Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC.O.C(OCC)(=O)C.CN1C(=O)N(C)CCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:17][OH:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCCCOc1ccc(S(=O)(=O)CCCO)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C(CCO)Cc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
Part A: To a solution of 4.0 g (15 mmol) of 3-[(4-butoxyphenyl)sulfonyl]propan-1-ol from Example 26 and 6 mL of DMPU in 100 mL of anhydrous THF at -70 C under nitrogen, was added 3.9 mL (1.9 g, 29 mmol) of a 10.0 M solution of n-butyllithium in hexane. After stirring for 30 min. at -70 C., 1.6 mL (2.3 g, 13 mmole) of benzyl bromide was added. After 15 hours, the reaction mixture was cooled to zero C. and 25 mL of saturated ammonium chloride solution was added. Ethyl acetate and water were added, the layers were separated and the aqueous layer was extracted 2×s with ethyl acetate. The 3 organic layers were combined and washed with brine, dried with magnesium sulfate, filtered and concentrated to afford 8.4 g of crude product. This was chromatographed on silica gel using 25%-35% ethyl acetate/hexane to yield 4.3 g of pure 3-[(4-butoxyphenyl)sulfonyl]-4-phenylbutan-1-ol.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:12]=1[C:13]([O:15]CC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.Cl.O.C(OCC)(=O)C>[NH:1]([C:8]1[S:9][C:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:11][C:12]=1[C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(-c2ccccc2)sc1Nc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a suspension of ethyl 2-anilino-5-phenylthiophene-3-carboxylate (51.7 mg, 0.160 mmol) in ethanol (3 mL) was added water (0.6 mL) and aqueous sodium hydroxide solution (2 M, 0.400 ml, 0.799 mmol). The reaction suspension was heated to 80° C. to afford a clear yellow solution; after one hour the suspension was allowed to cool to room temperature before being diluted with an aqueous hydrogen chloride solution (2 M, 1 mL), water (1.5 mL), and ethyl acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were combined and concentrated to afford 2-anilino-5-phenylthiophene-3-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([NH:10]C=O)=[C:4]([CH3:13])[C:3]=1[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=[C:15]([CH3:17])[CH3:16].[ClH:25]>C(O)C(C)C>[ClH:25].[CH3:16][C:15]1([CH3:17])[CH:14]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:3]2[C:4]([CH3:13])=[C:5]([NH2:10])[C:6]([CH3:9])=[C:7]([CH3:8])[C:2]=2[O:1]1
Reactant: CC(C)=C(c1ccc(C)cc1)c1c(C)c(NC=O)c(C)c(C)c1O
Agent: Cl
Solvent: CC(C)CO
Product: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a mixture of N-[4-hydroxy-3-[2-methyl-1-(4-methylphenyl)-1-propenyl]-2,5,6-trimethylphenyl]formamide (740 g) and isobutanol (2220 ml) was added concentrated hydrochloric acid (2220 ml) under nitrogen stream and the mixture was refluxed under heating for 5 hr. The mixture was stirred at 0 to 5° C. for 1 hr. The crystals were collected by filtration and washed with toluene to give 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine hydrochloride. This hydrochloride was dissolved in a mixed solution of methanol (5180 ml)/water (740 ml) at 55 to 60° C. To the solution was added dropwise 25% aqueous ammonium at 50° C. to adjust the pH to 8.5, and the mixture was stirred for 30 min. The precipitated crystals were collected by filtration and washed with methanol/water (1:1) to give the title compound (587.2 g, yield 87.4%).
Reaction SMILES: [C:1]([NH:20][C@@H:21]1[CH2:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[NH:23][C:22]1=[O:32])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[CH:36]([N:23]1[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26][CH2:27][C@@H:21]([NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:22]1=[O:32])([CH3:38])[CH3:37]
Reactant: CC(C)I
Reactant: O=C1Nc2ccccc2CC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A 35 mL heavy-walled sealable tube was fitted with a stirbar and septa. The tritylated benzolactam from Step 4 (2.02 g, 4.83 mmol) and N,N-dimethylformamide (20 mL) were added, giving a solution that was cooled to 0° C. Sodium hydride (1.08 g, 60%/oil, 27.0 mmol) was added cautiously, giving a mixture that was stirred 5 minutes at 0° C., then removed from the cold bath and allowed to warm to room temperature. After 30 minutes, 2-iodopropane (1.0 mL, 10.0 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The rubber septa was then removed, the reaction vessel was sealed with a plastic screwcap, placed in an oil bath and warmed to 60° C. After 4 hours, the reaction was cooled to room temperature, diluted with H2O (100 mL) and extracted three times with diethyl ether (100 mL, then 2×50 mL). The organic extracts were combined, washed with saturated aqueous NaCl solution (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified via flash chromatography on silica gel (0% to 25% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18](O)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)(Cl)=O.[CH3:25][NH:26][CH:27]([CH2:29][CH3:30])[CH3:28]>>[CH3:25][N:26]([CH:27]([CH3:28])[CH2:29][CH3:30])[C:18]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=1)=[O:19]
Reactant: CCC(C)NC
Reactant: O=C(O)c1cc(-c2ccccc2Cl)nc2ccccc12
Solvent: O=S(Cl)Cl
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2Cl)nc2ccccc12

Procedure:
The procedure of Example 3 is followed using 2-(2-chlorophenyl)-quinoline-4-carboxylic acid (5.7 g), thionyl chloride (15 ml) and N-methylbut-2-ylamine (15 ml) as the starting materials.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH2:14][CH3:15])[CH2:12][CH3:13].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([C:5]1([CH2:14][CH3:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=2)[S:8][CH2:7][CH2:6]1)[CH3:13]
Reactant: CCC1(CC)CCSc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCC1(CC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 0 °C

Procedure:
A mixture of 1.96 g (6.90 mmol) of 6-bromo-4,4-diethylthiochroman (Compound 25), 0.11 g (0.59 mmol) of copper (I) iodide and 4.36 g (4.31 mmol) of triethylamine was degassed with argon for 15 minutes at -78° C. To the suspension was added 6.95 g (71 mmol) of (trimethylsilyl)acetylene then 0.41 g (58 mmol) of bis(triphenylphosphine) palladium (II) chloride. The solution was degassed with argon for an additional 5 minutes and the resulting mixture was allowed to warm to 0° C. The tube was sealed and the mixture heated to 55° C. for 15 hours.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([NH:12]C(=O)C)=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1)[CH3:2].[H-].[Na+].[Cl-].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([NH2:12])=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc([N+](=O)[O-])c(NC(C)=O)cc1CC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCO
Product: CCOc1cc([N+](=O)[O-])c(N)cc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
N-(4-Ethoxy-5-ethyl-2-nitrophenyl)acetamide [0.2 g, Reference Example 32(g)] was dissolved in ethanol (25 mL) and sodium hydride (100 mg; 50% dispersion in mineral oil, 2 mmol) was added. Mixture was stirred overnight at ambient temperature, aq ammonium chloride (3mL) was added and the mixture was evaporated. The residue was chromatographed on silica gel (heptane with gradient of 25-50% ethyl acetate) to give 4-ethoxy-5-ethyl-2-nitrophenylamine (0.1 g) as a red solid. LC-MS (Method E): RT=3.4 minutes, 211 (M+H)+. (h) 5-Chloro-4-methoxy-2-nitrophenylamine
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14](Cl)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:24]1C=C(NS(C2C=CC(NC(=O)C)=CC=2)(=O)=O)C=C(C(F)(F)F)[N:25]=1>CN.C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([NH:25][CH3:24])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Agent: CN
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(C(F)(F)F)n1
Yield: 70 %

Procedure:
0.052 g (0.00015 mol) of 4-amino-N-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-benzenesulfonamide was stirred in 30 ml of 8M methylamine in ethanol in an autoclave at 135° C. for 80 hours. The methylamine was allowed to evaporate, the residue was dissolved in ethanol, treated with 2 g of silica gel, concentrated and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:2. There was obtained 0.036 g (70%) of 4-amino-N-(2-methylamino-6-trifluoromethyl-pyridin-4-yl)-benzenesulfonamide as colorless crystals; m.p.: >68° C. (dec.).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl>>[NH:12]1[CH2:13][CH2:14][CH:9]([C:8]2[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1
Reactant: COc1ncccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: O=c1[nH]cccc1C1CCNCC1
Reaction time: 18 h

Procedure:
tert-Butyl 4-(2-methoxypyridin-3-yl)piperidine-1-carboxylate (204 mg, 0.70 mmol) was added to hydrochloric acid (6.0 M in water; 5.81 mL, 34.89 mmol). After 18 h, the reaction mixture was concentrated and dried under reduced pressure to give the title compound. MS 179.1 (M+1).
Reaction SMILES: [C:1]([CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[NH:14][C:15](=O)[CH3:16])(=[O:6])=[O:5])#[N:2].[OH-].[Na+]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:4](=[O:6])(=[O:5])[C:3]([C:1]#[N:2])=[C:15]([CH3:16])[NH:14][C:8]=2[CH:9]=1
Reactant: CC(=O)Nc1cc(F)ccc1S(=O)(=O)CC#N
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(C#N)S(=O)(=O)c2ccc(F)cc2N1

Procedure:
Treatment of N-(2-cyanomethylsulfonyl-5-fluoro-phenyl)acetamide with aqueous sodium hydroxide by a procedure similar to the procedure described in EXAMPLE 1 c) gave the title compound; mp 261-263° C. (sinters at 240-251° C.), 1H-NMR (DMSO-d6), δ (ppm): 12.03 (br s, 1H, NH), 8.06 (dd, 9.0 Hz/5.5 Hz, 1H, H8), 7.35 (m, 1H, H7), 7.20 (dd, 10.0/2.5 Hz, 1H, H5), 2.46 (s, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].C1(CC([O-])=O)C=CC=CC=1.[NH4+].C(=O)CCCC=O.[NH2:43][CH2:44][CH2:45][O:46][S:47](=[O:50])(=[O:49])[OH:48]>>[NH2:43][CH2:44][CH2:45][O:46][S:47](=[O:49])(=[O:48])[OH:50].[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: NCCOS(=O)(=O)O
Agent: O=C([O-])Cc1ccccc1
Agent: O=CCCCC=O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reaction time: 20 h

Procedure:
Escherichia coli ATCC 9637 is used for the production of penicillin acylase. The nutrient solution consists of 2% of corn steep liquor plus 1% of ammonium phenylacetate, and the pH value is 6.5. 200 ml of nutrient solution are inoculated with 1 ml of an Escherichia coli suspension in a 1 liter conical flask. The fermentation proceeds at 31° C. for 20 hours on a rotary shaking machine at 290 rpm. 20 ml of 4% strength tannin solution are first added dropwise to 500 ml of cell suspension, and the suspension is then flocculated completely with the aid of 100 ml of BETZ/glutaraldehyde mixture (60 g/liter of BETZ, 2.2% v/v of glutaraldehyde, pH 9.0). When flocculation is complete, a 50% excess of BETZ/glutaraldehyde are immediately added. Half of the batch is immediately replaced with solid (I) to a final concentration of 0.1M, in addition to the excess of BETZ/glutaraldehyde, and the other half is worked up without (I). After the cell mass has been separated off, washed and extruded, it is dried overnight at 40° to 45° C. and then ground and sieved. Without (I), splitting of penicillin G in 6-aminopenicillanic acid and phenylacetic acid gave a specific activity of 2.17 pen G units per gram of dry catalyst, corresponding to 8.36 NIPAB units/g.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[CH:35]([CH3:37])[CH3:36]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH:35]([CH3:37])[CH3:36])[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1c(N)ncnc1Cl
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C(C)C)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-isopropyl-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=490, obsd=490). 1H NMR (400 MHz, DMSO-d6) δ 8.39 (t, J=3.9 Hz, 1H), 8.03 (t, J=2.1 Hz, 1H), 7.80 (d, J=2.9 Hz, 1H), 7.54 (s, 1H), 7.52-7.42 (m, 1H), 6.10 (s, 2H), 3.92 (d, J=6.4 Hz, 2H), 3.37 (s, 1H), 3.18-3.06 (m, 4H), 3.02 (q, J=7.5 Hz, 1H), 2.90 (t, J=11.7 Hz, 3H), 2.72 (d, J=6.5 Hz, 2H), 2.01-1.81 (m, 5H), 1.36-1.17 (m, 11H).
Reaction SMILES: [SH:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:19][S:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: OC(CS)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
3-Mercapto-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (230 mg) (prepared as in the previous Example), potassium carbonate (138 mg, 2.7 equivalents), and methyl iodide (200 mg, 1.9 equivalents) were stirred together in acetone (15 ml) at room temperature for two hours. The acetone was then evaporated under reduced pressure, and the residue triturated with water to give the crude title compound as a solid, 220 mg. This was crystallized from isopropanol to yield the pure title compound, yield 190 mg, m.p. 117°-119° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:12]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH2:24]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:11]([C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[OH:2])=[N:12]1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCn1nc(-c2ccc(OC)cc2OC)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCCCn1nc(-c2ccc(O)cc2O)c2cccc(C(F)(F)F)c21
Yield: 94.1 %

Procedure:
Prepared according to Method D step C from 3-(2,4-dimethoxyphenyl)-1-pentyl-7-(trifluoromethyl)-1H-indazole (0.055 g, 0.14 mmol), boron tribromide (0.136 mL, 1.4 mmol) and 1.0 mL of cyclohexene to give the product (0.048 g) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:26][C:27]([F:40])([F:39])[C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][N:29]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([N:36]2[CH2:35][CH2:34][N:33]([C:31]3[S:32][C:28]([C:27]([F:39])([F:26])[F:40])=[N:29][N:30]=3)[CH2:38][CH2:37]2)=[O:10])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3nnc(C(F)(F)F)s3)CC2)c1

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, dichloromethane/methanol 98:2) to yield the title compound as a colorless solid. MS (m/e): 491.2 (M+H+, 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18]>>[F:18][C:17]([F:20])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: FC(F)(F)c1ccccc1I
Reactant: c1ccc2[nH]ccc2c1
Product: FC(F)(F)c1ccccc1-n1ccc2ccccc21

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-2-(trifluoromethyl)benzene: ESMS m/e: 262.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][CH3:23])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:5][CH:4]=1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH2:22]([N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:24])=[CH:15][CH:16]=1)[C:34](=[O:35])[CH2:33][O:32][CH3:31])[CH3:23]
Reactant: CCNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Reactant: COCC(=O)Cl
Product: CCN(Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1)C(=O)COC

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-ethylaminomethyl-benzamide and methoxy-acetyl chloride, the title compound was prepared as white solid (33% yield). MS: m/e=499(M+H+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][C:25]1([CH3:37])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:33]3[C:27]4[O:26][C:25]([CH3:37])([CH3:24])[CH2:29][C:28]=4[CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)Cc2cccc(C(=O)O)c2O1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OC(C)(C)C4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,2-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.96 min; [M+H]+=506.2.
Reaction SMILES: [N+:1](=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-:2].C(P(CCCC)CCCC)CCC>C(#N)C>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9](=[O:10])[C:3](=[N:1][NH2:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1ccccc1F
Agent: CCCCP(CCCC)CCCC
Solvent: CC#N
Product: CCOC(=O)C(=NN)C(=O)c1ccccc1F
Temperature: 0 °C

Procedure:
Ethyl 2-diazo-3-(2-fluorophenyl)-3-oxopropanoate (1.06 g, 4.49 mmol) was dissolved in acetonitrile (20 mL), cooled to 0° C. and treated with tri-n-butylphosphine (1.16 mL, 4.71 mmol, 1.05 equiv). The mixture was warmed to ambient temperature and after 10 minutes, was concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 75:25; hexanes:ethyl acetate) to provide the titled compound.
Reaction SMILES: B(O)(O)O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15](=[O:31])[CH:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=2)C(OC)=O)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.C1(C)C=CC=CC=1>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15](=[O:31])[CH2:16][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[CH:25][CH:26]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: COC(=O)C(C(=O)c1cc(OC)cc(OC)c1)c1ccc(OC(C)C)cc1
Agent: OB(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(C(=O)Cc2ccc(OC(C)C)cc2)c1
Temperature: 152.5 °C
Reaction time: 3 h

Procedure:
9.65 g of boric acid (0.16 mol) and 58 g of crude methyl 3-(3,5-dimethoxyphenyl)-2-(4-isopropyloxyphenyl)-3-oxopropionate (0.16 mol) prepared according to Example 25 are introduced into a round-bottomed flask. The mixture is heated with stirring at 150-155° C. for 3 h and then cooled to approximately 80° C. 200 ml of toluene and then 150 ml of water are added. Separation by settling is carried out and the organic phase is recovered. The aqueous phase is re-extracted with 20 ml of toluene. The organic phases are concentrated to recover 48.8 g of crude 1-(3,5-dimethoxyphenyl)-2-(4-isopropyloxyphenyl)ethanone in the form of a viscous oil with a dark brown color.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6](=[O:8])[N:7]=1.[NH3:28]>CO>[NH2:28][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[C:6](=[O:8])[N:7]=1
Reactant: N
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncc(C#N)c(-c4ccccc4)c3c2)S1
Solvent: CO
Product: N#Cc1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1-c1ccccc1

Procedure:
Similar procedure as described in example 41c was used, starting from 6-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-4-phenyl-quinoline-3-carbonitrile (example 62e), and ammonia in methanol to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-phenyl-quinoline-3-carbonitrile. LC-MS m/e 357 (MH+).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9](=[O:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH:6]=1>C1COCC1>[Br:4][C:5]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]([CH3:1])([OH:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH:6]=1
Reactant: C[Mg]Br
Reactant: O=c1c2ccccc2cc(Br)c2ccncc12
Solvent: C1CCOC1
Product: CC1(O)c2ccccc2C=C(Br)c2ccncc21
Reaction time: 22 h

Procedure:
Methyl magnesium bromide (27.6 ml., 2.9 M in ether) is added dropwise to a solution of 5-bromobenzo[5,6]cyclohepta[1,2-c]pyridin-11-one (20.02 g., 0.07 mol) in dry THF (300 ml.) with cooling. When addition is complete, the cooling bath is removed and the mixture is stirred for 20-24 hours. The solvent is removed in vacuo, the residue is taken up in water (300 ml.) and acidified by the addition of acetic acid. The solid that forms is collected, washed with water then recrystallized from 2-propanol to give 16.25 g., m.p. 226.5°-229.5° C.