Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[B:28](OC)([O:31]C)[O:29]C.[NH4+].[Cl-]>C1COCC1.O>[CH3:19][C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:4]2[CH:3]=[C:2]([B:28]([OH:31])[OH:29])[CH:7]=[CH:6][CH:5]=2)[CH2:10][C@@H:11]1[CH3:22])=[O:16])([CH3:21])[CH3:20]
Reactant: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 103.8 %

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-[(3-bromophenyl)methyl]-2-methyl-1-piperazine carboxylate (1.8 g, 4.9 mmol) in THF (4.9 mL) was mixed with nBuLi (3.7 mL, 1.6 M in Hexane, 5.9 mmol) at −78° C. and stirred for 30 min before B(OMe)3 (2.2 mL, 19.6 mmol) was added. After addition, the resulting solution was warmed up to room temperature within 2 hours. The mixture was then mixed with saturated aqueous NH4Cl solution (10 mL), stirred for 25 minutes at room temperature, diluted with H2O (5 mL) and extracted with Et2O (2×30 mL). The organic layers were collected, dried over Na2SO4, filtered and concentrated to afford the crude title compound (1.7 g, quantitative yield): LC/MS: m/z 335 (M+H); 1H-NMR (MeOD) δ 1.24 (d, 3H), 1.46 (s, 9H), 2.00 (m, 1H), 2.13 (m, 1H), 2.68 (d, 1H), 2.82 (d, 1H), 3.12 (m, 1H), 3.44 (m, 1H), 3.56 (m, 1H), 3.80 (d, 1H), 4.18 (m, 1H), 7.33 (m, 1H), 7.38 (m, 1H), 7.51 (d, 1H), 7.59 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C1(C=CC(O)=CC=1)O.[OH-].[K+]>>[C:10]([CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])#[N:11]
Reactant: N#CCc1cccc(F)c1F
Reactant: C=CC(=O)OCC
Agent: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)CCC(C#N)c1cccc(F)c1F
Temperature: 160 °C

Procedure:
To a mixture of (2,3-difluorophenyl)acetonitrile (40.5 g, 265 mmol), ethyl acrylate (24 mL, 220 mmol), and hydroquinone (50 mg, 0.45 mmol) was added KOH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160° C. for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=207.9 (M−OEt).
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[O:24]=[CH:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([CH2:34][OH:35])[OH:33])[OH:31])[OH:29])[OH:27]>>[O:24]=[C:25]1[O:31][C@H:30]([C@H:32]([CH2:34][OH:35])[OH:33])[C:28]([OH:29])=[C:26]1[OH:27]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 0.29 h

Procedure:
Isolation and Culture of Growth Plate Chondrocytes: Six-to eight-week old broiler chickens were obtained commercially, sacrificed by cervical displacement, and the tibiae harvested. Epiphyseal growth plate chondrocytes were obtained from the tibiae as described (Ali et al., 1970, Proc Natl Acad Sci USA 67: 1513-1520). Briefly, cartilage slices were digested in 1% trypsin solution prepared in synthetic cartilage lymph (SCL). SCL contains 2mM Ca2+ and 1.42 mM Pi, in addition to 104.5 mM Na+, 133.5 mM Cl−, 63.5 mM sucrose, 16.5 mM N-tris methyl-2-aminoethane sulfonic acid (TES), 12.7 mM K+, 5.55 mM D-glucose, 1.83 mM HCO3−, 0.57 mM Mg2+, and 0.57 mM SO4−. Cartilage slices were digested for 15 to 20 minutes at 37° C. After digestion, part of the trypsin solution was removed and 10 ml of SCL and 0.5 ml of 0.78% collagenase solution added to the tissue slices. After 30 min of collagenase/trypsin digestion at 34° C., the liquid was removed from the slices and replaced with 0.5 ml of 0.78% collagenase solution plus 15 ml DMEM, with 10% FBS. The collagenase-DMEM solution was removed from the cartilage digestate after 15 hours (overnight) of digestion. The chondrocytes were released from the residual tissues by vortexing for a total of 3 min (1 min each time) in fresh medium. Isolated cells were demineralized in iso-osmotic citrate buffer (8.0 mM citric acid in 80.5 mM sodium citrate, pH 6.0) for 15 min at 34° C. After demineralization, cells were washed with fresh medium, resuspended in 10 ml of DMEM with 10% FBS, and counted using a hemocytometer. Cell viability was determined by trypan blue exclusion. Cells were plated at 3-4×105 cells per 35 mm dish in 2 ml of medium. The cells were initially cultured in DMEM with 10% FBS and 1% penicillin/streptomycin solution. The culture medium was changed twice a week for the duration of the experiments. On day 7, the cell cultures were changed into a 1:1 (v/v) mixture of DMEM with 10% FBS and serum-free HL-1 medium. Ascorbic acid was provided at 50 μg/ml medium after day 3. For treatment of endothelial cell cultures, the concentrated fusarochromanone solution was diluted in methanol to final concentrations of 0.6, 3, 15 mM. On day 7, 2 μl samples of the FC solutions or pure methanol for the control were added to the cultures in 2 ml of media. FIGS. 5A to 5D show there is no appreciable change in the morphology of chondrocytes treated with FC101 for seven days. Note that there is little difference between the control cells (5A) and those treated with FC101 (B:0.6 μM; C:3 μM; D:15 μM FC101).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:26])[CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O>ClCCl>[C:33]([O:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10](=[O:26])[CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:15])=[O:16])[CH2:8][CH2:9]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])N1CCN(CCO)CC1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCN1CCN(C(=O)CCNS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-hydroxyethyl)-1-[3-(2-nitrobenzenesufonylamino)propionyl]piperazine (1.15 g) and pyridine (1.47 mL) in dichloromethane (10 mL) was added acetic anhydride (1.72 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2-dichloromethane/methanol=10/1) to give the title compound (0.38 g).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=O.N12CCCC1=NCCC2>CO>[S:8]1[C:4]2[S:5][CH:6]=[CH:7][C:3]=2[CH:1]=[C:9]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CSc1sccc1C=O
Agent: C1CN=C2CCCN2C1
Solvent: CO
Product: COC(=O)c1cc2ccsc2s1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of methyl (3-formylthiophene-2-ylthio)acetate (19.31 g, 91 g, 91 mmol) in methanol (150 mL) was added 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (1 mL, 1 g, 8.05 mmol) and the stirred reaction flask was immediately immersed in an ice-water bath. Stirring was continued for 30 minutes and the mixture was filtered to give a tacky solid product which was washed with a little cold (-20° C.) methanol. The solvent was evaporated in vacuo from the mother liquor and the residue was partitioned between ether and aqueous sodium bicarbonate. The water layer was washed with ether twice, and the combined ether extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo to give an oil which solidified when triturated with a little cold (-20° C.) methanol. This was combined with the original solid product to give a total of 14.55 g of methyl thieno[2,3-b]thiophene-2-carboxylate, m.p. 101°-105° C. Recrystallization from methanol gave product with m.p. 106°-107° C. Anal. Calc'd for C8H6O2S2 : C, 48.47; H, 3.05. Found: C, 48.80; H, 3.32.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:13]>C(#N)C>[Br-:10].[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH2:11][N+:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CC(C)c1ccncc1
Solvent: CC#N
Product: CC(C)c1cc[n+](CC(=O)c2ccc(Cl)cc2)cc1
Product: [Br-]
Temperature: 23 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of 4-isopropylpyridine (3.12 g, 25.7 mmol) in acetonitrile (25 mL) is added 2-bromo-4′-chloro-acetophenone (6.01 g, 25.7 mmol). The mixture is stirred at 23° C. overnight then the resulting precipitate is filtered, collected, and dried to afford the title intermediate (7.10 g, 78%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:28]=1[OH:36].O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:28]=2[OH:36])=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: Nc1cccc([N+](=O)[O-])c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc([N+](=O)[O-])c2O)cc1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
Ref.: WO 96/11917. To a solution of 4-tert-butyl benzoic acid (0.81 g, 4.57 mmol) in CH2Cl2 (10 mL) cooled in an ice bath was added 1,1′-carbonyldiimidazole (0.94 g, 5.80 mmol). The solution was stirred for 5 min., then the bath was removed and the reaction was stirred at room temperature for 1.5 h. To a solution of 2-amino-6-nitro phenol (0.829 g, 5.38 mmol) in CH2Cl2 (40 mL) cooled in an ice bath was added the activated acid solution dropwise. The reaction was allowed to stir and gradually come to room temperature overnight. To the solution was added CH2Cl2 (50 mL) and H2O (25 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layers were washed with H2O (25 mL), 1 N HCl (25 mL), and brine (25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was adsorbed onto silica gel and purified by silica gel chromatography, eluting with 66% CH2Cl2/hexane to 75% CH2Cl2/hexane to afford the title compound (0.579 g) as a golden solid. MS (ESI-POS): [M+H]+=315; Anal. Calc'd for C17H18N2O4: C, 64.96; H, 5.77; N, 8.91. Found: C, 64.98; H, 5.78; N, 8.89.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]=1[NH2:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:22][C:16]1[C:17]([NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:19]=[CH:20][N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 48 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (9.59 g, 48.1 mmol) and pyridine-2,3-diamine (5.0 g, 45.8 mmol) were combined and dissolved in 1,2-dichloroethane (75 ml). Sodium triacetoxyborohydride (14.5 g, 68.4 mmol) was added to the mixture. Reaction stirred at room temperature for 7 hours. Additional sodium triacetoxyborohydride (3.60 g, 16.99 mmol) was added to the mixture. Reaction stirred at room temperature for 18 hours. Reaction was quenched with 1N sodium hydroxide. Material was extracted twice with dichloromethane and the aqueous phase was discarded. Material was washed successively with 1N sodium hydroxide, water, and brine and the aqueous phases were discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting methanol-dichloromethane afforded the title compound as tan foam in 48% yield. MS (M−H)−=291.2.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[OH:29])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]([C:25]([F:27])([F:28])[F:26])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[O:29][C:31]3[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1c(-c2ccc(OCc3ccccc3)cc2)c(C(F)(F)F)cc2ccccc12
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2c(-c3ccc(OCc4ccccc4)cc3)c(C(F)(F)F)cc3ccccc23)cc1
Yield: 71 %

Procedure:
2-{4-[(Phenylmethyl)oxy]phenyl}-3-(trifluoromethyl)-1-naphthalenol (186) (0.25 g, 0.64 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMSO at 100° C. for 5 h using microwave synthesizer to give 0.23 g (71%) of the title compound (187) as a light brown viscous oil. 1H NMR (400 MHz, CDCl3): δ 5.01 (s, 2H), 6.67 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 7.30-7.44 (m, 5H), 7.57-7.68 (m, 4H), 7.88 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 8.25 (s, 1H), 9.82 (s, 1H). LCMS (ESI): m/z 521 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]4[B:18]([OH:25])[O:19][C:20]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16]=4[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(=O)CCCC1>CCC(=O)CC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:28]([F:29])([F:31])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]4[B:18]([OH:25])[O:19][C:20]5([CH2:23][CH2:24][CH2:22][CH2:21]5)[C:16]=4[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCC1(CC)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Solvent: O=C1CCCC1
Solvent: CCC(=O)CC
Product: OB1OC2(CCCC2)c2cc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc21

Procedure:
The title compound was prepared by using the same method as described for 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethyl-benzo[c][1,2]oxaborol-1(3H)-ol with cyclopentanone to replace 3-pentanone. It was obtained as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1 H), 7.80 (t, J=1.8 Hz, 1 H), 7.72 (s, 3 H), 7.61 (d, J=1.5 Hz, 2 H), 4.44 (d, J=18.3 Hz, 1 H), 4.31 (d, J=18.3 Hz, 1 H), 2.11-1.71 (m, 8 H) ppm.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][NH2:15])=[O:13])[CH:6]=[CH:7][CH:8]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[N:15][NH:14][C:12]([C:11]1[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=2)=[N:19][CH:18]=[CH:17][CH:16]=1)=[O:13]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-(3-trifluoromethyl-phenylamino)-nicotinic acid-hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 12.30 (s, 1H), 10.58 (s, 1H), 8.53 (s, 1H), 8.45 (d, J=4.5 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=8.1 Hz, 1H), 8.12 (s, 1H), 8.06 (d, J=8.1 Hz), 7.84 (m, 3H), 7.54 (t, J=8.1 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.03 (q, J=4.5 Hz, 1H).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:14]([C:11]2[CH:12]=[N:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][CH:10]=2)=[O:16])=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1cnc(Oc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cnc(Oc3ccccc3)nc2)c(O)n1
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A solution of 2-phenoxypyrimidine-5-carboxylic acid (300 mg, 1.4 mmol) in dichloromethane (15.0 mL) was added N-hydroxybenzotriazole (270 mg, 2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (384 mg, 2 mmol), triethylamine (202 mg, 2 mmol). Then the mixture was stirred for 30 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (270 mg, 2 mmol) was added and the mixture was stirred at room temperature 24 hours. The mixture was washed with water (50 mL), and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulphate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, methanol/dichloromethane=1:20, 1% NH3) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-phenoxypyrimidine-5-carboxamide (200 mg, 46%) as white solid. LRMS (M+H+) m/z: calcd 350.14. found 350. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, CD3OD): δ 8.93 (s, 2H), 7.46-7.16 (m, 5H), 6.10 (s, 1H), 4.48 (s, 2H), 2.35 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[CH3:21][O:20][CH2:19][CH2:18][CH2:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)(=[O:30])=[O:29])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(OCCCOC)cc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OCCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a mixture of ethyl 7-amino-5-(3-methoxypropoxy)-1H-indole-2-carboxylate (3.00 g) and pyridine (50 mL) was added pyridine-2-sulfonyl chloride (2.0.g) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, 1N hydrochloric acid and ethyl acetate were added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:1-1:1, volume ratio) to give the title compound (4.02 g, yield 90%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 126-127° C.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[Br:15]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[Br:15][CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1
Reactant: OCC1COC(c2ccccc2)OC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: BrCC1COC(c2ccccc2)OC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a vigorously stirred solution of 19.4 g (0.1M) of 5-hydroxymethyl-2-phenyl-1,3-dioxane m1 and 33.1 g (0.1M) of tetrabromomethane in 60 ml of anhydrous benzene at 70° C., is added 26.2 g (0.1M) of triphenylphosphine in 45 minutes. After stirring at 70° C. for an another 30 minutes, the solvent is evaporated. To the residue is added 200 ml of ether and ether insoluble triphenylphosphine oxide is removed by filtration. After repeating this procedure twice, the solvent of the filtrated is evaporated. Distillation of the residual product gives 19.391 g (75.4% yield) of the titled compound m2.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:12]1[C:16]([CH:17]=O)=[CH:15][N:14]=[CH:13]1.[CH2:20]([SH:23])[CH2:21][SH:22].Cl[Si](C)(C)C>ClCCl>[S:22]1[CH2:21][CH2:20][S:23][CH:17]1[C:16]1[N:12]([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2([CH3:19])[CH3:1])[CH:13]=[N:14][CH:15]=1
Reactant: CC1(C)CCc2ccccc2C1n1cncc1C=O
Reactant: SCCS
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC1(C)CCc2ccccc2C1n1cncc1C1SCCS1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a stirred mixture of 5.1 parts of 1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazole-5-carboxaldehyde, 2.7 parts of 1,2-ethanethiol and 130 parts of dichloromethane were added dropwise 9.6 parts of chlorotrimethylsilane. Upon complete addition, stirring was continued overnight at 40° C. After cooling, the reaction mixture was washed with a potassium carbonate solution 10% in water and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.69 parts (55.8%) of 5-(1,3-dithiolan-2-yl)-1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazole; mp. 109.3° C. (compound 2.52).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[C:12](=O)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:4]=2[NH:3]1.C([SiH](CC)CC)C.CO.C(Cl)Cl>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:4]=2[NH:3]1
Reactant: O=C1c2ccccc2-c2[nH]c(=O)c3ccccc3c21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c2c(c3ccccc13)Cc1ccccc1-2
Reaction time: 96 h
Yield: 88.7 %

Procedure:
To a stirred suspension of 2 (40 g, 0.16 mol) in trifluoroacetic acid (2.5 L) was added triethylsilane (94 g, 0.8 mol) in small portions at room temperature and the reaction mixture was stirred for 96 h, during which time the reaction progress was monitored using TLC (eluent −5% MeOH/CH2Cl2). The reaction mixture was slowly poured on ice, filtered, washed with copious amounts of H2O and MeOH and dried in vacuo to provide the above-titled compound 6 (33.1 g, 88%), whose spectral data were identical to those of a sample of compound 6 that was obtained using Method I.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH3:35])[C:30]([S:36](Cl)(=[O:38])=[O:37])=[CH:29]2>ClCCCl.CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:36]([C:30]3[N:31]([CH3:35])[C:32]4[C:28]([CH:29]=3)=[CH:27][C:26]([F:25])=[CH:34][CH:33]=4)(=[O:38])=[O:37])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(S(C)(=O)=O)c2)CC1
Reactant: Cn1c(S(=O)(=O)Cl)cc2cc(F)ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)cc2cc(F)ccc21
Temperature: 80 °C
Reaction time: 72 h
Yield: 24.8 %

Procedure:
To a solution of 4-(4-amino-3-methanesulfonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (cf. Example 24e, 0.048 g) in 1,2-dichloroethane (3.0 ml) was added 5-fluoro-1-methyl-1H-indole-2-sulfonyl chloride (0.035 g) and DMAP (0.025 g). The reaction mixture was stirred at 80° C. for 72 h, diluted with dichloromethane (2 ml) and chromatographed on silica gel using dichloromethane/ethyl acetate as eluent to obtain the title compound (0.019 g) as an off-white foam. MS (ISN): 564.3 (M−H)−