19H20BrN3 requires 369/371 (acidic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC[N:32]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:32])=[O:23])=[CH:20][CH:19]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3ccc(C(=O)O)cc3)nc3scnc23)cc1OC
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Nc2nc(-c3ccc(C(N)=O)cc3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
To a mixture of 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (210 mg, 0.52 mmol), EDCI (147 mg, 0.77 mmol), HOBt (104 mg, 0.77 mmol) and Et3N (104 mg, 1.07 mmol) in DCM (20 mL) was bubbled ammonia until saturation. The mixture was stirred at room temperature for 3 h, then was filtered and the filtrate was concentrated to give residue which was purified by column chromatography (DCM:MeOH=50:1) to afford 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (38 mg, 22%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.14 (s, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.62 (d, 1H, J=2.4 Hz), 7.32-7.28 (m, 1H), 6.92 (d, 1H, J=9.0 Hz), 3.75 (s, 3H), 3.72 (s, 3H). LC-MS: 599 [M+H]+, tR=1.54 min. HPLC: 95.59% at 214 nm, 95.99% at 254 nm, tR=4.594 min. LC-MS: 408 [M+H]+, tR=1.392 min. HPLC: 95.38% at 214 nm, 96.23% at 254 nm, tR=5.259 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[CH2:12]([O:19][CH2:20][CH:21]1[CH2:25][N:24]([C:26]2[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=2)[C:23](=[O:32])[CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH2:12]([O:19][CH2:20][CH:21]1[CH2:25][N:24]([C:26]2[C:30]([N+:1]([O-:4])=[O:2])=[CH:29][N:28]([CH3:31])[N:27]=2)[C:23](=[O:32])[CH2:22]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cn1ccc(N2CC(COCc3ccccc3)CC2=O)n1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2CC(COCc3ccccc3)CC2=O)n1

Procedure:
To a mixture of fuming nitric acid (0.32 mL) and acetic anhydride (5.0 mL) was added 4-((benzyloxy)methyl)-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (1.1 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, water was added thereto, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.1 g).
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: 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
Reactant: Cc1ncsc1CCNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
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: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>>[Si:37]([O:13][C:11]1[CH:10]=[CH:9][C:8]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:20]=3)[CH2:15]2)=[C:7]([NH:6][CH2:5][C:4]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:2]([F:1])[CH:3]=2)[CH:12]=1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2c(c1)CCC(c1ccc(O)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Yield: 85.3 %

Procedure:
Synthesized from 6-{2-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzylamino]-4-hydroxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol (240 mg) and tert-butyldimethylsilyl chloride (220 mg) according to an analogous synthetic method to Example 201 described below, the title compound (300 mg) was obtained.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])(=[O:15])[CH3:14].[CH2:30](O)[CH:31]([OH:33])[CH3:32].C1(C)C=CC=CC=1>O>[CH3:14][C:13]1([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]3([CH3:29])[CH3:28])[O:33][CH:31]([CH3:32])[CH2:30][O:15]1
Reactant: CC(O)CO
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1COC(C)(c2ccc3c(c2)C(C)(C)CCC3(C)C)O1
Temperature: 110 °C

Procedure:
p-Toluenesulphonic acid monohydrate (2 g) is added to a suspension of 120 g (0.5 mol) of 6-acetyl-1,1,4,4-tetra-methyl-tetralin, 120 g (1.6 mol) of propylene glycol and 600 ml of toluene. The mixture is heated to 110° C. The reaction water is removed azeotropically within 5 hours. After cooling to room temperature the mixture is adjusted to pH 7.5 to 8 by the addition of 10% potassium hydroxide in ethanol. Thereupon, the mixture is filtered. The solvent is evaporated and the residual liquid is distilled under a vacuum, whereby there separate as the main product 123 g of 2.4-dimethyl-2-(1,1,4,4-tetramethyl-tetralin-6-yl)-1,3-dioxolane as a mixture of the boiling point is 112° C. at 0.5 mmHg; nD20 =1.5130. The product has a strong woody, animalic odour.
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([CH2:29][OH:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:41]1([N:47]2[CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:49]=[N:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:50]3[CH:49]=[N:48][N:47]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:51]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([CH2:29][OH:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CC1(C)OB(c2cnn(-c3ccccc3)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Temperature: 90 °C
Yield: 72.4 %

Procedure:
A mixture of ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate (270 mg, 0.383 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (135 mg, 0.498 mmol), PdCl2(dppf)CH2Cl2 (31.3 mg, 0.038 mmol), and K3PO4 (244 mg, 1.15 mmol) in dioxane/H2O (3/0.3 mL) was degassed and then heated at 90° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.55 in 50% EtOAc) to afford ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate as a pale yellow solid (200 mg). HPLC-MS TR=3.06 min (UV 254 nm, 5 min method); mass calculated for formula C37H56N6O5Si2 720.4, observed LCMS m/z 721.3 (M+H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15](C)[C:14]([C:20]([O:22]CC)=O)=[CH:13]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25].[NH2:26][C:27]([NH2:29])=[NH:28].[CH3:30][O-].[Na+]>CO>[ClH:25].[C:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:20]([N:28]=[C:27]([NH2:29])[NH:26][CH3:30])=[O:22])=[CH:13]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3)ccc2n1C
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2cc(NC(=O)c3ccccc3)ccc2[nH]1

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 0.62 g-(1.92 mmol) of ethyl 5-benzamido-1-methyl-2-indole-carboxylate, 3.68 g (38.4 mmol) of guanidine hydrochloride and 50 ml of a methanol solution of 2.08 g (38.4 mmol) of sodium methoxide. 5-Benzamido-1-methyl-2-indoloylguanidine hydrochloride was obtained in an amount of 0.38 g (53.1%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](Cl)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:14][CH2:12][CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc2cccc(Br)c2s1
Reactant: CCN
Product: CCNc1nc2cccc(Br)c2s1
Temperature: 70 °C
Yield: 92.4 %

Procedure:
7-Bromo-2-chlorobenzothiazole (100 mg, 0.40 mmol) was added to ethylamine (2.0 M in THF, 1 mL, 2 mmol) and the solution was heated at 70° C. for 1 h. The crude mixture was purified by ISCO chromatography (100% DCM) to afford 95 mg (92%) of the title compound as white solid. MS (ESI): 257.33, 259.31 [M+H]+; HPLC tR=1.27 min (HPLC: Anayltical—2 min).