Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])[CH3:4].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>CN(C)C=O>[C:3]([N:6]([CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[Cl:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])[CH3:4]
Reactant: ClCc1ccccc1Cl
Reactant: CC(=O)Nc1ccccc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(Cc1ccccc1Cl)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a suspension of 400 mg of sodium hydride (60% in oil) in 30 ml of dimethylformamide was added 2.00 g of N-acetyl-2-phenoxyaniline at room temperature, followed by stirring at room temperature for 30 minutes. To the solution was added dropwise 1.64 g of 2-chlorobenzyl chloride at room temperature with stirring, followed by stirring for 30 minutes. After addition of ice-water, the reaction mixture was extracted with ether. The extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:4) to give 2.92 g of N-acetyl-N-(2-chlorobenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:16]([O:25]CC)(=[O:24])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[CH2:22]([O:21][C:19]([C:18](=[C:6]([C:5]1[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:17][C:16]([OH:25])=[O:24])=[O:20])[CH3:23]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(CC(=O)O)=C(c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of commercially available 4-fluorobenzophenone (42 g., 0.21 mole), diethyl succinate (43.6 g., 0.25 mole) and potassium t-butoxide (23.7 g., 0.21 mole) in t-butanol (250 ml.) was stirred at reflux for 6 hours and then stirred at room temperature for an additional 16 hours. The reaction mixture was then acidified with 6N hydrochloric acid (200 ml.), evaporated under vacuum to remove the t-butanol and extracted with ether (2×250 ml.). The combined ether extract was extracted with 10% aqueous ammonium hydroxide (2×350 ml.). The combined aqueous extract was washed with ether (2×200 ml.), re-acidified with 6N hydrochloric acid and extracted again with ether (2×400 ml.). The combined ether extract was dried (MgSO4), filtered and evaporated under vacuum to an oil, which was crystallized by dissolution in hexane (100 ml.) followed by scratching the flask to initiate crystallization (48 g., 70% yield, m.p. 98°-99° C., elemental analysis calculated: 69.50% C; 5.22% H; 5.78% F; found: 69.34% C; 5.36% H; 6.09% F).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:26][S:27]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:29])=[O:28]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 13.3 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with methanesulfonyl chloride (0.013 mL, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.009 g of white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[NH2:9][C:4]1[CH:3]=[C:2]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:7]=[N:6][C:5]=1[Cl:8]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: Nc1cc(Br)cnc1Cl
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N)c3)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
5-bromo-2-chloropyridin-3-amine (1.00 g, 4.82 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (1.73 g, 5.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.836 g, 0.723 mmol) and potassium carbonate (2.20 g, 15.9 mmol) was suspended in 1,4-dioxane (25 ml) with water (2.5 ml). Argon was bubbled through the suspension for about 30 seconds. The flask was fitted with a reflux condenser and placed into a heat bath (100° C.). The mixture was allowed to stir under inert atmosphere for 3 hours. The progress of the reaction was monitored by LC/MS, which showed desired product. The mixture was allowed to cool to ambient temperature. The mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was extracted with DCM (3×25 ml). Combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with ethyl acetate and the precipitate was collected by filtration. The precipitate was washed with hexanes to give N-(6-(5-amino-6-chloropyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.500 g, 32.5% yield) as a brown crystalline solid. MS (ESI pos. ion) m/z: 319 (MH+). Calc'd exact mass for C14H11ClN4OS: 318. 1H NMR (400 MHz, DMSO-d6): 2.22 (s, 3H), 5.66 (s, 2H), 7.42 (s, 1H), 7.65 (d, J=8.53 Hz, 1H), 7.81 (d, J=8.53 Hz, 1H), 7.94 (s, 1H), 8.24 (s, 1H), 12.41 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:18][CH2:19][OH:20])([CH2:15][CH2:16][OH:17])[C:12](=[O:14])[N:13]=1.C(N(C(C)C)CC)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:15][CH2:16][O:17][S:31]([CH3:30])(=[O:33])=[O:32])([CH2:18][CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])[C:12](=[O:14])[N:13]=1
Reactant: O=C1N=C(NC2CC3CCC2C3)SC1(CCO)CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)SC(NC2CC3CCC2C3)=NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(bicyclo[2.2.1]heptan-2-ylamino)-5,5-bis(2-hydroxyethyl)thiazol-4(5H)-one (280 mg, 0.94 mmol) and diisopropylethylamine (Aldrich, 412 mg, 3.19 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (344 mg, 3.00 mmol, 3.2 eq), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated in vacuo to provide the title compound which was used without further purification. MS (ESI, pos. ion) m/z: 455 (M+H).
Reaction SMILES: Cl[C:2]1C=C(C=C(C)N=1)C(O)=O.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:24])[N:23]=1)[C:18]([OH:20])=[O:19])[CH3:13]>C(O)(C)C>[CH:12]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:24])[N:23]=1)[C:18]([OH:20])=[O:19])([CH3:2])[CH3:13]
Reactant: CCOc1cc(C(=O)O)cc(C)n1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Solvent: CC(C)O
Product: Cc1cc(C(=O)O)cc(OC(C)C)n1

Procedure:
2-Isopropoxy-6-methyl-isonicotinic acid is prepared starting from 2-chloro-6-methyl-isonicotinic acid in analogy to 2-ethoxy-6-methyl-isonicotinic acid using isopropanol as solvent; LC-MS: tR=0.70 min, [M+1]+=196.04.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.CO.[N+](=[CH:17][Si](C)(C)C)=[N-]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(I)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CCc1ccc(I)cc1
Reaction time: 8 h

Procedure:
To a stiffed solution of 3-(4-iodophenyl)propanoic acid (commercially available) in toluene and methanol (9:1, 0.2 M) 0° C. was added (diazomethyl)trimethylsilane (1 N solution in Et2O, 2 eq). After stiffing at room temperature overnight the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford methyl 3-(4-iodophenyl)propanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)=S.C1([N:39]=[C:40]=[N:41]C2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C.N#CN>C(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)=[N:41][C:40]#[N:39]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)Nc4ccccc4F)cc3)c2cc1OC
Agent: N#CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NC(=NC#N)Nc4ccccc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
N-(2-Fluorophenyl)-N'-(4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}thiourea (42 mg) obtained in Example 167, dicyclohexylcarbodiimide (37 mg) and a catalytic amount of diisopropylethyl amine were dissolved in methylene chloride (10 ml). To this solution, a solution of cyanamide (20 mg) in THF (1 ml) was added, and the admixture was stirred at room temperature overnight. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) to obtain 41 mg of the title compound (yield: 99%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10]/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10]/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/C#Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC/C=C/C#Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
In 4 ml of toluene were dissolved 480 mg (1.79 mmol) of ethyl (E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-ynoate, and 2.38 ml (3.58 mmol) of a 1.5 M diisobutyl aluminum hydride-toluene solution were added to the solution with stirring at 0° C. After 10 minutes, ice was added to the mixture and the insolubles were removed by filtration using Celite. After the organic layer was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent of ethyl acetate-hexane (3:17) to obtain 353 mg (yield: 87%) of the title compound as an oil.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][CH3:14])[C:5]=1[C:6]([NH2:8])=[NH:7].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>>[ClH:1].[NH2:8][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[F:3])[N:13]([CH3:14])[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:7]=1
Reactant: CNc1cccc(F)c1C(=N)N
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(F)cccc1N2C

Procedure:
This was prepared by the method of Example 173 using 2-fluoro-6-(methylamino)benzamidine dihydrochloride (Example K) and ethyl 4-oxopiperidine-1-carboxylate to give the title compound, m.p. 234°-235° C.
Reaction SMILES: [N+]([O-])(O)=O.[I:5]I.[CH:7]1([C:10]2[O:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH2:9][CH2:8]1>O>[CH:7]1([C:10]2[O:14][N:13]=[C:12]([CH3:15])[C:11]=2[I:5])[CH2:9][CH2:8]1
Reactant: II
Reactant: Cc1cc(C2CC2)on1
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cc1noc(C2CC2)c1I
Yield: 109.6 %

Procedure:
Concentrated nitric acid (10 ml) was added dropwise to a stirred heated mixture of iodine (23.8 g) and 5-cyclopropyl-3-methylisoxazole (24.6 g containing approximately 20% 3-cyclopropyl-5-methylisoxazole) whilst maintaining the temperature in the range 90°-95° C. The mixture was stirred and heated at 95°-100° C. for 1 hour. It was cooled, poured into cold water and extracted with ether. The combined extracts were washed with aqueous sodium bicarbonate solution (saturated), aqueous sodium metabisulphate solution (saturated), water, dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated to dryness and the residue was triturated with petroleum spirit and filtered. The solid was recrystallized from petroleum spirit to give 5-cyclopropyl-4-iodo-3-methylisoxazole (25.6 g) as a white solid, m.p. 71° C.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.I[C:19]1[NH:23][C:22]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:21][C:20]=1[CH3:30].IC1NC(C)=NC=1C.[CH3:39][C:40]1[CH:49]=[C:48]([CH3:50])[C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46][C:41]=1[C:42]([O:44]C)=[O:43].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1>>[CH3:39][C:40]1[CH:49]=[C:48]([CH3:50])[C:47]([C:19]2[NH:23][C:22]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:21][C:20]=2[CH3:30])=[CH:46][C:41]=1[C:42]([OH:44])=[O:43]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Reactant: Cc1nc(C2CCOCC2)[nH]c1I
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1cc(C)c(-c2[nH]c(C3CCOCC3)nc2C)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except 5-iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (compound 164.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.[CH2:18]([O:20][C:21](=[O:26])[CH:22]=[C:23](Cl)[CH3:24])[CH3:19]>O1CCCC1>[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[C:23](/[O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:8]([F:16])([F:17])[F:7])[CH:10]=1)\[CH3:24])[CH3:19]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(C(F)(F)F)c1
Temperature: 23 °C
Yield: 62.7 %

Procedure:
Potassium t-butoxide (6.90 g, 0.061 mol) was added to a stirred solution of 3-trifluoromethyl-phenol (5.00 g, 0.031 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 4.56 g, 0.031 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (5.33 g, 63%) as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.S(=O)=[O:16].C1(NC2C=CC=CC=2)C=CC=CC=1>CCOCC>[C:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=S=O
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
Ten millimoles of diphenylmethane was heated at 400° C. for 1 hour with 1.35 ml of water saturated with sulfur dioxide in the microreactor described in Comparative Examples 1 to 10. After cooling, the product was entracted with ether. The ether layer was dried (Na2So4) and concentrated to yield 95% of benzophenone and 5% of diphenylamine. Colloidal sulfur was observed in the aqueous layer.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:22])[C@@H:12]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[O:23][CH3:24].[Cl:25][C:26]1[S:27][C:28]([CH2:31]Cl)=[CH:29][CH:30]=1.C[O-].[Na+].[OH-].[Na+]>CO>[Cl:25][C:26]1[S:27][C:28]([CH2:31][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:22])[C@@H:12]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:13]([CH3:14])[CH3:15])=[CH:4][C:3]=2[O:23][CH3:24])=[CH:29][CH:30]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2ccc(Cl)s2)c(OC)c1)C(C)C

Procedure:
A mixture of 2.0 g of (S)-2-(ethylsulfonylamino)-3methyl-butyric acid N-[2-(4hydroxy-3-methoxy-phenyl)-ethyl]-amide, 1.2 g of 2-chloro-5-chloromethylthiophene and 12 ml of a 1 M sodium methanolate solution in methanol (prepared beforehand by dissolution of 23 g of sodium in 1 liter of methanol) is heated at reflux in 30 ml of methanol for 16 hours. After cooling, the reaction mixture is introduced into 300 ml of 2N sodium hydroxide solution. Extraction is carried out twice using 400 ml of tert-butyl methyl ether each time. The organic phases are washed once with 100 ml of 2N sodium hydroxide solution and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-{2-[4-(5-chloro-thiophen-2-yl-methoxy)-3-methoxy-phenyl]-ethyl}-amide, which can be purified by chromatography on silica gel with ethyl acetate/n-hexane 1:1 and recrystallisation from ethyl acetate/n-hexane, m.p. 124-127° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34][CH3:35])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([NH:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:38](O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34][CH3:35])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([N:26]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH3:38])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(NCCN(C)C)COc1ccccc1-3
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(N(C)CCN(C)C)COc1ccccc1-3
Reaction time: 0.08 h

Procedure:
To a solution of methyl 14-cyclohexyl-7-{[2-(dimethylamino)ethyl]amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in Example 9, Step 5) in DCM (0.1 M), was added formaldehyde (3.0 eq) and acetic acid (5.5 eq), followed by sodium cyanoborohydride (3 eq). NaOH (20 eq, 1 N) was added after 2 h, and after stirring for 5 min the mixture was taken into EtOAc and washed with water and brine. Drying over sodium sulfate and concentration in vacuo gave the crude product, which was used without further purification; MS (ES+) m/z 490 (M+H)+.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C@@H:23]2[CH2:25][C@H:24]2[C:26]([NH:28][CH3:29])=[O:27])[CH2:6]1)(=O)C.O(P(O[C:47]1[C@H:48]([CH3:71])[C@H:49]2[C@@H:66]([C@H:67]([OH:69])[CH3:68])[C:65](=[O:70])[N:50]2[C:51]=1[C:52]([O:54][CH2:55]C1C=CC([N+]([O-])=O)=CC=1)=[O:53])(OC1C=CC=CC=1)=O)C1C=CC=CC=1>>[OH:69][C@@H:67]([C@H:66]1[C:65](=[O:70])[N:50]2[C:51]([C:52]([O:54][CH2:55][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:53])=[C:47]([S:4][C@@H:5]3[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)=[O:11])[C@H:7]([C@@H:23]4[CH2:25][C@H:24]4[C:26]([NH:28][CH3:29])=[O:27])[CH2:6]3)[C@H:48]([CH3:71])[C@H:49]12)[CH3:68]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: CNC(=O)[C@@H]1C[C@H]1[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: CNC(=O)[C@@H]1C[C@H]1[C@@H]1C[C@H](SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 223.7 %

Procedure:
The same procedure as in EXAMPLE 1a and 1b was carried out by using trans-2-[(2S,4S)-4-acetylthio-N-(4-nitrobenzyloxycarbonyl) pyrrolidin-2-yl]-N-methylcyclopropanecarboxamide (180 mg, 0.42 mmol)and 4-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate(203 mg, 0.34 mmol) to give 4-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[trans-2-(N-methylaminocarbonyl) cyclopropyl]-N-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (340 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[H-].[Na+].Cl[C:12]1[C:13]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[N:17]=1.O>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:12]2[C:13]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)[N:17]=2)=[N:5][CH:4]=[N:3]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1N1CCCC1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3)nnc2cc1N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (2-methyl-2H-1,2,4-triazol-3-yl)methanol (2.5 g, 0.022 mol; EP-A-421210) in DMF (200 ml) was added a 60% suspension of sodium hydride in mineral oil (1.2 g, 0.031 mol), and the resultant slurry was stirred at room temperature under nitrogen for 1 h. 6-Chloro-3-phenyl-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine (6.0 g, 0.020 mol) was added, and the mixture was stirred as before for 30 min. Water (600 ml) was added, precipitating a solid. This was filtered off, then washed with water and diethyl ether. The crude product was dissolved in a mixture of ethanol (50 ml) and dichloromethane (110 ml), and then the chlorinated solvent was boiled off. The resultant solution was cooled to 4° C. precipitating the title compound as a white solid (6.3 g, 83%). 1H NMR (400 MHz, CDCl3) δ1.97 (4H, m), 3.47 (4H, m), 3.97 (3H, s), 5.59 (2H, s), 6.72 (1H, s), 7.48 (3H, m), 7.95 (1H, s), 8.28 (2H, m); MS (ES+) m/e 377[MH]+.