Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].C1([N:13]2[CH2:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]5([C:45](=[O:52])[NH:46][CH2:47][C:48]([F:51])([F:50])[F:49])[C:44]6[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=6[C:38]6[C:33]5=[CH:34][CH:35]=[CH:36][CH:37]=6)[CH2:24][CH2:23]4)=CC=3)C2=O)CCCCC1.[C:54](OCC)(=O)[CH3:55]>CN(C=O)C>[F:51][C:48]([F:50])([F:49])[CH2:47][NH:46][C:45]([C:32]1([CH2:31][CH2:30][CH2:29][CH2:28][N:25]2[CH2:24][CH2:23][N:22]([C:17]3[CH:16]=[CH:15][C:20]([C:1]([O:2][CH2:54][CH3:55])=[O:4])=[CH:21][N:13]=3)[CH2:27][CH2:26]2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=2[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:52]
Reactant: CCOC(C)=O
Reactant: O=C1c2cc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)ccc2CN1C1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
The compound (494 mg, 2.1 mmol) prepared just above in step (b) was dissolved in 8 ml of anhydrous DMF. Potassium carbonate (580 mg) and the compound (892 mg, 2.1 mmol) prepared in step (b) of Example 92 were added to the solution, and the mixture was stirred at 50° C. overnight. The reaction solution was diluted with ethyl acetate, and the dilution was washed twice with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography (development system, n-hexane:ethyl acetate=1:1) to give ethyl 6-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]butyl]-piperazin-1-yl]nicotinate (742 mg, yield 62%) as a pale yellow oil.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])[CH3:4].OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:9]1[CH:8]=[C:7]([CH3:11])[C:6]([OH:12])=[C:5]([CH2:3][CH3:4])[CH:10]=1
Reactant: BrBr
Reactant: CCc1cccc(C)c1O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)cc(C)c1O
Reaction time: 2 h

Procedure:
A solution of 12.7 mL (247 mmol) bromine in 10 mL chloroform was added dropwise at RT to a solution of 33.6 g (247 mmol) 2-ethyl-6-methyl-phenol in 350 mL chloroform and the mixture was stirred for 2 h. The reaction mixture was combined with an aqueous NaHSO3 solution and stirred for 20 min. The phases were separated and the organic phase was washed with saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation i. vac. Column chromatography (silica gel, Cyc/EtOAc 9:1) yielded the product.
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][N:13]=[C:14]([C:18]1[N:19]([CH3:28])[C:20](=[N:23][S:24]([CH3:27])(=[O:26])=[O:25])[S:21][CH:22]=1)[C:15]([OH:17])=O.[NH2:29][CH:30]1[C:48](=[O:49])[N:32]2[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH3:44])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12>C(Cl)Cl.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>[CH3:11][O:12][N:13]=[C:14]([C:18]1[N:19]([CH3:28])[C:20](=[N:23][S:24]([CH3:27])(=[O:26])=[O:25])[S:21][CH:22]=1)[C:15]([NH:29][CH:30]1[C:48](=[O:49])[N:32]2[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH3:44])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12)=[O:17]
Reactant: CON=C(C(=O)O)c1csc(=NS(C)(=O)=O)n1C
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(=NS(C)(=O)=O)n1C
Temperature: 40 °C
Yield: 66.6 %

Procedure:
A mixture of dimethylformamide (0.22 g.) and phosphorus oxychloride (0.46 g.) was warmed for 1 hour at 40° C. The mixture was dissolved in dry methylene chloride (20 ml.) and 2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetic acid (anti isomer) (0.73 g.) was added thereto with stirring and ice-cooling, after which the resulting mixture was stirred for 1.5 hours under ice-cooling. On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.82 g.) was dissolved in a solution of bis(trimethylsilyl)acetamide (1.5 g.) in dry methylene chloride (20 ml.). To this solution was added at -30° C. the above obtained methylene chloride solution, after which the mixture was stirred for 2 hours at -5° to -20° C. After distilling off methylene chloride at low temperature, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and water (50 ml.) was added thereto. The resulting mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the aqueous layer was separated. The aqueous layer was adjusted to pH 1.5, saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized by a mixture of diisopropyl ether and ether. The powder was collected by filtration and dried to give 7-[2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (1.0 g.). This powder (1.0 g.) was suspended in water (30 ml.) and dissolved by adjusting to pH 6 by an aqueous solution of sodium bicarbonate. After removing the solvent by bubbling of nitrogen gas, the aqueous solution was lyophilized to give sodium 7-[2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (anti isomer) (0.98 g.).
Reaction SMILES: N.[Cl:2][C:3]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:4]=1[O:5][CH:6]([CH3:10])[C:7]([NH2:9])=O.C[N:17]1CCO[CH2:19][CH2:18]1.Cl.NCCN>C(O)C.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:4]=1[O:5][CH:6]([C:7]1[NH:17][CH2:18][CH2:19][N:9]=1)[CH3:10]
Reactant: CC(Oc1c(Cl)cccc1Cl)C(N)=O
Reactant: CN1CCOCC1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: NCCN
Product: CC(Oc1c(Cl)cccc1Cl)C1=NCCN1

Procedure:
Another process is also based on (+)-2-(2,6-dichlorophenoxy)-propionic acid ethylester which is reacted with an ethanolic solution of ammonia at room temperature and is converted in to (-)-2-(2,6dichlorophenoxy)-propionic acid amide which is difficultly soluble in ethanol. This amide is dehydrated at from 0° to 30° C. with a titanium tetrachloride/tetrahydrofuran complex and 4-methyl-morpholine in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionic acid nitrile. By introducing hydrogen chloride at 0° C., the nitrile is then converted with ethanol in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionimido acid ethylester hydrochloride, this compound is dissolved in ethanol and is cyclised by adding 1,2-diaminoethane to produce (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene. Analogously to the previous process, (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene hydrochloride is produced from the (+) base thus obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@H:7]1[OH:19])=[O:4].[H-].[Na+]>C1COCC1>[O:4]=[C:3]1[CH2:2][O:19][C@@H:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11][C@H:6]2[NH:5]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)CCl)[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]2NC(=O)CO[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 9.6 %

Procedure:
To a stirred mixture of 249B (410 mg, 14.0 mmol) in 10 mL of dry THF under N2 at room temperature was added 60% NaH (84.0 mg, 2.10 mmol). This mixture was stirred at room temperature for 45 min and quenched with 3 mL of saturated NH4Cl solution. The mixture was concentrated in vacuo and diluted with 40 mL of saturated NaHCO3 solution. The aqueous solution was extracted with EtOAc (3×60 mL). The combined EtOAc extracts were washed with brine (1×30 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo to give 344 mg (yield: 96%) of 249C. It had an analytical HPLC retention time=2.01 min. (Chromolith SpeedROD 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm) and a LC/MS M+=257.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C(O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:31][CH3:30])[CH:37]=3)=[CH:3][CH:4]=2)[N:9]=[C:10]([C:20]([C:22]([F:24])([F:23])[F:25])([C:26]([F:28])([F:29])[F:27])[OH:21])[CH2:11]1
Reactant: OC(C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1cccc(-c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 6.8 %

Procedure:
1-(4-Bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (50.0 mg, 0.10 mmol) prepared in Step 5 of Preparation 24, 3-methylthiophenylboronic acid (25.1 mg, 0.15 mmol), Pd(PPh3)4 (11.5 mg, 0.01 mmol), and a 2N sodium carbonate solution (0.5 mL) were added to a mixed solvent of 1,2-dimethoxyethane (2.0 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 90° C. for 2 hours and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 3.7 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CO.O.CCOC(C)=O>[NH2:1][C:2]1[C:11]([F:23])=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cnc(N)c(Cl)c1Nc1ccc(I)cc1F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cnc(N)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-amino-5-chloro-4-(2-fluoro-4-iodophenylamino)nicotinate (2.0 g, 4.74 mmol) (Example 11, step E) in a mixture of MeOH/water (1/1) (20 ml) is added selectfluor (1.6 g, 4.74 mmol). The mixture is stirred at room temperature overnight, diluted with EtOAc and washed with 0.5 N HCl and brine. The organic extracts are dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by HPLC (reverse phase) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)c1ccc(=O)[nH]c1C
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(=O)[nH]c1C=CN(C)C

Procedure:
A mixture containing 25 g of 6-methyl-5-(n-propanoyl)-2-(1H)-pyridinone, 200 ml of dimethylformamide and 25 ml of dimethylformamide dimethyl acetal was heated on a steam bath for 5 and 1/2 hours and the dimethylformamide was removed by heating the reaction mixture on a rotary evaporator. The residue was refluxed with 100 ml of ethanol, the mixture cooled, and the yellow solid was collected, washed with ethanol and dried in an oven at 90°-95° C. to yield 12.8 g of 6-(2-dimethylaminoethenyl)-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][NH:30]C(OC(C)(C)C)=O)[CH:25]=[CH:26][C:27]=1[F:28].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:24]2[CH:25]=[CH:26][C:27]([F:28])=[C:22]([Cl:21])[CH:23]=2)[N:30]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)c(Cl)c1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 28.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-(3-chloro-4-fluorophenyl)hydrazinecarboxylate (Intermediate-85, 0.455 g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.200 g of the desired product.
Reaction SMILES: [CH3:1][CH:2]1[S:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19].C[C@H](N)[C@H](O)C1C=CC=CC=1>CO>[CH3:1][C@@H:2]1[S:8][C@@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19]
Reactant: CC1SC(C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Agent: C[C@H](N)[C@H](O)c1ccccc1
Solvent: CO
Product: C[C@@H]1S[C@@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Reaction time: 0.5 h

Procedure:
In 5 mL of methanol was suspended 0.5 g of a racemic mixture, 1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (content 99.5%; trans compound 88.1%, cis compound 11.4%). To the suspension was added 0.27 g (1 equivalent) of (1R,2S)-norephedrine, which was once made into a solution, followed by crystallization in about 5 minutes. Then, the crystals were aged for 30 minutes at room temperature (25° C.). The crystals were collected by filtration, washed with 5 mL of cold methanol and dried overnight at room temperature under reduced pressure to afford 0.25 g of substantially pure (2R,4S)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid.(1R,2S)-norephedrine salt as colorless crystals [HPLC area percentage: (2R,4R):(2S,4S):(2S,4R):(2R,4S)=0.7%:0%:3.7%:95.3%]
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[CH3:14][C:15]([OH:29])([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)CC(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][CH:23]([C:15]([OH:29])([CH3:14])[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:24][CH2:25]2)=[CH:8][CH:9]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CC(O)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(O)(c1ccc(F)cc1)C1CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
A mixture of 2.7 g of 4-chloro-4'-fluorobutyrophenone, 2.5 g of α-methyl-α-(4-piperidyl)-p-fluorobenzyl alcohol, 8 g of sodium carbonate, a crystal of sodium iodide and 30 ml of 4-methyl-2-pentanone is stirred and refluxed for 72 hours. The reaction mixture is worked up in the usual manner as described in the previous Examples. The product is isolated as described above and recrystallized from isopropanol to afford the 4'-fluoro-4-[4-(α-hydroxy-α-methyl-p-fluorobenzyl)-piperidino]-butyrophenone, melting at 116°-118°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:12]#N)[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O.C[N:34](C)C=O>>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[O:16][CH2:15][CH2:14][C:11]1[C:6]([CH:7]([C:8]#[N:34])[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:5][C:4]([Cl:3])=[C:9]([Cl:10])[CH:12]=1
Reactant: CCOC(=O)CCCBr
Reactant: CN(C)C=O
Reactant: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCCC(C#N)c1cc(Cl)c(Cl)cc1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.6 g of 60% NaH are added in small portions to a solution of 36 g of the above 3,4-dichloro-α-[(2-tetrahydropyranyloxy)ethyl]benzeneacetonitrile (prepared according to PREPARATION II (a)) in 100 ml of dimethylformamide. The reaction mixture is stirred for 3 hours at room temperature and cooled to 0° C. and 22.4 g of ethyl 4-bromobutyrate in 40 ml of dimethyl-formamide are then added. The reaction mixture is stirred for 3 hours at room temperature, poured into water and extracted with ether and the extract is washed with a saturated solution of NaCl, dried over Na2SO4 and concentrated under vacuum. The residue obtained is purified by chromatography on silica gel using toluene as the eluent to give 24 g of the expected product.
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][C:11]2([O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.Cl>[Pd].O>[O:15]1[C:11]2([CH2:18][CH2:19][NH:8][CH2:9][CH2:10]2)[C:12](=[O:17])[NH:13][C:14]1=[O:16]
Reactant: O=C1NC(=O)C2(CCN(Cc3ccccc3)CC2)O1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C2(CCNCC2)O1
Reaction time: 12 h
Yield: 69 %

Procedure:
A mixture of 8-benzyl-3,8-diaza-1-oxaspiro[4.5]decane-2,4-dione (1.1 g, 4.2 mmol), 10% palladium on carbon (330 mg), acetic acid 10 mL, concentrated hydrochloric acid (2 mL) and water (20 mL) was hydrogenated approximately 12 hours at 15 psi of pressure. The mixture was filtered and concentrated and the residue was crystallized from isopropanol to give 3,8-diaza-1-oxaspiro[4.5]decane-2,4-dione (0.6 g, 2.9 mmol).
Reaction SMILES: [CH2:1]([N:7]1[C:11]([C:12]2[S:19][C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH:13]=2)=[CH:10][CH:9]=[C:8]1[C:20]1[S:27][C:26]2[CH:25]=[CH:24][S:23][C:22]=2[CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].P(Cl)(Cl)(Cl)=O.CN([CH:36]=[O:37])C.[C:38](=O)([O-])[OH:39].[Na+]>ClCCl>[CH:38]([C:24]1[S:23][C:22]2[CH:21]=[C:20]([C:8]3[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:11]([C:12]4[S:19][C:18]5[CH:17]=[C:16]([CH:36]=[O:37])[S:15][C:14]=5[CH:13]=4)=[CH:10][CH:9]=3)[S:27][C:26]=2[CH:25]=1)=[O:39]
Reactant: O=C([O-])O
Reactant: CCCCCCn1c(-c2cc3sccc3s2)ccc1-c1cc2sccc2s1
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCn1c(-c2cc3sc(C=O)cc3s2)ccc1-c1cc2sc(C=O)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-hexyl-2,5-bis(thieno[3,2-b]thiophen-5-yl)pyrrole (74) in dichloromethane is added a solution of phosphorus oxychloride and DMF in DCM. The reaction mixture is refluxed for 16 h, then sat. sodium hydrogencarbonate solution is added and the mixture is stirred at room temperature for 2 h. After phase separation, the organic phase is dried over sodium sulfate. After the solvents have been distilled off, the residue is recrystallized from toluene to obtain the product.
Reaction SMILES: C[Al](C)C.[CH:5]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:11][C:12]1[C:13]2[CH:37]=[C:36]([CH3:38])[O:35][C:14]=2[N:15]=[C:16]([NH:18][C:19]([NH:21][S:22]([C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27](OC)=[O:28])(=[O:24])=[O:23])=[O:20])[N:17]=1.Cl>C1(C)C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>[CH3:11][C:12]1[C:13]2[CH:37]=[C:36]([CH3:38])[O:35][C:14]=2[N:15]=[C:16]([NH:18][C:19]([NH:21][S:22]([C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:10][CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:28])(=[O:23])=[O:24])=[O:20])[N:17]=1
Reactant: OC1CCCC1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2cc(C)oc2n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2c(C)nc(NC(=O)NS(=O)(=O)c3ccccc3C(=O)OC3CCCC3)nc2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 30 ml of dry methylene chloride was added 7.5 ml of 2M trimethylaluminum in toluene under a nitrogen atmosphere. Subsequently, 2.0 g of cyclopentanol in 2 ml methylene chloride was added via syringe and the mixture stirred at ambient temperature for 15 minutes. After addition of 2.0 g of methyl 2-{[(4,6-dimethylfuro[2,3-d]pyrimidin-2-yl)aminocarbonyl]aminosulfonyl}benzoate to the mixture, the reaction was heated to reflux for 48 hours. The mixture was then cooled and poured into excess dilute hydrochloric acid and mixed with ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:19](=[O:30])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)(C)(C)C.[O:31]=[C:32]1[CH2:37][S:36][C:35]2[CH:38]=[CH:39][C:40](C(O)=O)=[N:41][C:34]=2[NH:33]1>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([O:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:40]4[CH:39]=[CH:38][C:35]5[S:36][CH2:37][C:32](=[O:31])[NH:33][C:34]=5[N:41]=4)=[O:30])[CH2:26][CH2:25]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: COc1ccc2ccc(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Product: COc1ccc2ccc(OCCN3CCC(NC(=O)c4ccc5c(n4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as an off-white lyophilizated powder following Scheme 1 and in analogy to Examples 1 and 12 using 2-chloro-7-methoxy-quinoline, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16](Br)=[C:15]([Br:18])[N:14]=[C:13]2[CH:19]2[O:23][CH2:22][CH2:21][O:20]2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[O:24]1CCC[CH2:25]1.C([Mg]Br)C.Cl>CCOCC.C(OCC)(=O)C.CN(C)C=O>[Br:18][C:15]1[N:14]=[C:13]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[N:12]([CH2:11][C:3]2[C:2]([Cl:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=2)[C:16]=1[CH:25]=[O:24]
Reactant: Clc1cc2c(cc1Cn1c(C3OCCO3)nc(Br)c1Br)OCO2
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=Cc1c(Br)nc(C2OCCO2)n1Cc1cc2c(cc1Cl)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of the product obtained in Stage A above is introduced into 200 ml of tetrahydrofuran and 10 ml of ethyl magnesium bromide in a 3M solution in ether is added dropwise. The reaction medium is maintained under agitation for 20 minutes at ambient temperature. 10 ml of dimethylformamide is then added to the reaction medium obtained and agitation is carried out for 2 hours at ambient temperature. The medium is hydrolyzed by the addition of 200 ml of dilute hydrochloric acid, extraction is carried out with ethyl acetate, followed by washing with water then drying and after impasting in isopropyl ether, 7.6 g of expected product is recovered, which is used as it is for the following stage.