Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].C([O-])([O-])=O.[Na+].[Na+].[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O.O1CCOCC1>[CH2:17]([O:16][C:14]([NH:3][C:2]([CH3:4])([C:5]([OH:7])=[O:6])[CH3:1])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-methylalanine (50 g, 0.49 mmol) and Na2CO3 (156 g, 1.47 mol) in water (1 L) was added a solution of CbzCl (91 g, 0.54 mmol) in dioxane (500 mL) at 0° C. over 15 minutes. The resulting solution was stirred at room temperature for 18 hours. The reaction was extracted with Et2O (2×500 mL), and the aqueous layer collected, acidified to pH=1 with cHCl and extracted with EtOAc (2×500 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford a white solid as the title compound that was used directly in the next step (111 g, 97%).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]2[C:11](=[O:26])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:13]=[C:14]([Cl:16])[N:15]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>C1COCC1.[Cu](I)I.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:16][C:14]1[N:15]=[C:10]([NH:9][C:3]2[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[C:11](=[O:26])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3Br)c2=O)cc1
Agent: I[Cu]I
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3C#C[Si](C)(C)C)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
In a 1 L round bottom combined 3-(3-bromo-5-methylpyridin-2-ylamino)-5-chloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (51.90 g, 119.12 mmol), triphenylphosphine (1.56 g, 5.96 mmol), (Ph3P)PdCl2 (4.18 g, 5.96 mmol) and suspended in anhydrous THF (450 mL). Triethylamine (18.08 g, 178.68 mmol) and trimethylsilyl acetylene (35.10 g, 357.36 mmol) were added next and mixture was stirred at ambient temperature, under N2 for 10 minutes. Copper iodide (catalytic) was added last and reaction was stirred at ambient temperature. Reaction was monitored by analytical LCMS at one hour intervals and CuI was added until reaction is complete. The completed reaction was concentrated in vacuo, taken up with ethyl acetate (700 mL) and brine (300 mL) and filtered off undissolved solids before taking on to extraction. The organic layer was washed with additional brine (4×300 mL), dried with MgSO4, filtered and concentrated in vacuo. Chromatography on silica gel plug with ethyl acetate/hexanes (1/9), two attempts, afforded the desired product (43.36 g. 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.11 (s, 9H) 2.26 (s, 3H) 3.73 (s, 3H) 5.00 (s, 2H) 6.91 (d, J=8.59 Hz, 2H) 7.38 (d, J=8.59 Hz, 2H) 7.45 (s, 1H) 7.74 (d, J=2.27 Hz, 1H) 8.25 (d, J=2.27 Hz, 1H) 9.51 (s, 1H). ESI-MS: m/z 453.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl-].[F:12][C:13]1[CH:22]=[CH:21][C:16]([CH:17]=[N+:18]([CH3:20])[CH3:19])=[CH:15][CH:14]=1.FC1C=CC(C=O)=CC=1.CNC>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH:17]([N:18]([CH3:20])[CH3:19])[C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[NH:6][CH:5]=2)=[CH:21][CH:22]=1
Reactant: Cc1cccc2[nH]ccc12
Reactant: C[N+](C)=Cc1ccc(F)cc1
Agent: CNC
Agent: O=Cc1ccc(F)cc1
Agent: [Cl-]
Product: Cc1cccc2[nH]cc(C(c3ccc(F)cc3)N(C)C)c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-methyl-1H-indole and (4-fluoro-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 4-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH3:11][CH:12]1[CH2:17][C:16](=[O:18])[CH2:15][C:14](=O)[CH2:13]1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.O>C(O)C.C(O)(=O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:14]3[CH2:13][CH:12]([CH3:11])[CH2:17][C:16](=[O:18])[C:15]2=3)=[CH:23][CH:22]=1
Reactant: CC1CC(=O)CC(=O)C1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC1(C)CC(=O)C=C(N)C1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC1CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of 1.39 g of 3-amino-5,5-dimethyl-2-cyclohexen-1-one, 1.26 g of 5-methyl-cyclohexane-1,3-dione and 1.51 g of 4-bromobenzaldehyde in 18 ml of absolute ethanol and 6 ml of glacial acetic acid was heated under reflux under a nitrogen atmosphere for 12 hours. The mixture was then cooled to room temperature and about 10 ml of water was added until the product precipitated. The product was filtered off and washed with three 50 ml portions of cold diethyl ether to give 9-(4-bromophenyl)-3,4,6,7,9,10-hexahydro-3,3,6(RS)-trimethyl-1,8(2H,5H)-acridinedione as a pale yellow solid. The product was shown to be a 9:1 mixture of diastereoisomers by HPLC and gave a mass ion of 414 (FAB, [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[C:36]1([NH:42][NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:43][NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: NNc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NNc4ccccc4)c(F)c3)c2cc1OC
Yield: 65.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, phenylhydrazine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (47 mg, yield 66%).
Reaction SMILES: C(=O)([O-])O.[Na+].[Br:6]Br.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:6][C:16]1[CH:17]=[C:10]([O:9][CH3:8])[C:11]([O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:26]([CH3:28])[CH3:27])=[CH:12][C:13]=1[CH:14]=[O:15]
Reactant: COc1ccc(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)c(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
After adding 10.9 g of sodium hydrogen carbonate and 2.32 ml of bromine to a solution of 10g of 4-methoxy-3-triisopropylsilanyloxybenzaldehyde [CAS No. 179260-96-6] in 200 ml of chloroform at 0° C., the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium sulfite was then added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (11.7 g) as a light yellow oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([N:13]2[C:17]([SH:18])=[N:16][N:15]=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22](=[O:23])[O:21]1>CN(C)C=O>[C:30]1([C:20]2([S:18][C:17]3[N:13]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:14]=[N:15][N:16]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22](=[O:23])[O:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: O=C1OC(Cl)(c2ccccc2)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OC(Sc2nnnn2-c2ccccc2)(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 300 ml of dried dimethylformamide, was added 14.56 g (0.12 mol.) of potassium tert-butoxide and 18 g (0.1 mol.) of 1-phenyl-5-mercaptotetrazole. The mixture was stirred for 20 minutes at room temperature. Thereafter, to the mixture cooled to 5° C. and kept there, was gradually added dropwise a solution prepared by adding 25 g (0.1 mol.) of 3-chloro-3-phenylphthalide to 75 ml of dried dimethylformamide. At the conclusion of the dropwise addition, the cooling bath was removed, and the mixture was stirred for 2 hours at room temperature. Thereto, 300 ml of a saturated aqueous solution of ammonium chloride was added. The reaction mixture was extracted with ethyl acetate repeatedly. The extract was washed with water, and the resulting organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was filtered off with suction, and the filtrate was concentrated to yield 35 g of oily substance. This oily substance was separated and purified by flash column chromatography (silica gel: 700 g, eluate: hexane-ethyl acetate (3:1 by vol.) mixture). Thus, the intended compound, 3-phenyl-3-(1-phenyltetrazole-5-ylthio)phthalide (1), was obtained in the form of white crystals. Yield 21.5 g, Melting Point 137°-139° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17].O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[N:17]/[NH:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N/N=C/c1ccc(-c2ccccn2)cc1
Yield: 97 %

Procedure:
4-(2-Pyridyl)benzaldehyde (15 g, 0.082 mol) was dissolved in ethanol (150 mL) and treated with t-butyl carbazate (10.3 g, 0.078 mol) at 80° C. for 4 h. The mixture was combined with water (200 mL), the solids were filtered, washed with water, and dried under vacuum to give 22.5 g (92%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([CH:37]([OH:39])[CH3:38])=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].CS(O[Na])=O>CN(C=O)C.O.CCOC(C)=O>[F:32][C:33]1[CH:41]=[CH:40][C:36]([CH:37]([O:39][C:2]2[N:7]=[C:6]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)[CH:5]=[C:4]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[N:3]=2)[CH3:38])=[CH:35][CH:34]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Reactant: CC(O)c1ccc(F)cc1
Agent: CS(=O)O[Na]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(OC(C)c4ccc(F)cc4)n3)cccc2s1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide (465 mg, 1.0 mmol, Example 7(d)), 4-fluoro-α-methylbenzyl-alcohol (140 mg, 1 mmol, Aldrich), K2CO3 (207 mg, 1.5 mmol) and 85% MeSO2Na (30 mg, 0.25 mmol, Aldrich) in DMF (50 mL) was heated at 120° C. with stirring for 5 h. The reaction mixture was allowed to reach room temperature and was diluted with water (50 mL), and exacted with EtOAc (2×50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue purified by silica gel column chromatography (20% EtOAc/hexane) to give the title compound. MS (ESI, pos. ion) m/z: 569 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[C:3]1[C:11](OCC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:12][CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][N:9]=2
Reactant: CCOC(=O)c1cc2cccnc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(CO)cc2cccnc21
Yield: 106.5 %

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 130 mg of ethyl 1-methyl -7-azaindole-2-carboxylate (prepared as described in Preparation 80), 23 mg of lithium aluminum hydride and 2 ml of tetrahydrofuran were used, to give 110 mg of the title compound having Rf=0.47 (on silica gel thin layer chromatography using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C:14]([CH2:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:41]([O:45][C:46](=[O:52])[CH2:47][S:48](Cl)(=[O:50])=[O:49])([CH3:44])([CH3:43])[CH3:42]>ClCCl>[CH:26]1([CH2:25][CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][S:48]([CH2:47][C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:52])(=[O:50])=[O:49])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:29])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)Cl
Reactant: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC3CC3)C1=O)N2
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a stirring solution of Example 158 (0.070 g, 0.160 mmol) in dichloromethane containing N,N-diisopropylethylamine (0.036 mL, 0.208 mmol) was added chlorosulfonyl-acetic acid tert-butyl ester (0.041 g, 0.192 mmol). The reaction mixture was stirred overnight and then partitioned between ethyl acetate and water. The organic layer was washed sequentially with 10% 1N HCl in water, bicarb, and brine. The product was purified by flash chromatography on SiO2 eluting with 0-50% ethyl acetate/hexanes yielding the title compound (0.030 g, 30.5% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm −0.23 (dd, J=9.01, 4.23 Hz, 2 H) 0.25 (d, J=6.62 Hz, 2 H) 0.45 (m, 2 H) 0.85 (m, 1 H) 1.25 (m, 1 H) 1.39 (s, 9 H) 1.57 (m, 3 H) 2.34 (m, 1 H) 4.22 (m, 2 H) 7.55 (m, 2 H) 7.62 (dd, J=10.29, 2.21 Hz, 2 H) 7.75 (m, 3 H) 8.15 (d, J=7.72 Hz, 1 H) 10.61 (s, 1 H) 13.73 (m, 1 H). MS (ESI+) m/z=516 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:31][O:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=1>CN(C1C=CN=CC=1)C>[CH3:31][O:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:18](=[O:19])[CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:36]([C:41]([F:43])([F:42])[F:44])[CH:35]=1
Reactant: COC(=O)c1ccc(N)c(C(F)(F)F)c1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-3-trifluoromethyl-benzoic acid methyl ester (CAS Reg. No. 34040-64-7 167760-75-0) in the presence of DMAP to give the title compound as yellow oil. MS: m/e=574.4 [M+H+].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([O:9][N:10]=[C:11]([C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[S:18][CH:19]=2)[C:12]([OH:14])=O)[CH2:8][CH2:7]1.[NH2:27][C@@H:28]1[C:45](=[O:46])[N:30]2[C:31]([C:42]([OH:44])=[O:43])=[C:32]([CH2:35][S:36][C:37]3[S:38][CH:39]=[N:40][N:41]=3)[CH2:33][S:34][C@H:29]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[CH:6]1([O:9][N:10]=[C:11]([C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[S:18][CH:19]=2)[C:12]([NH:27][C@@H:28]2[C:45](=[O:46])[N:30]3[C:31]([C:42]([OH:44])=[O:43])=[C:32]([CH2:35][S:36][C:37]4[S:38][CH:39]=[N:40][N:41]=4)[CH2:33][S:34][C@H:29]23)=[O:14])[CH2:7][CH2:8]1
Reactant: O=C(O)C(=NOC1CC1)c1csc(NC(=O)C(F)(F)F)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2[C@H](NC(=O)C(=NOC3CC3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
Phosphorus oxychloride (0.24 ml) was dropwise added to a mixture of N,N-dimethylformamide (0.2 ml) and tetrahydrofuran (0.4 ml) under ice-cooling. After being stirred for 10 minutes at the same temperature, the mixture was cooled until a precipitate appeared. To the suspension was added 2-cyclopropyloxyimino-2-(2-trifluoroacetamidothiazol-4-yl) acetic acid (syn isomer) (647 mg) and additional tetrahydrofuran (4 ml). The mixture was stirred at the same temperature for 30 minutes to give an activated acid solution. On the other hand, a mixture of 7β-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (793 mg) and bis(trimethylsilyl)acetamide (2 ml) in tetrahydrofuran (20 ml) was stirred at 30° C. for 30 minutes to give a clear solution. To the clear solution was added the activated acid solution prepared above at -30° C. The mixture was stirred for 30 minutes at -20° C. to -15° C. The mixture was poured into ice-water, adjusted to pH 7.2 with saturated aqueous solution of sodium bicarbonate, and washed with ethyl acetate. The aqueous solution was adjusted to pH 2.5 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether to give 7β-[2-cyclopropyloxyimino-2-(2-trifluoroacetamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.21 g) as a solid.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:25])([F:24])[CH2:22][OH:23]>>[F:20][C:21]([F:25])([F:24])[CH2:22][O:23][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Reactant: OCC(F)(F)F
Product: CC(C(=O)NC(=O)OCC(F)(F)F)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p.=143-145° C., MS: m/e=351.3 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl isocyanate and 2,2,2-trifluoro-ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Br:12])=[CH:8][C:9]=2[F:11])[NH:4][C:3]=1[C:13]([NH2:15])=[O:14].[O:16]=[C:17](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[Br:12][C:7]1[CH:8]=[C:9]([F:11])[C:10]2[C:2]3[NH:1][C:17](=[O:16])[NH:15][C:13](=[O:14])[C:3]=3[NH:4][C:5]=2[CH:6]=1
Reactant: NC(=O)c1[nH]c2cc(Br)cc(F)c2c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(=O)c2[nH]c3cc(Br)cc(F)c3c2[nH]1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
15.4 g (56.6 mmol) 3-amino-6-bromo-4-fluoro-1H-indole-2-carboxylic acid amide was suspended in 300 ml dioxan and after the addition of 7.5 ml (61.8 mmol) diphosgene the suspension was refluxed for 2 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was subsequently sucked off. 12.5 g (74%) 7-bromo-9-fluoro-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 296, 298 [M−H]−
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([O:14]C(OCC)C)[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)O[C@@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 2-benzyl 3-methyl (2S,3S,5R)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate (5.70 g, 0.0125 mol) in 100 mL of THF was added 20 mL of water followed by 20 mL of 1N HCl. The mixture was stirred at rt for 1 h. After diluted with EtoAc, the mixture was neutralized with 1N NaOH, washed with brine, dried. The residue obtained after concentration was applied on silical, eluting with 0 to 50% EtOAc in hexane, to provide the alcohol compound (4.80 g, 89.6%). MS (ESI): (M+H)+=384.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([Cl:22])=[CH:16][C:17]=2[CH3:21])[NH:12]1)=[O:10].I[CH3:24]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([Cl:22])=[CH:16][C:17]=2[CH3:21])[N:12]1[CH3:24])=[O:10]
Reactant: CI
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)NCCc3cccs3)c(=O)c12
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)NCCc1cccs1)n2C

Procedure:
In analogy to example 2, 100 mg (0.297 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydropyrazolo[3,4-b]pyridine-2-carboxylic acid (2-thiophen-2-ylethyl)amide were reacted with 22.2 μl of iodomethane in THF. Yield: 18 mg (77%), M+H+: 351.12.
Reaction SMILES: [CH3:1][C:2]([O:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][O:16]C1CCCCO1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>C(O)C>[OH:16][CH2:15][C:14]#[C:13][CH2:12][CH2:11][CH2:10][O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)OCCCC#CCOC1CCCCO1
Solvent: CCO
Product: CCOC(=O)C(C)(C)OCCCC#CCO
Temperature: 57.5 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Ethyl 2-methyl-2-[6-(tetrahydro-2H-pyran-2-yloxy)-4-hexynyloxy]propionate (3.72 g) was dissolved in 37 ml of ethanol, and 15.372 mg of Amberlyst® was added thereto and the mixture was stirred for 1 hour at 55-60° C. After cooling, the mixture was filtrated and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=9:1-3:1) to provide 1.98 g of the objective compound as pale yellow oil.