Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Br[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:18][CH3:19])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nc(Nc2cc(Br)cn(C)c2=O)cc1C
Temperature: 85 °C
Yield: 48.4 %

Procedure:
A 100-mL round-bottomed flask was charged with 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 115a (800 mg, 2.83 mmol), bromoethane (216 mg, 1.98 mmol), K2CO3 (780 mg, 5.66 mmol), and DMF (20 mL). The mixture was heated at 85° C. overnight. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 252a as a red solid (298 mg, 37%). MS-ESI: [M+H]+ 311.0. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 5.85 (s, 1H), 3.98-3.94 (m, 2H), 3.48 (s, 3H), 2.19 (s, 3H), 1.27 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([NH:33][C:34]4([C:40]([OH:42])=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:32])=[CH:27][CH:26]=3)[N:24]=2)[CH2:16][CH2:15]1>CN(C)C=O>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[O:32][C:40](=[O:42])[C:34]5([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)[N:33]=4)=[CH:27][CH:26]=3)[N:24]=2)[CH2:18][CH2:19]1
Reactant: CN1CCN(c2nc(-c3ccc(C(=O)NC4(C(=O)O)CCCCC4)cc3)cs2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(-c3ccc(C4=NC5(CCCCC5)C(=O)O4)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
450 mg (2.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 910 mg (2.1 mmol) of 1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylic acid in 20 ml of dimethylformamide. After the mixture was stirred at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 577 mg (67%) of the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]2[CH:16]=[CH:15][C:14](=[N:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=[CH:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30].[Na]>>[C:1]1([S:7]([NH:10][C:11]2[C:12](=[N:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:13]=[C:14]([NH:17][S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:15](=[N:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:16]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(NCl)c1ccccc1
Reactant: O=S(=O)(N=C1C=CC(=NS(=O)(=O)c2ccccc2)C=C1)c1ccccc1
Agent: [Na]
Product: O=S(=O)(N=C1C=C(NS(=O)(=O)c2ccccc2)C(=NS(=O)(=O)c2ccccc2)C=C1NS(=O)(=O)c1ccccc1)c1ccccc1

Procedure:
N,N′-Bis[phenylsulfonyl]-1,4-benzoquinone diimine is sulfanylamidated by sodium N-chlorobenzenesulfonamide to form 2,5-bis(phenylsulfonylamino)-N,N′-bis(phenylsulfonyl)-1,4-benzoquinone diimine. Similarly, amidation of N,N′-bis[phenylsulfonyl]-1,4-benzoquinone diimine with N-chloroamides gives the corresponding sulfonyl benzoquinone diimine derivatives in one step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[CH2:16][CH2:17][NH:18]C(=O)OCC1C=CC=CC=1)[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:18][CH2:17][CH2:16][C:15]1[CH:14]=[C:13]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][O:11][CH3:12])[CH:31]=[CH:30][CH:29]=1
Reactant: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: COCC(NC(=O)OC(C)(C)C)c1cccc(CCN)c1
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A mixture of benzyl 3-{(1R/S)-1-[(tert-butoxycarbonyl)amino]-2-methoxyethyl}phenethylcarbamate (preparation 120) (289 mg, 0.68 mmol) and 10% palladium on charcoal (30 mg) in methanol (10 ml) was hydrogenated at 15 psi and room temperature for 16 hrs. The reaction mixture was filtered through Arbocel®, and the filtrate evaporated under reduced pressure to give the title compound, (196 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=O)[S:5][C:6]=1[Br:7].C([SiH](CC)CC)C.B(F)(F)F>C(Cl)Cl.CC#N>[Br:7][C:6]1[S:5][C:4]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[C:3]([CH3:18])[C:2]=1[Br:1]
Reactant: CCc1ccc(C(=O)c2sc(Br)c(Br)c2C)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Product: CCc1ccc(Cc2sc(Br)c(Br)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of (4,5-dibromo-3-methylthiophen-2-yl)(4-ethylphenyl)methanone (54) (4.28 g, 10.6 mmole) in DCM/CH3CN (30 mL/30 mL) were added triethylsilane (5.1 mL, 31.9 mmole) and borontrifluoride diethyletherate (3.1 mL, 25.4 mmole) at 0° C. The resulting solution was stirred at ambient temperature overnight. The reaction mixture was quenched by adding MeOH (10 mL) and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the compound 55 2,3-dibromo-5-(4-ethylbenzyl)-4-methylthiophene (3.65 g, 9.76 mmole, 92%) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([C:14]4[CH:18]=[CH:17][NH:16][N:15]=4)[N:11]([CH2:19][C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([C:14]4[CH:18]=[CH:17][N:16]([CH3:30])[N:15]=4)[N:11]([CH2:19][C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc3c(cc(-c4cc[nH]n4)n3Cc3cccc(C#N)c3)n12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4ccn(C)n4)n3Cc3cccc(C#N)c3)n12
Reaction time: 0.17 h

Procedure:
3-{[1-Methyl-7-(1H-pyrazol-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl]methyl}benzonitrile (50. mg, 0.14 mmol, from Example 182, Step 4) in DMF (3.0 mL) was treated with NaH (60% in mineral oil, 34 mg, 0.85 mmol). After 10 minutes, MeI (26 μL, 0.42 mmol, Aldrich) was introduced. After 10 minutes, the reaction was quenched by the addition of water. The product was isolated via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (30 mg, 58%).
Reaction SMILES: [CH2:1]([N:8](C)[C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]([CH3:25])=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:1][NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]([CH3:25])=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10]1
Reactant: Cc1c(O[C@@H]2CCC[C@H](N(C)Cc3ccccc3)C2)ccc2[nH]ncc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2C)C1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
Under nitrogen, the N-benzyl-N-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine (80 mg, 0.229 mmol) obtained in Example 729 was dissolved in ethanol (4 ml), followed by adding thereto ammonium formate (144 mg, 2.29 mmol) and then 10%-Pd/C (containing 50% water) (20 mg), and the resulting mixture was stirred with heating under reflux for 2 hours. The reaction mixture was cooled to room temperature and the Pd/C was filtered off. Then, the solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/1, 100/2, 100/4) to obtain N-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine (50 mg, yield 84.2%) as a white amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([C:24]([O:27][CH3:28])([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:29]([C:36]([NH:38][OH:39])=O)C1C=CC=CC=1>C1COCC1>[OH:39][NH:38][C:36]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH2:17][C:18]2[C:23]([C:24]([O:27][CH3:28])([CH3:25])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:16][CH2:15]1)=[O:29]
Reactant: O=C(NO)Oc1ccccc1
Reactant: COC(C)(C)c1cccnc1CN(Cc1ncc(C)cc1C)C1CCNCC1
Solvent: C1CCOC1
Product: COC(C)(C)c1cccnc1CN(Cc1ncc(C)cc1C)C1CCN(C(=O)NO)CC1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a solution of (3,5-Dimethyl-pyridin-2-ylmethyl)-[3-(1-methoxy-1-methyl-ethyl)-pyridin-2-ylmethyl]-piperidin-4-yl-amine (0.245 g, 0.64 mmol) in dry THF (4 mL) was added N-(phenoxycarbonyl)hydroxylamine (0.193 g, 1.26 mmol) and the resultant solution was stirred at 60° C. overnight. The mixture was cooled to room temperature and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 177 mg (54%) of COMPOUND 263 as a white solid. 1H NMR (CDCl3) δ 1.52-1.74 (m, 8H), 1.94-1.98 (m, 2H), 2.10 (s, 3H), 2.25 (s, 3H), 2.67 (t, 2H, J=12.6 Hz), 2.77-2.95 (m, 4H), 3.93-4.02 (m, 4H), 4.16 (s, 2H), 6.80 (s, 1H), 7.13-7.18 (m, 2H), 7.62 (d, 1H, J=8.1 Hz), 8.14 (s, 1H), 8.49 (dd, 1H, J=4.5, 1.5 Hz); 13C NMR (CDCl3) δ 18.31, 18.54, 27.87, 28.29, 44.05, 50.79, 54.01, 54.53, 54.86, 58.20, 122.10, 131.99, 133.18, 135.73, 139.25, 139.97, 146.56, 147.36, 161.04; ES-MS m/z 442 (M+H). Anal. Calcd. For C24H35N5O3.0.8CH2Cl2: C, 58.46; H, 7.24; N, 13.75. Found: C, 58.40; H, 7.20; N, 13.89.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([NH:15][CH2:16][C:17]1[S:18][CH:19]=[C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])[N:21]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>ClCCl.C(O)=O>[CH:13]([NH:15][CH2:16][C:17]1[S:18][CH:19]=[C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])[N:21]=1)=[O:12]
Reactant: COC(=O)Nc1csc(CNC(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Nc1csc(CNC=O)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 100 %

Procedure:
A 3.9 ml portion of trifluoroacetic acid was added to 776 mg of 2-(N-t-butoxycarbonylamino)methyl-4-methoxycarbonylaminothiazole, followed by stirring at room temperature for 50 minutes. The reagent was evaporated under reduced pressure to obtain a light brown solid, and this solid was then dissolved in 13.5 ml of dichloromethane and 10 ml of a 15% aqueous potassium carbonate solution to adjust the pH of the solution to 10.0. Further, a mixed solution of 2.55 ml of anhydrous acetic acid and 1.27 ml of formic acid was added dropwise over 10 minutes under ice-cooling with vigorous stirring. After adjustment to pH 6 with potassium carbonate, the ice bath was removed, and the solution was then stirred for 30 minutes. After the addition of 100 ml of dichloromethane and 20 ml of distilled water as well as sufficient shaking, the organic layer was separated. After the pH of the aqueous layer was adjusted to 11 with potassium carbonate, extraction was carried out twice with 100 ml of dichloromethane, and the extract was then combined with the above organic layer. Further, the solution was dried (anhydrous magnesium sulfate and anhydrous potassium carbonate), and then filtered. The solvent was then evaporated under reduced pressure to obtain 581 mg of 2-(formylamino)methyl-4-methoxycarbonylaminothiazole as a light yellow powder.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[C@@H:8]3[O:10][C@@H:9]3[C@H:3]1[CH2:4][C@@H:5]([O:11]C([C@@H](C1C=CC=CC=1)CO)=O)[CH2:6]2.O.O.O.Br.[BH4-].[Na+].O.[ClH:30]>C(O)C.C(OCC)C>[CH3:1][N:2]1[C@@H:7]2[C@@H:8]3[O:10][C@@H:9]3[C@H:3]1[CH2:4][CH:5]([OH:11])[CH2:6]2.[ClH:30]
Reactant: CN1[C@@H]2C[C@@H](OC(=O)[C@H](CO)c3ccccc3)C[C@H]1[C@@H]1O[C@@H]12
Agent: Br
Agent: Cl
Agent: [BH4-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CN1[C@@H]2CC(O)C[C@H]1[C@@H]1O[C@@H]12
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
10.0 g (22.84 mmol) of scopolamine hydrobromide trihydrate was suspended in 100 mL of absolute ethanol, and cooled to about 0° C. Sodium borohydride (4.0 g, 105.7 mmol) was then added portion-wise while maintaining the temperature at a maximum of 30° C. 4.8 mL of water was then added to the reaction mixture. After 3.5 hours, the reaction was completed and 50 mL of diethyl ether was then added. The reaction was then cooled to 0° C., and acidified with 2M hydrochloric acid in diethyl ether to a pH of about 2. The suspension was stirred at room temperature for 30 minutes and then filtered on GochP3. The white solid was dried at 45° C. under vacuum for 4 hours, yielding 9 g of product containing 79% of salts determined by sulphuric ashes.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH:27]2[CH2:29][CH2:28]2)[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH:27]2[CH2:28][CH2:29]2)[N:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccccc1
Reactant: CCCCc1nc(C2CC2)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc(C2CC2)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 66.8 %

Procedure:
A mixture of 4′-[(4-butyl-2-cyclopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), phenylboronic acid (0.64 g), copper(II) acetate (0.95 g), pyridine (1.1 mL), triethylamine (1.8 mL), molecular sieves 4A (2.0 g) and dichloromethane (20 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.80 g, 59%) as a pale-yellow liquid.
Reaction SMILES: S(=O)(=O)(O)O.C([NH2:8])=O.[CH2:9]([O:11][CH2:12][C:13]([O:15][CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=O)[CH3:10].Cl>O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:8]=[C:13]([CH2:12][O:11][CH2:9][CH3:10])[O:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: CCOCC(=O)OCC(=O)c1ccc(Cl)cc1
Reactant: NC=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOCc1nc(-c2ccc(Cl)cc2)co1
Temperature: 140 °C
Yield: 45.6 %

Procedure:
40 g (0.41 mol) of concentrated sulphuric acid were added dropwise while stirring to 150 g (3.3 mol) of formamide, the temperature of the solution being held below 10° C. by cooling with ice. 50 g (0.2 mol) of (4-chlorobenzoyl)methyl ethoxyacetate were added and the solution was stirred and heated at 140° C. for 2 hours. The mixture was cooled, poured into 2 l of water, acidified to pH 1 by the addition of concentrated hydrochloric acid and extracted once with 500 ml of toluene and then twice with 250 ml of toluene each time. The combined toluene extracts were washed with water, dried over sodium sulphate, filtered and evaporated. The residual syrup was extracted with 700 ml of hot petrol (b.p. 60°-80° C.). The solution was evaporated to dryness and the residue was redissolved in 150 ml of hot petrol (b.p. 40°-60° C.). Upon cooling in acetone/CO2 the product crystallized and was filtered off rapidly and dried to give 21.7 g (47%) of 4-(4-chlorophenyl)-2-ethoxymethyl-oxazole in the form of a soft solid of indeterminate melting point.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH2:34][O:35][CH3:36])[CH:28]=1>>[CH3:36][O:35][CH2:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:27]1[CH:28]=[C:23]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH:24]=[N:25][CH:26]=1
Reactant: COC[C@@H]1CCCN1c1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: COC[C@@H]1CCCN1c1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [C], 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to 3-bromo-5-((S)-2-methoxymethyl-pyrrolidin-1-yl)-pyridine (intermediate A-6) to give the title compound as a yellow oil. MS: 352.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[CH3:25][O:26][CH2:27][CH2:28][CH:29]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:29][CH2:28][CH2:27][O:26][CH3:25]
Reactant: COCCC=O
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Product: COCCC=NOCCC1=C(C)/C(=C/c2ccc(SC)cc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-methoxypropanal by the method of Example 1.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:7]=[CH:6][C:5]=1[NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28](C(=O)C(F)(F)F)[CH2:27][CH2:26]2)(=[O:22])=[O:21]>C(O)C.O>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:7]=[CH:6][C:5]=1[NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27][CH2:26]2)(=[O:22])=[O:21]
Reactant: O=C(N1CCc2cc(S(=O)(=O)Nc3ccc(OCCc4ccccn4)cc3F)ccc2C1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)(Nc1ccc(OCCc2ccccn2)cc1F)c1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Powdered potassium hydroxide (2 mg, 36.2 μmol) was added to a solution of N-{2-fluoro-4-[2-(pyridin-2-yl)ethoxy]phenyl}-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (10 mg) in an ethanol-water mixture (9:1) (2 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure and water was added thereto. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Thereafter, the desiccant was filtered off, followed by concentration under reduced pressure to afford the title compound as a colorless solid (10 mg).
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[N:7][C:8]=1[F:9].ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:43][C:44]1[CH:45]=[C:46]([NH:51][NH2:52])[CH:47]=[CH:48][C:49]=1[F:50]>>[Cl:43][C:44]1[CH:45]=[C:46]([N:51]2[C:10]([C:5]3[CH:6]=[N:7][C:8]([F:9])=[C:3]([Cl:2])[CH:4]=3)=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[N:52]2)[CH:47]=[CH:48][C:49]=1[F:50]
Reactant: CCOC(=O)C(=O)C=C([O-])c1cnc(F)c(Cl)c1
Reactant: NNc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cnc(F)c(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
240 mg (0.86 mmol) of the compound of Example 15A is reacted analogously to the synthesis of the compound of Example 20A with 253 mg (1.29 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 16 mg (5% of theory) of the title compound is obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([Br:20])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.Cl.N1CCC(C(C2C=CC3C(=CC=CC=3)C=2)=O)CC1.[Cl:40][CH2:41][CH2:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)=[O:44].ClCCCC(C1C=CC=CC=1)=O>>[ClH:40].[Br:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:41][CH2:42][C:43]([C:45]3[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=3)=[O:44])[CH2:3][CH2:4]2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(Br)c2ccccc12)C1CCNCC1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(CCCCl)c1ccccc1
Agent: O=C(c1ccc2ccccc2c1)C1CCNCC1
Product: O=C(CCN1CCC(C(=O)c2ccc(Br)c3ccccc23)CC1)c1ccc(Cl)cc1

Procedure:
When in the procedure of Example 19, 4-bromo-1-naphthyl 4-piperidyl ketone hydrochloride is substituted for 2-naphthyl 4-piperidyl ketone hydrochloride and 3-chloro-1-(4-chlorophenyl)-1-propanone substituted for 4-chloro-1-phenyl-1-butanone, 3-[4-(4-bromo-1-naphthoyl)-1-piperidyl]-1-(4-chlorophenyl)-1-propanone hydrochloride is produced.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC(OC(C)=O)=[O:20]>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:20])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
A stirred solution of 4-(4-(trifluoromethyl)phenyl)pyridine 1-oxide (465 mg, 1.94 mmol) in Ac2O (10 mL) under nitrogen atmosphere was heated from 110 to 130° C. over 4.5 h. Then the mixture was heated at reflux for 2 h and then allowed to cool. The mixture was concentrated to dryness and then treated with MeOH and water (10 mL, 1:1). After stirring at room temperature for 6 h, the mixture was heated to reflux for 2.5 h. The mixture was allowed to cool and was concentrated to dryness. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 95:5) gave the title compound (336 mg, 72%) as a light brown powder: 1H NMR (500 MHz, CDCl3) δ 12.67 (br s, 1H), 7.76 (d, J=8.2 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.47 (d, J=6.8 Hz, 1H), 6.80 (d, J=1.6 Hz, 1H), 6.54 (dd, J=6.8, 1.8 Hz, 1H); ESI MS m/z 240 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:27]1([CH2:33][CH:34]([OH:36])[CH3:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:36][CH:34]([CH3:35])[CH2:33][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:4][CH:3]=1
Reactant: CC(O)CN1CCCCC1
Reactant: Ic1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(CN1CCCCC1)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.54 g (7.00 mmol) iodobenzene and 2.75 g (10.5 mmol) triphenylphosphane are added successively to a solution of 1.00 g (6.98 mmol) 1-piperidin-1-yl-propan-2-ol in 20 mL DCM. 2.19 mL (10.5 mmol, 95%) diisopropyl azodicarboxylate is added dropwise at RT and the reaction is stirred for 2 h at RT. It is diluted with water, the organic phase is washed with water and dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, DCM/MeOH 9:1). The oily residue is triturated with diisopropylether, filtered off from the insoluble residue and the filtrate is evaporated to dryness i.vac.