Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[CH:24]=[N:23]2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:14])[F:13])[C:25]=3[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: O=C(Cc1ccccc1C(F)(F)F)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 59 %

Procedure:
The compound was prepared from 2-trifluoromethylphenylacetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 72 mg (59%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.46 (s, 0.8H), 7.70 (m, 1H), 7.55 (m, 1.2H), 7.41-7.50 (m, 4H), 7.15 (m, 2H), 4.19 (s, 0.3H), 4.06 (s, 1.7H), 3.95 (m, 0.3H), 3.76 (m, 1.7H), 2.82-2.88 (m, 2H), 2.03 (m, 2H); MS: (ES) m/z calculated for C21H18F4N3O [M+H]+ 404.1, found 404.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:15][CH3:14])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: C[O-]
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(SC)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A mixture of 4,6-Dichloro-2-methylthio-5-nitropyrimidine (5.25 g, 21.88 mmol) in methanol (40 mL) was treated with sodium methoxide (1.3 g, 24.06 mmol). The mixture was stirred at room temperature for 3 h. At this point the reaction was poured onto ice to give a brown solid which was filtered and washed with water. The solid was dried under vacuo to give 4-Chloro-6-methoxy-2-methylthio-5-nitropyrimidine (4.40 g, 85%) as a brown solid. LRMS for C6H6Cl1N3O3S (M+H)+ at m/z=235. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[CH:14]=[CH:15]\[CH2:16][OH:17])[CH:5]=[CH:4][C:3]1=2.[CH2:19](I)I>CCOCC.[Zn].Cl[Cu]>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]3[CH2:19][CH:15]3[CH2:16][OH:17])[CH:5]=[CH:4][C:3]1=2
Reactant: ICI
Reactant: CC1(C)CCC(C)(C)c2cc(/C=C\CO)ccc21
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(C3CC3CO)ccc21

Procedure:
12.5 g of Zn-dust (activated by washing with HCl, H2O, EtOH, acetone, and EtOEt) and 1.89 g of freshly purified CuCl were refluxed in 120 ml of abs. EtOEt for 20 minutes. After cooling, 18.0 g of (Z)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-prop-2-en-1-ol, dissolved in 40 ml of EtOEt, were added, followed by 15.2 ml of CH2I2. The mixture was kept under reflux for 16 hours. Afterwards, it was poured onto crashed ice, extracted with EtOEt, washed with H2O, and dried over Na2SO4. Evaporation of the solvent and ensuing flash chromatography (silica gel, hexane/AcOEt=90:10) yielded 11.28 g of (1RS,2SR)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropylmethanol as yellowish oil (GC-purity: 97.6%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A164) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.C(O)(C)C.Cl.[H][H]>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[NH:8][CH:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: [H][H]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC12CCNCC2
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)NC12CCNCC2

Procedure:
4.0 g (0.012 mole) of 7-chloro-5-phenyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2(3H)-one are hydrogenated in 160 ml of methanol with the addition of 10 ml of a 30% strength isopropanol/HCl solution in the presence of platinum at 25° C. in the course of 3 hours, until the calculated amount of hydrogen has been taken up. After filtration, the solvent is distilled off, the residue is rendered alkaline with aqueous concentrated ammonia solution and the base is extracted by shaking with methylene chloride. The organic phase is washed with water, dried over Na2SO4 and concentrated and the residue is chromatographed on silica gel 60 (Merck); eluting agent: methylene chloride/methanol/25% strength aqueous ammonia solution (14:2.5:0.5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10]C(=O)OCC)=S.Cl.NO.CC[N:21](C(C)C)C(C)C.C(O)C>CO>[N:7]1[C:8]([NH2:10])=[N:21][N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=12
Reactant: CCOC(=O)NC(=S)Nc1cnccn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2cnccn2n1
Temperature: 65 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 270a (6.00 g, 26.43 mmol, 1.0 eq.), hydroxylamine hydrochloride (3.32 g, 47.52 mmol, 1.8 eq.), DIPEA (12 mL), ethanol (40 mL), and methanol (40 mL). The reaction mixture was stirred at 65° C. for 16 hours. After the reaction was complete, it was cooled to room temperature and concentrated to a volume of around 20 mL under reduced pressure. The resulting suspension was collected by filtration and the solid was washed with 60:1 dichloromethane/ethanol (50 mL) to afford 270b (3.3 g, 92%) as a white solid. MS-ESI: [M+H]+ 136.3. 1H NMR (500 MHz, DMSO-d6) δ 8.84 (d, J=1.0 Hz, 1H), 8.70 (dd, J=1.0, 4.0 Hz, 1H), 7.98 (d, J=5.0 Hz, 1H), 6.47 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH3:17])=[C:6]([NH:18][C:19](=O)[CH2:20][C:21]2[S:25][CH:24]=[N:23][CH:22]=2)[CH:5]=1.CO.[OH-].[Na+]>C1COCC1>[CH3:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:27])=[CH:5][C:6]=2[N:18]=[C:19]1[CH2:20][C:21]1[S:25][CH:24]=[N:23][CH:22]=1
Reactant: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c(NC(=O)Cc2cncs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CCCC[C@H]1n1c(Cc2cncs2)nc2cc(C(=O)O)ccc21
Yield: 99.7 %

Procedure:
0.35 g 4-((1R,2R)-2-Methyl-cyclohexylamino)-3-(2-thiazol-5-yl-acetylamino)-benzoic acid methyl ester was dissolved in 6 ml of THF and 3 ml of methanol and 7 ml of 2 M aqueous sodium hydroxide solution were added at rt for 4 h. The reaction was concentrated and the pH was adjusted to 5 by addition of 2 M aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate and concentrated to afford 0.32 g (95%) of 1-((1R,2R)-2-Methyl-cyclohexyl)-2-thiazol-5-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].C([O:14][C:15](OC(OC(C)(C)C)=O)=[O:16])(C)(C)C.O.[C:26](O)([CH3:29])([CH3:28])[CH3:27]>>[C:5]([CH2:4][CH2:3][CH:2]([NH2:1])[C:15]([OH:16])=[O:14])([O:7][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:6]
Reactant: NCCCC(=O)O
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)CCC(N)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Aminobutanoic acid (1 g, 9.7 mmol) was dissolved in tert-butyl alcohol (15 ml), 5N NaOH (1.93 ml, 9.7 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. Di-tert-butyl-dicarbonate (2.33 g, 10.7 mmol) dissolved in tert-butylalcohol (17 ml) was added thereto and stirred for 24 hours at room temperature. Water (12 ml) was added thereto and the resultant was concentrated under a reduced pressure and cooled to 0° C. Then, 2N H2SO4 was added thereto dropwise until pH of the mixture became 2. The resultant was extracted with ethyl acetate and the extract was washed with water. The organic layer was dried over MgSO4 and concentrated to obtain the title compound (2.1 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C=O>[CH3:23][N:14]1[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]2[CH:10]=[N:9][C:8]([C:5]3[N:4]=[C:3]([CH2:2][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[O:7][N:6]=3)=[C:12]2[CH2:13]1
Reactant: C1CCNCC1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCCC4)n3)ncn2-c2ccccc2C1=O
Yield: 74 %

Procedure:
1.15 g (3.5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 1 hour with 1 g (11.7 mmol) of piperidine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/ethanol 9/1 there was obtained 0.98 g (74%) of 5-methyl-3-[5-(piperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 167°-168°, which was converted into the hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3](=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 18 °C
Reaction time: 18 h

Procedure:
Methyl 2-methoxy-3-(4-nitrophenyl)acrylate (7.8 g, 32.8 mmol) was dissolved in IMS (156 ml). A solution of NaOH (1.44 g, 36.1 mmol) in water (78 ml) was added and the mixture stirred at ambient temperature (18° C.) for 18 hr. The reaction mixture was acidified with 1M HCl (120 ml) and the resulting precipitated solid was collected by filtration, washed with water (2×100 ml) and partially suction dried on the filter for 30 mins, followed by vacuum oven drying at 18° C. for 18 hr. Thus 2-methoxy-3-(4-nitrophenyl)acrylic acid was afforded as a tan solid containing some water of crystallisation (6.7 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.Cl.[CH2:13]([OH:15])[CH3:14]>>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8](=[NH:9])[O:15][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)COc1ccc(Cl)cc1

Procedure:
Commercially available 2-(4-chlorophenoxy)acetonitrile (Aldrich), HCl gas and ethanol were processed using the method described for Example 4A to obtain the titled compound. MS (ESI+) m/z 214 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.Cl[CH2:21][C:22](=[O:24])[CH3:23].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:21][C:22]([CH3:23])=[O:24])[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CC(C)=O)C3

Procedure:
A solution of 26.1 g (0.1 m) of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridine-5-one, prepared in Example 1, 13 g (0.14 m) of chloroacetone, and 14.2 g (0.14 m) of triethylamine in 450 ml of ethanol was refluxed overnight. After evaporation, the residue was partitioned between dilute NaOH solution and CHCl3. After drying (Na2SO4) and evaporation of the CHCl3 extract, the residue was triturated with pet ether and 27.2 g of product filtered off. Crystallization from methanol afforded analytical material, mp 168°-72° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH2:17])[C:6]1[C:14]2[C:9](=[C:10]([CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:17][CH:5]([C:6]1[C:14]2[C:9](=[C:10]([CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(N)c1c[nH]c2c(CC)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc2c(C(N)CO)c[nH]c12
Yield: 85.7 %

Procedure:
α-Amino-7-ethyl-1H-indole-3-acetic acid ethyl ester 6 (4.9 g, 0.02 mol) in THF (50 mL) was added to LiAlH4 (2.3 g, 0.06 mol) in THF (25 mL) and the mixture was refluxed for 2 hours to give β-amino-7-ethyl-1H-indole-3-ethanol 7 (3.5 g, 85.7%). A sample recrystallized from ethyl acetate-hexane had m.p. 84°-86° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CCOCC>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][N:6]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.3 %

Procedure:
A solution containing 5-bromo-2-methylpyridine (1.2 g, 6.98 mmol) in ether (14 mL) at −78° C. was treated with n-butyllithium (5.2 mL, 1.6 M in hexanes) dropwise, stirred at −78° C. for 1 hour, treated with tributyltin chloride (2.25 mL, 8.30 mmol), stirred at −78° C. for 0.5 hours, and then at 0° C. for 0.5 hours. The reaction was quenched with saturated ammonium chloride solution and the reaction was partitioned between ether and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (2.97 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:23])[C:14]([NH:16][CH2:17][CH:18](OC)OC)=[O:15].FC(F)(F)C(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:18]=[CH:17][NH:16][C:14](=[O:15])[C:13]1=[O:23]
Reactant: COC(=O)c1ccc(Cl)c(NC(=O)C(=O)NCC(OC)OC)c1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cl)c(-n2cc[nH]c(=O)c2=O)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 115.6 %

Procedure:
A suspension of methyl 4-chloro-3-{[[(2,2-dimethoxyethyl)amino](oxo)acetyl]amino}benzoate (Example 330c, 8.5 g) in acetic acid (26 mL) was treated with trifluoroacetic acid (8.5 mL) under nitrogen. The resulting mixture was stirred at 120° C. for 3 h. The mixture was quenched with water (20 mL) and the resulting solid filtered off to give the subtitle compound (8.00 g).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][C:9](=[CH:11][CH2:12][CH2:13][CH:14]([CH2:16][CH2:17][OH:18])[CH3:15])[CH3:10].N1C=CC=CC=1.CCOCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][CH:14]([CH2:13][CH2:12][CH:11]=[C:9]([CH3:8])[CH3:10])[CH2:16][CH2:17][O:18][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: CC(C)=CCCC(C)CCO
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)=CCCC(C)CCOC(=O)CCC(=O)O
Yield: 47.4 %

Procedure:
A solution of 30.0 g succinic anhydride, 46.9 g citronellol, 36.0 g pyridine and 2.2 g 4-dimethylaminopyridine in 300 ml of dichloromethane was refluxed for 22 hours. Then the solution was cooled, ether was added and the organic phase was washed with 2N HCl and water to neutrality, dried and evaporated to dryness. The residue was wipe-film distilled to yield 36.4 g of a colourless liquid.
Reaction SMILES: [O:1]=[C:2]([C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][N:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][Si](C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[O:1]=[C:2]([C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][N:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8]
Reactant: C[Si](C)(C)C#CCCCCC(=O)c1ncc(-c2ccccn2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCCCCC(=O)c1ncc(-c2ccccn2)o1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 77.7 %

Procedure:
A solution of 1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-7-(trimethylsilyl)hept-6-yne (3a, 570 mg, 1.75 mmol, 1 equiv) in anhydrous THF (6 mL) at 0° C. was treated with a solution of Bu4NF in THF (1 M, 2.1 mL, 2.1 mmol). After stirring for 35 min at 0° C., the reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. Column chromatography (SiO2, 2.5×3 cm, 30% EtOAc-hexanes) afforded 1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-hept-6-yne (3b, 340 mg, 1.36 mmol, 77%) as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 8.68-8.66 (m, 1H), 7.89-7.86 (m, 2H), 7.82 (td, 1H, J=7.6, 1.8 Hz), 7.34-7.31 (m, 1H), 3.15 (t, 2H, J=7.3 Hz), 2.27 (td, 2H, J=7.2, 2.7 Hz), 1.96 (t, 2H, J=2.7 Hz), 1.94-1.88 (m, 2H), 1.68-1.62 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 187.9, 157.2, 153.2, 150.1, 146.2, 137.1, 126.8, 124.1, 120.3, 83.8, 68.7, 38.4, 27.7, 22.9, 18.2; IR (film) νmax 2938, 2867, 2115, 1698, 1603, 1575, 1505, 1470, 1426, 1385, 1283, 1245, 1127, 1086, 1024, 991, 962, 853, 785, 743 cm−1; ESI-TOF m/z 255.1135 (C15H14N2O2+H+ requires 255.1128).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:38](Br)[CH3:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:32])[F:33])[CH:25]=3)(=[O:23])=[O:22])[CH2:38][CH3:39])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCN(c1ccc(OC)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1)S(=O)(=O)c1cccc(OC(F)F)c1

Procedure:
The compound was prepared by analogy to the methods described for Preparation Example 2 and Examples 1 and 5 from 4-{5-[(3-difluoromethoxybenzenesulfonyl)-amino]-2-methoxyphenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was reacted with sodium hydride and ethylbromide to yield 4-{5-[(3-difluoromethoxy-benzenesulfonyl)-ethyl-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was deprotected and subsequently subjected to reductive amination with aqueous formaldehyde and sodium triacetoxyborohydride as described for example 5 to yield the title compound.
Reaction SMILES: Br[C:2]1[C:3](=O)[C:4](Br)=[CH:5][C:6]([Br:9])(Br)[CH:7]=1.[O:12]1C2C=CC=CC=2[N:14]=[C:13]1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[C:27]([O:29][CH3:30])=[O:28]>ClCCl>[Br:9][C:6]1[CH:7]=[CH:2][C:3]2[N:14]=[C:13]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]3[C:27]([O:29][CH3:30])=[O:28])[O:12][C:4]=2[CH:5]=1
Reactant: COC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCCN1c1nc2ccc(Br)cc2o1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
2,4,4,6-Tetrabromo-2,5-cyclohexadien-1-one (4.7 g) was added to a solution of methyl (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (3.0 g) [see Preparation 2] in dichloromethane (60 ml) at −10° C. over a period of 10 minutes. The reaction mixture was then warmed to room temperature and diluted with dichloromethane. The organic layer was washed with saturated sodium hydrogen carbonate, then with 1N sodium hydroxide solution, dried over sodium sulphate and the solvent removed under reduced pressure to afford methyl (2S)-1-(6-bromo-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (3.7 g) as a purple coloured oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>CCOCC>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: CN(C)CCO
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CN(C)CCOc1ccc2c(c1)CCCC2=O

Procedure:
Ether linked analogs such as 61, are prepared by the convergent synthesis depicted in scheme 15. The 6-hydroxy-1-tetralone 15 is reacted with an amine, such as N,N-dimethylethanolamine, preferably in the presence of PPh3 and DEAD at a temperature preferably between about 0° C. and about RT to form the 6-(2-dimethylamino-ethoxy)-3,4-dihydro-2H-naphthalen-1-one 59. The 6-(2-dimethylamino-ethoxy)-3,4-dihydro-2H-naphthalen-1-one 59 is reacted with hydroxylamine hydrochloride and base, such as Et3N. The reaction is heated above RT, preferably at reflux to form the oxime 60. Hydrogenation of the oxime 60, such as with Pd/C and H2 provides the amine 61.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.Cl.[N:19]1([C@H:24]2[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:29][CH2:28]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: N[C@H]1CC[C@H](N2CCCC2)CC1
Agent: Cl
Product: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N2CCCC2)CC1)C1CC1

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (220 mg, 0.708 mmol) was reacted with trans-4-(pyrrolidin-1-yl)cyclohexanamine hydrochloride (350 mg, 2.08 mmol) to afford the desired product (75 mg, 24%) as an off-white solid: ESI MS m/z 442 [C23H28BrN3O+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:21][CH:20]2[O:22][CH:17]([CH2:18][CH2:19]2)[CH2:16]1>>[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([S:28][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)[S:26][CH:27]=2)[CH2:21][CH:20]2[O:22][CH:17]([CH2:18][CH2:19]2)[CH2:16]1
Reactant: OC1(c2csc(S)c2)CC2CCC(C1)O2
Reactant: CN1C(=O)CCc2cc(I)ccc21
Product: CN1C(=O)CCc2cc(Sc3cc(C4(O)CC5CCC(C4)O5)cs3)ccc21
Yield: 28 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 3-hydroxy-3-(2-mercaptothien-4-yl)-8-oxabicyclo[3,2,1]octane to give 3-hydroxy-3-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]-8-oxabicyclo[3,2,1]octane in 28% yield.