Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.O[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCN1CCOCC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
N-(3-Morpholinopropoxy)phthalimide may be obtained in the following manner: solution of 3-morpholinopropanol (27.5 g), N-hydroxyphthalimide (30.2 g) and triphenylphosphine (47.2 g) in tetrahydrofuran (400 cc) is cooled to a temperature in the region of 0° C. and ethyl azodicarboxylate (37.65 g) is added in the course of 1 hour 30 minutes. The solution obtained is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. The residue is taken up with ethyl acetate (500 cc) and the suspension obtained is filtered. The filtrate is extracted with N aqueous hydrochloric acid solution (200 cc). The aqueous phase is separated after settling has taken place and then extracted 3 times with ethyl acetate (600 cc in total). The aqueous phase is brought to a pH in the region of 10 by adding N aqueous sodium hydroxide solution and is extracted 3 times with ethyl acetate (300 cc in total). The organic extracts are combined, washed 3 times with distilled water (150 cc in total), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. A crude product (25.8 g) is thereby obtained, which is chromatographed on a column 8 cm in diameter containing silica (0.060 mm) (1 kg). The column is eluted with pure ethyl acetate, collecting 500-cc fractions. The first 12 fractions are discarded; the next 48 fractions are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. N-(3-Morpholinopropoxy)phthalimide (15.5 g) is thereby obtained in the form of white crystals, m.p. 98° C. 3-Morpholinopropanol may be obtained according to O. HROMATKA, Ber., 75, 131, (1942).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: CNC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To 400 mg of N,N-dimethylformamide were added 90 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine dihydrochloride, and 160 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.5 ml of ethanol, the mixture-was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 92 mg of the title compound as a colorless powder.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccnc(Br)c1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3cc(C)ccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 2-bromo-4-methylpyridine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]#[N:12])=[C:5]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl.[CH2:23]([OH:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[NH:12])[O:25][CH2:23][CH3:24])=[C:5]2[S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14]
Reactant: CCO
Reactant: N#Cc1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Agent: Cl
Product: CCOC(=N)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
5-Chloro-3-phenylsulfonylindole-2-carbonitrile is allowed to react with ethanol saturated with hydrogen chloride at 0°-10° C. for 7 days. Evaporation to dryness affords the title compound as a hydrochloride salt. The title compound is obtained as a free base by adding the reaction mixture to an ice cold solution of excess potassium carbonate and extracting the product with chloroform.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1=CC=C(C=O)SS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 3-[(tert-butyldimethylsilyloxy)methyl]-6-(hydroxymethyl)-1,2-dithiin (U.S. Ser. No. 08/212,096) (600 mg, 2.07 mmol) in THF (25 mL) at 0° C. was added quickly the Dess-Martin periodinane reagent (1.20 g, 2.83 mmol) and the mixture was stirred at 0° C. for 30 min, then at room temperature for another 30 min. Upon completion of the reaction (monitored by TLC), 12 mL of H2O was added and the mixture was extracted with ether (3×). The combined organics washings were washed with H2O, sodium hydrogen carbonate (3%-soln.), brine, dried (Na2SO4) and evaporated. Flash chromatography (eluting with hexane/EtOAc 3/1) yielded 560 mg (94%) of the title aldehyde as a dark red, almost purple, crystalline compound.
Reaction SMILES: I[CH3:2].[CH3:3][N:4]1[CH:14]=[N:13][C:6]([CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:5]1>C(#N)C>[CH3:3][N:4]1[CH2:14][N:13]([CH3:2])[C:6]([CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:5]1
Reactant: Cn1cnc(C[C@H](N)C(=O)O)c1
Reactant: CI
Solvent: CC#N
Product: CN1C=C(C[C@H](N)C(=O)O)N(C)C1

Procedure:
Methylated histamine and histidine are also expected to have low toxicity because histamine and histidine occur naturally in the body. The reaction of L-histidine methyl ester dihydrochloride 28 with carbonyldiimidazole in DMF results in 29. The combination of three equivalents of iodomethane with 29 in refluxing acetonitrile gives 30. The iodide salt of 30 is reacted with methanol in the presence of N,N-diisopropylethylamine at reflux for 3 days to obtain 1-methyl-L-histidine 31. The combination of three equivalents of iodomethane with compound 31 in refluxing acetonitrile gives 1,3-dimethyl-L-histidine 32. The combination of 32 with Ag2O in DMSO forms the silver carbene complex 33. Compound 33b has been shown to have significant antimicrobial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa by the Kirby-Bauer technique.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([C:10]1([CH2:26][C:27](OCC)=[O:28])[C:23]2[C:18](=[N:19][CH:20]=[C:21]([Br:24])[CH:22]=2)[O:17][C:16]2[C:11]1=[CH:12][C:13]([I:25])=[CH:14][CH:15]=2)=[N+]=[N-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:7][C:10]1([CH2:26][CH2:27][OH:28])[C:23]2[C:18](=[N:19][CH:20]=[C:21]([Br:24])[CH:22]=2)[O:17][C:16]2[C:11]1=[CH:12][C:13]([I:25])=[CH:14][CH:15]=2
Reactant: CCOC(=O)CC1(N=[N+]=[N-])c2cc(I)ccc2Oc2ncc(Br)cc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NC1(CCO)c2cc(I)ccc2Oc2ncc(Br)cc21
Temperature: 78 °C
Reaction time: 0.25 h

Procedure:
LAH (1M in THF; 6.12 ml, 6.12 mmol) was added slowly to a −78 C cooled solution of ethyl 2-(5-azido-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate (2.10 g, 4.08 mmol) in THF (40.8 ml). The reaction mixture was stirred at 78° C. for 15 min, and the reaction mixture was allowed to warm to RT and stirred for additional 30 min. The reaction mixture was cooled to 0° C., quenched with sodium sulfate decahydrate (2.90 g, 20.38 mmol) and allowed to stir 20 min. The solution was filtered through a pad of celite, the filter cake was eluted with 10% MeOH/DCM and the filtrate was concentrated. The residue was purified via flash chromatography (0-25% EtOAc/CH2Cl2) to afford 2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:23][C:24](=[O:26])[CH3:25]>>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([CH2:23][C:24](=[O:26])[CH3:25])[C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Product: COC(=O)c1nn(CC(C)=O)c(C(=O)OC)c1OCc1ccccc1

Procedure:
The title compound was prepared from dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate using a procedure similar to that described in Example 2, Step 2, except that chloroacetone was used in place of bromo(phenyl)acetonitrile, and the silica gel chromatography gradient elution was 0-60% EtOAc/hexanes. 1H NMR (400 MHz, d6-DMSO) δ 7.46-7.34 (m, 5h), 5.44 (s, 2H), 5.06 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 2.20 (s, 3H); ES MS (M+1)=347.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:14]1([CH2:17][NH:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[CH:14]1([CH2:17][N:18]([CH2:19][CH2:20][CH3:21])[C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:16][CH2:15]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CCCNCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (5.38 g) and cyclopropylmethyl-propyl-amine (4.75 g) are dissolved in toluene (50 ml), and thereto is added potassium carbonate (11.6 g) and the mixture is stirred at 120° C. for 4 hours. The reaction solution is cooled to room temperature, and thereto is added water and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (8.0 g). MS (m/z): 286 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:34]([O:36][CH2:37][CH2:38][NH2:39])[CH3:35]>>[CH2:34]([O:36][CH2:37][CH2:38][NH:39][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:35]
Reactant: CCOCCN
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOCCNc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-y)-isonicotinamide with cesium carbonate and 2-ethoxyethylamine. ES-MS m/e (%): 458 (M+H+, 100).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2>CC(O)(C)C>[Br:6][C:7]1[C:15]2[C:11](=[CH:12][N:13]([C:11]([CH3:15])([CH3:12])[CH3:10])[N:14]=2)[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ncc2c1
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: CC(C)(C)n1cc2cc([N+](=O)[O-])cc(Br)c2n1

Procedure:
2-Methyl-2-propanol (5 mL) and concentrated sulfuric acid (0.1 mL) were added to 7-bromo-5-nitro-1H-indazole (484 mg), and the reaction solution was allowed to react in a microwave reactor at 100° C. for 1 hour. After dilution with ethyl acetate, the reaction solution was washed successively with an aqueous sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum to obtain 7-bromo-2-(tert-butyl)-5-nitro-2H-indazole as a light yellow solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1F)[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:25]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=4[F:17])=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1
Temperature: 85 °C

Procedure:
A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) (100 mg, 0.46 mmol), 3,4-difluorobenzonitrile (70 mg, 0.51 mmol) and potassium carbonate (159 mg, 1.15 mmol) in dimethylsulfoxide (2 ml) was heated at 85° C. for 2 hours. The reaction mixture was cooled and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol (1:9). The combined basic fractions were concentrated in vacuo to afford the title compound (E271). MS (ES+) m/e 337 [M+H]+.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].C([Li])CCC.CN(C)CCN(C)C.[C:25]([C:29]1[CH:53]=[C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:32]2[O:33][P:34](Cl)[O:35][C:36]3[C:42]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:41][C:40]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:39][C:37]=3[CH2:38][C:31]=2[CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>CCCCCC.O1CCCC1>[C:25]([C:29]1[CH:53]=[C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:32]2[O:33][P:34]([C-:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[O:35][C:36]3[C:42]([C:43]([CH3:45])([CH3:44])[CH3:46])=[CH:41][C:40]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:39][C:37]=3[CH2:38][C:31]=2[CH:30]=1)([CH3:28])([CH3:27])[CH3:26].[C-:6]1([P:34]2[O:35][C:36]3[C:42]([C:43]([CH3:44])([CH3:45])[CH3:46])=[CH:41][C:40]([C:47]([CH3:50])([CH3:48])[CH3:49])=[CH:39][C:37]=3[CH2:38][C:31]3[CH:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:53]=[C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:32]=3[O:33]2)[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: c1cc[cH-]c1
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Agent: [Fe+2]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP([c-]1cccc1)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Yield: 58.5 %

Procedure:
The general procedure of Example 1 is followed using 3.5 g (18.8 mmol) of ferrocene in 30 mL of hexane, 25 mL of a 1.6M hexane solution of n-butyl lithium, 4.5 g (38.7 mmol) of N,N,N',N'-tetramethylethylenediamine and 20 g (41 mmol) of 2,4,8,10-tetrakis(tert-butyl)-6-chloro-12H-dibenzo[d,g][1,3,2]dioxaphosphocin in 100 mL of tetrahydrofuran. The residue is triturated with hexane and the resultant solid is recrystallized from an acetonitrile/tetrahydrofuran mixture to give 12 g (58.5% yield) of a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:24]=1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C@H:32]([OH:34])[CH3:33].CC(C)(C)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[OH:34][C@@H:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:9]1[S:8][C:7]2[CH:24]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)[CH3:33]
Reactant: C[C@@H](O)c1ccccc1Br
Reactant: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3[C@@H](C)O)sc3cc(OC)ccc23)cc1
Yield: 20.4 %

Procedure:
To a microwave vial containing (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (100 mg, 0.294 mmol) in DMA (2.5 mL) was added (R)-1-(2-bromophenyl)ethanol (118 mg, 0.588 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos Palladacycle 1st generation, 23.47 mg, 0.029 mmol), trimethylacetic acid (90 mg, 0.881 mmol) and potassium carbonate (122 mg, 0.881 mmol) The microwave vial was sealed, purged and back-filled with nitrogen. The reaction mixture subjected to microwave irradiation for 2 h at 150° C. Upon completion the reaction was diluted with EtOAc, and washed with water and brine. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (R,E)-methyl 3-(4-((2-(2-(1-hydroxyethyl)phenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (27.5 ms, 0.060 mmol, 20% yield). LC/MS (m/z, MH+): 459.0.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][CH:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][S:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH:31]1[C:18]2[CH:17]([O:16][CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:32][CH2:33][CH3:34])[C:4]([OH:35])=[O:3])=[CH:8][CH:9]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][S:20][C:19]=2[CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CSc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCOC2c3ccccc3CSc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
3-(4-[2-(6,11-Dihydrodibenzo[b,e]thiepin-11-yloxy)-ethoxy]-phenyl)-2-ethoxy-propionic acid ethyl ester (example 2) (220 mg, 0.44 mmol) in ethanol (5 mL) was added NaOH 1N (0.9 mL, 0.9 mmol). The mixture was stirred at room temperature for 16 h. The ethanol was evaporated of and pH adjusted with HCl 1N to pH 1. After extraction with dichloromethane the product was purified by chromatography, using dichloromethane/methanol (9:1) as eluent, to give 126 mg (62%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H), 2.85-3.10 (m, 2H), 3.32-3.42 (m, 1H), 3.52-3.65 (m, 1H), 2.85 (t, 2H), 3.95-4.05 (m, 1H), 4.10-4.22 (m, 2H), 4.5-5.1 (bs, 1H), 5.60-5.75 (bs, 1H), 6.82 (d, 2H), 7.05-7.50 (m, 10H).
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C1NC=C(C(OCC)=O)C=1.FC1C=CC(S(Cl)(=O)=O)=CC=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]2[C:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]([F:56])([F:55])[F:54])=[CH:45][C:44]([C:57](OCC)=[O:58])=[CH:43]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]2[C:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]([F:54])([F:56])[F:55])=[CH:45][C:44]([CH:57]=[O:58])=[CH:43]2)(=[O:40])=[O:41])=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2C(F)(F)F)n(S(=O)(=O)c2ccc(F)cc2)c1
Agent: CCOC(=O)c1c[nH]c(-c2ccccc2C(F)(F)F)c1
Agent: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=Cc1cc(-c2ccccc2C(F)(F)F)n(S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
Using ethyl 5-(2-trifluoromethylphenyl)-1H-pyrrole-3-carboxylate and 4-fluorobenzenesulfonyl chloride, a procedure as in Reference Example 4 was performed to synthesize ethyl 1-[(4-fluorophenyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate, and procedures as in Reference Examples 5 and 6 were sequentially performed to give the title compound as crystals.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1.C(=O)=O>CC(C)=O>[N:5]([C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[N:7]=1)=[C:1]=[S:2]
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Reactant: S=C(Cl)Cl
Agent: O=C=O
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(N2CCC(N=C=S)=N2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
Thiophosgene (11.5 g) was added slowly to a solution of 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline (23 g) (prepared according to Reference Example 1 of European patent specification No. 22-578) in acetone (250 ml) at 0° in an atmosphere of carbon dioxide. The addition was completed in about 20 minutes and was then allowed to warm to room temperature for 1 hour. The resulting insoluble solid, the hydrochloride of the starting base, was filtered off and washed with fresh acetone. The combined filtrate and washings were evaporated in vacuo to give crude 3-isothiocyanato-1-(3-trifluoromethylphenyl)-2-pyrazoline as a gum (13 g) which subsequently crystallised. This compound was used directly without purification but the presence of the isothiocyanate group was confirmed by infra red spectroscopy which exhibited a broad band in the region of 2005 cm-1. This gum (3.8 g) was suspended in toluene (40 ml) and stirred during the addition of butylamine (1.5 g). When the gum changed into a colourless solid. After 2 hours, the mixture was warmed to about 35° for 10 minutes and then cooled back to room temperature. The resulting solid was collected, washed with a little fresh toluene and recrystallised from propanol in long prisms, m.p. 197°-198° of 3-(3-butylthioureido)-1-(3-trifluoromethylphenyl)-2-pyrazoline.
Reaction SMILES: C(OC([N:11]1[CH2:16][C@@H:15]([C:17](=[O:19])[NH2:18])[N:14]([CH2:20][CH2:21][CH2:22][C:23]([N:25]2[CH2:32][CH2:31][C:28]3([CH2:30][CH2:29]3)[C@H:27]([OH:33])[CH2:26]2)=[O:24])[C:13](=[O:34])[C@@H:12]1[CH3:35])=O)C1C=CC=CC=1.[H][H]>[Pd]>[OH:33][C@@H:27]1[CH2:26][N:25]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][N:14]2[C:13](=[O:34])[C@H:12]([CH3:35])[NH:11][CH2:16][C@H:15]2[C:17]([NH2:18])=[O:19])[CH2:32][CH2:31][C:28]21[CH2:29][CH2:30]2
Reactant: [H][H]
Reactant: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)[C@H](C(N)=O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Product: C[C@@H]1NC[C@@H](C(N)=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O

Procedure:
In analogy to the procedure described in the first part of example 120 step E, (2S,5S)-5-carbamoyl-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester was treated with 10% palladium on charcoal and the reaction was stirred under 1 atmosphere of hydrogen affording the titled compound in quantitative yield as a colorless foam. MS: 353.4 (MH+).