Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.CON(C)[C:17](=[O:31])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][Si](C)(C)C)=[C:21]([F:30])[CH:20]=1>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:30])[CH:20]=2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CON(C)C(=O)Cc1ccc(O[Si](C)(C)C)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(O)c(F)c1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A solution of 45 ml of n-butyllithium (1.6M in hexane) is added dropwise to a suspension, cooled to -78° C., of 18.2 g of 1,4-dibromobenzene in 140 ml of THF. Then, 10 g of N-methoxy-N-methyl-2-(3-fluoro-4-trimethylsilanyloxy-phenyl)-acetamide (paragraph Bb)) in 35 ml of THF are added dropwise at -78° C. The reaction mixture is stirred at -78° C. for 2 hours, then left to stand at room temperature for 1 hour while stirring. After dilution with ethyl acetate, the mixture is washed with 10% aqueous KHSO4 solution, saturated NaHCO3 solution and 10% aqueous NaCl solution. After extraction with ethyl acetate, the organic phases are dried and concentrated. Then, the silyl group is cleaved with 105 ml of THF, 11 ml of H2 and 5 drops of 1N HCl. Concentration, dissolution in methylene chloride, drying and column chromatography over silica gel with methylene chloride/0.5% methanol as the eluent, give 9.2 g of 1-(4-bromo-phenyl)-2-(3-fluoro-4-hydroxy-phenyl)-ethanone. MS: m/e 308 (M+, 1 Br).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[C:18]2Cl>CN1CCCC1=O.C(OCC)C>[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=3)[NH:3][C:2]=1[CH3:1])[CH:19]=[CH:18]2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Cc1cccc2c(Cl)ccnc12
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Cc1ccc2[nH]c(C)c(-c3ccc4cccc(C)c4n3)c2c1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
2,5-Dimethylindole (290 mg) and 8-methyl-4-chloroquinoline (360 mg) were suspended in N-methylpyrolidinone (0.5 ml), and maintained under a nitrogen atmosphere. The reaction was heated to 140° C. with stirring for 45 minutes. On cooling a deep red precipitate formed, the mixture was diluted with diethylether and the solid collected by filtration, and dried to give the sub-title compound (570 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (400 mg, 1.57 mmol) in DCM (16 mL) was added acetic anhydride (177 μL, 1.88 mmol) and triethylamine (656 μL, 4.71 mmol) and the mixture was stirred (rt, 16 h). The reaction mixture was diluted with DCM (16 mL), washed with water (3×10 mL) and brine (1×10 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the 9-acetyl-3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (466 mg, 100%). This intermediate was dissolved in DCM (4 mL), treated with HCl (4 M in dioxane, 4 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to provide the title compound as a white powder (365 mg, 100%). MS (ESI): mass calcd. for C11H20N2O, 196.16; m/z found, 197.1 [M+H]+. 1H NMR (400 MHz, MeOD): 3.63-3.51 (m, 4H), 3.23-3.17 (m, 4H), 2.13 (s, 3H), 1.82-1.73 (m, 4H), 1.67-1.53 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH3:12]>CN(C)C=O>[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:12]
Reactant: CCc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: CCc1ccccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 110 °C

Procedure:
In a 20 mL microwave vial 2-chloro-5-nitropyridine (500 mg, 3.15 mmol) was dissolved in N,N-dimethylformamide (10 mL) to give a light brown solution. 2-ethylphenol (0.378 mL, 3.15 mmol) and K2 CO3 (1308 mg, 9.46 mmol) were added. The reaction vessel was sealed and heated in Biotage Initiator at 110° C. for 1 hour. After cooling the reaction was complete. The reaction mixture was quenched with 10 mL of water and diluted with 10 mL of Et2O. Phases were separated through a separating funnel. The organic phase was washed with 3×10 mL of water, 10 mL of brine, dried over sodium sulphate, filtered and evaporated under vacuum to give the title compound as a pale orange oil. (623 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11](=[O:25])[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Mg]I.[Cl-].[NH4+]>CCOCC>[CH2:1]([N:8]([CH2:10][C:11]([CH3:26])([OH:25])[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)C(c1ccccc1)c1ccccc1)Cc1ccccc1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(Cc1ccccc1)CC(C)(O)C(c1ccccc1)c1ccccc1

Procedure:
3-(N-Benzyl-N-methylamino)-1,1-diphenyl-propan-2-one (10g) in dry ether (250 ml.) was added to a solution of methyl magnesium iodide (from 2.4g. magnesium and 14 2g methyl iodide) in dry ether (250 ml.) and the mixture heated at reflux for 2 hours. Saturated ammonium chloride solution was added; isolation through ether in the usual manner gave 3-(N-benzyl,N-methylamino)-2-methyl-1,1-diphenyl-propan-2-ol, purified by chromatography on alumina using progressively graded mixtures of light petroleum and ether as eluant and isolated as the hydrochloride (6 8g , 65%), m.p. 121° - 124° (from ethanol-ether).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[C:26]([C:27](O)=[O:28])[C:20]=4[N:19]=3)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:64][S:65]([C:68]1[CH:75]=[CH:74][C:71]([CH2:72][NH2:73])=[CH:70][CH:69]=1)(=[O:67])=[O:66]>CN(C=O)C>[CH3:64][S:65]([C:68]1[CH:75]=[CH:74][C:71]([CH2:72][NH:73][C:27]([C:26]2[C:20]3[N:19]=[C:18]([NH:17][C:15]([C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:8]#[C:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:14]=4)=[O:16])[NH:22][C:21]=3[CH:23]=[CH:24][CH:25]=2)=[O:28])=[CH:70][CH:69]=1)(=[O:66])=[O:67]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C(Nc1nc2c(C(=O)O)cccc2[nH]1)c1cccc(C#Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cccc3[nH]c(NC(=O)c4cccc(C#Cc5ccccc5)n4)nc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.6 %

Procedure:
To a solution of 30 mg (0.07 mmol) of above 2-[(6-Phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid in DMF (1 mL) was added 40 mg (0.1 mmol) of HBTU and DIEA (0.1 mL), the resulting mixture was stirred at room temperature for 10 min, then 40 mg (0.1 mmol) of 4-methanesulfonyl-benzylamine HCl salt was added. After usual work up as described in general procedure A, 21 mg (48%) of 2-[(6-phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid 4-methanesulfonyl-benzylamide was obtained after column chromatography purification eluting with DCM/EtOAc (v/v from 5:1 to 1:1). LCMS: 550 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.N>O1CCCC1.CN(C)C(=O)C>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(F)cc(F)c1C(=O)O
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: NC(=O)c1c(N)cc(F)cc1F
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of 2-amino-4,6-difluoro benzoic acid (4.0 g, 23.12 mmol, Butt Park Ltd.) in tetrahydrofuran (1.0 L) and N,N-dimethylacetamide (150 mL) was added EDCl.HCl (13.44 g, 70 mmol, Aldrich), HOBT (9.5 g, 70 mmol, Aldrich) and ammonia as a 0.5M solution in dioxanes (460 mL, 230 mmol, Aldrich). The resultant slurry was stirred for 24 hours, and then solids removed by filtration through celite. The filtrate was taken to a residue under reduced pressure and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by chromatography on SiO2 (Ethyl acetate/Hexanes) to afford analytically pure 2-amino-4,6-difluorobenzamide as a white crystalline solid (3.11 g, 78% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 6.21-6.27 (m, 1 H), 6.27-6.32 (m, 1 H), 6.52 (s, 2 H), 7.48 (s, 1 H), 7.53 (s, 1 H).
Reaction SMILES: Cl.[N:2]12C[CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[OH:12])C1)[CH2:9]2.[O:13]1C2(CCC(=O)CC2)O[CH2:15][CH2:14]1.CC1C=CC(S(C[N+]#[C-])(=O)=O)=CC=1>>[O:12]1[C:5]2([CH2:4][CH2:10][CH:8]([C:9]#[N:2])[CH2:7][CH2:6]2)[O:13][CH2:14][CH2:15]1
Reactant: OC1C2CC3CC1CN(C3)C2
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Product: N#CC1CCC2(CC1)OCCO2

Procedure:
U.S. Pat. No. 8,314,119, issued 20 Nov. 2012, shows synthesis of (4s)-1-azaadamantan-4-ol HCl salt from a 7-step process of: (1) Reducing 1,4-dioxaspiro[4.5]decan-8-one with TOSMIC to form 1,4-dioxaspiro[4.5]decane-8-carbonitrile; (2) Reducing resulting product with LAH to form 1,4-dioxaspiro[4.5]decan-8-ylmethanamine; (3) Cyclizing resulting product with a double-Mannich type condensation using paraformaldehyde and sulfuric acid to form azaadamantan-4-one; (4) Reducing the ketone group of azaadamantan-4-one to an alcohol using NaBH4 in presence of borane-THF complex to form a diastereomer mixture of 1-azaadamantan-4-ol N-borane complex; (5) Coupling resulting product with 4-chlorobenzoic acid; (6) Separating (4s) isomer by column chromatography (silica gel, using 3:1 hexanes-EtOAc), followed by removing 4-chlorobenzoic acid moiety with NaOH; and (7) Removing BH3 group with HCl giving (4s)-1-azaadamantan-4-ol HCl salt. Alternatively, the (4s)-isomer from Step (6) can be coupled with 2-chloro-5-phenyl-1,3,4-thiadiazole, giving (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.3.1.13,7]-decane N-borane complex. Removal of borane group affords the free base, which was crystalized as a dihydrogen citrate salt. Resulting ether-linked azaadamantane derivative is useful for treating diminished CNS function associated with traumatic brain injury or treating conditions such as arthritis or osteoarthritic pain.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[Cl:9]N1C(=O)CCC1=O>C1COCC1.O>[Br:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCc1ccsc1Br
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(Cl)sc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-bromo-3-hydroxymethylthiophene from Example 1, Step 1 (13.0 g, 67.3 mmol) in THF (100 mL) and water (10 mL) was added N-chlorosuccinimide (9.88 g, 74.0 mmol) and the mixture was stirred at r.t. for 5 h and concentrated in vacuo. The residue was worked up as above to afford the desired product. The crude product was used directly.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>[Ir].ClCCl>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCCC1=Cc1ccccc1
Agent: [Ir]
Solvent: CO
Solvent: ClCCl
Product: O=C1NCCCC1Cc1ccccc1
Yield: 97.5 %

Procedure:
This example describes the preparation of I where n=2 and R1=phenyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (10 mg, 0.012 mmol) and 3-(benzylidene)-2-piperidone (250 mg, 1.3 mmol). Methanol (3 mL) and dichloromethane (3 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 MPa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-benzyl-2-piperidone (240 mg, 96%) as a white crystalline solid. Chiral HPLC analysis (Chiralpak AS, 60% heptane, 39.2% isopropanol, 0.4% trifluoroacetic acid, 0.4% n-hexylamine, 40° C.) indicated that conversion was 100% and the enantiomeric excess was 83%. 13C NMR: δ 20.10, 24.33, 36.42, 41.31, 41.74, 125.11, 127.32, 128.21, 138.84, 173.69;
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1ccccn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 85.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-(chloromethyl)pyridine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.74 g) was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:9]([O:10][CH2:11][CH2:12][CH3:13])=[CH:8][S:7][CH:6]=1)CC.C(O)C(O)CC[OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:10]1[CH:11]([CH2:12][CH2:13][OH:18])[CH2:1][O:4][C:5]2=[CH:6][S:7][CH:8]=[C:9]12
Reactant: OCCC(O)CO
Reactant: CCCOc1cscc1OCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCC1COc2cscc2O1

Procedure:
9.06 g (45.2 mmol) of 3,4-di-n-propoxythiophene, 24.0 g (226 mmol) of 1,2,4-butanetriol and 0.09 g (0.5 mmol) of p-toluenesulphonic acid were heated to 150 to 160° C. (bath temperature) under N2 for 2 h. During this time, 5.89 g of distillate (substantially n-propanol) were collected. The cooled liquid was diluted with 50 ml of methylene chloride, washed to neutrality with water and the organic phase was dried over Na2SO4. After filtering and evaporating the methylene chloride at 1 mbar, distillation was then effected. According to 1H NMR spectroscopy, the fraction collected between 45 and 128° C. (1.63 g=19.4% of overall theoretical yield of transetherification products) consisted of approx. 81.5% of 2-(2,3-dihydrothieno[3,4-b][1,4]dioxin-2-yl)ethanol, 6.5% of 3,4-dihydro-2H-thieno[3,4-b][1,4]dioxepin-2-ylmethanol and 12% of 2,3,4,5-tetrahydrothieno[3,4-b][1,4]dioxocin-3-ol.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C[CH2:28][CH2:27][CH2:26]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(I)C=C>C(OCC)(=O)C.CCCCCC>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH:15]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:28][CH:27]=[CH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
Combine (S)-4-benzyl-3-(3,4-dichlorophenyl)acetyl-2-oxazolidinone (13.9 g, 38.2 mmol) and tetrahydrofuran (140 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of sodium bis(trimethylsilyl)amide (42 mL, 1.0 M in tetrahydrofuran, 42 mmol). After 30 minutes, add allyl iodide (19 g, 114.5 mmol) and then replace the bath with a dry-ice/carbon tetrachloride bath. After 1 hour, partition the reaction the reaction mixture between a saturated aqueous ammonium chloride solution and diethyl ether. Separate the layer, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give (S)-4-benzyl-3-(2-(3,4-dichlorophenyl)pent-4-enoyl)-2-oxazolidinone: Rf=0.50 (silica gel, 20% ethyl acetate/hexane).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.[ClH:61].[N:62]1([CH2:67][C:68](O)=[O:69])[CH:66]=[CH:65][N:64]=[CH:63]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:61].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([O:21][C:68](=[O:69])[CH2:67][N:62]2[CH:66]=[CH:65][N:64]=[CH:63]2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:32][C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C(O)Cn1ccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)Cn2ccnc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
A suspension comprising 422 mg (0.80 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12), 311 mg (1.51 mmol) of dicyclohexylcarbodiimide, 142 μl (1.76 mmol) of pyridine, 20 mg (0.16 mmol) of 4-(N,N-dimethylamino)pyridine and 156 mg (0.96 mmol) of 2-(1-imidazolyl)acetic acid hydrochloride in 10 ml of methylene chloride was stirred for 3 days. At the end of this time, insoluble materials were filtered off, and the filtrate was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 75 g of silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give 507 mg (a quantitative yield) of the title compound as a colorless foam-like material.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[Cu](C#N)[C:21]#[N:22].Cl>CN1C(=O)CCC1>[CH2:12]([N:7]1[C:6]2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=[C:2]([C:21]#[N:22])[C:11]=2[O:10][CH2:9][CH2:8]1)[CH2:13][CH2:14][CH3:15]
Reactant: N#C[Cu]C#N
Reactant: CCCCN1CCOc2c(Br)cc(C(=O)OC)cc21
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCCCN1CCOc2c(C#N)cc(C(=O)OC)cc21
Temperature: 175 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a flask containing methyl 8-bromo-4-butyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (0.33 g) was added NMP (7 mL), followed by copper cyanide (0.18 g). The mixture was then heated to 175° C. and stirred overnight. The resulting mixture was cooled to room temperature and poured into 1 N hydrochloric acid. The acidic aqueous layer was extracted with ethyl acetate, washed with 1 N hydrochloric acid (15 mL), saturated sodium bicarbonate (15 mL), and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 ethyl acetate/hexanes) provided 184 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.55, 7.43, 4.41, 3.89, 3.39, 3.31, 1.58, 1.40, 0.97.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: Cc1ccc(-c2cc(Cl)c3cc(C)ccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Solvent: O
Solvent: Oc1ccccc1
Product: Cc1ccc(-c2cc(N3CCC(C(N)=O)CC3)c3cc(C)ccc3n2)cc1
Yield: 74 %

Procedure:
A mixture of 3.2 g of 4-chloro-6-methyl-2-(4-methylphenyl)quinoline, 3.06 g (24 mmol) of isonipecotamide, and 6 g of phenol was stirred and heated in an oil bath at 160° for 4 hr. It was then cooled and diluted with water. Crystallization was induced by the addition of ethanol and scratching. The solid was collected and washed with ether to give 3.18 g of crude product. Recrystallization from n-butanol gave off-white prisms, mp 242°-244° dec.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@H:29]([OH:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[OH:39][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[N:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Product: O=C1N=C(N2CCCCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and 4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; mp>85° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H), 2.55-2.95 (m, 6 H), 3.60 (br s, 2 H), 3.70-3.95 (m, 6 H), 6.66 (d, J=9.0 Hz, 2 H), 6.75 (d, J=9.0 Hz, 2 H), 7.02 (d, J=9.0 Hz, 1 H), 7.48 (d, J=9.0 Hz, 1 H), 7.50 (s, 1 H), 8.90 (brs, 1 H); MS (ES) m/z: 269.0 ((M+2H)2+, 100%); 537.6 (MH+, 10%); HRMS Calcd. for C29H37N4O4S (MH+): 537.2536. Found: 537.2500.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[N:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=3)[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1C(=O)N(Cc2ccc(Cl)s2)c2ccccc21
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccccc2N1Cc1ccc(Cl)s1
Temperature: 140 °C
Yield: 55.6 %

Procedure:
A mixture of 1-[(5-chloro-2-thienyl)methyl]-2H-indole-2,3-dione (25 mg, 0.09 mmol) (prepared as described below) and 3-trifluoromethylaniline (11.3 μL, 0.09 mmol) was heated neat at 140° C. for 2 h. The crude material was purified by preparative TLC using a mixture of 3:7 ethyl acetate in hexane as the eluent, giving the desired product (23 mg 0.05 mmol, 61%). 1H NMR (400 MHz): δ (major isomer) 7.57 (t, J=7.7, 1H), 7.53 (t, J=7.8, 1H), 7.33 (t, J=7.8, 1H), 7.28 (s, 1H), 7.19 (d, J=7.6, 2H), 6.94-6.72 (m, 4H), 6.56 (d, J=7.7, 1H), 5.02 (s, 2H); ESI-MS m/z found 421 (MH+).