Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[NH2:13]/[C:14](/[CH3:18])=[CH:15]\[C:16]#[N:17]>C(O)(=O)C>[CH3:18][C:14]1[NH:13][C:9]([CH3:8])=[C:10]([C:2]#[N:3])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:15]=1[C:16]#[N:17]
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: C/C(N)=C/C#N
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.3 %

Procedure:
A mixture of 17.0 g (106.13 mmol) 3-methyl-1H-indazole-5-carbaldehyde, from Synthetic Preparation 10, and 17.86 g (217.57 mmol) 3-aminocrotononitrile were dissolved in 340 mL acetic acid and refluxed for 3 hours. After stirring overnight at room temperature the mixture was cooled with an ice bath, filtered and washed with a small amount of acetic acid. The product was dried under vacuum at 60° C. to afford 1,4-dihydro-2,6-dimethyl-4-(3-methyl-1H-indazol-5-yl)-3,5-pyridinedicarbonitrile (17.7 g, 57.6%) (Cpd. No. 81, Table 2). 1H-NMR (DMSO-D6): δ=12.68 (s, 1H), 9.51 (s, 1H), 7.53 (s, 1H), 7.49 (d, 1H), 7.27 (d, 1H), 4.50 (s, 1H), 2.49 (s, 3H), 2.05 (s, 6H) ppm. MS (ES+): 290.42 (M++1, 100%).
Reaction SMILES: [NH2-:1].[Li+].Cl[SiH:4]1[N:8]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[CH:6][N:5]1[C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].CCCCCC>COCCOC>[NH2:1][SiH:4]1[N:8]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[CH:6][N:5]1[C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: [NH2-]
Reactant: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
In an argon atmosphere, 439 mg (purity: 95%, 18.2 mmol) of lithium amide was suspended in 20 mL of 1,2-dimethoxyethane and after adding 6.07 g (17.6 mmol) of Si(tOctNCHCHNtOct)(H)Cl, the mixture was stirred at room temperature for 4 hours. To the reaction mixture, 20 mL of hexane was added, and the mixture was stirred at room temperature for 10 minutes. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 116° C./1.3×102 Pa) to obtain 2-amino-1,3-bis(1,1,3,3-tetramethylbutyl)-1,3-diaza-2-silacyclopent-4-ene (Si(tOctNCHCHNtOct)(H)NH2) as a pale yellow liquid (yielded amount: 4.99 g, yield: 87%).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3(O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[NH:10][N:9]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[O:20]1[CH2:19][CH:18]=[C:17]([C:13]2[CH:12]=[C:11]3[C:16]([C:8]([C:6]([OH:7])=[O:5])=[N:9][NH:10]3)=[CH:15][CH:14]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2cc(C3(O)CCOCC3)ccc12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1n[nH]c2cc(C3=CCOCC3)ccc12
Temperature: 25 °C
Yield: 76 %

Procedure:
6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic acid (3 mL) and the mixture was maintained at room temperature for 16 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to provide 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid (76%). The acid was coupled with the bicyclobase according to procedure A.
Reaction SMILES: O[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(Cl)Cl>[Br:13][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCC/C=C\CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCC/C=C\CBr
Reaction time: 0.67 h
Yield: 95.7 %

Procedure:
To a solution of alcohol 39 (1.48 g, 9.36 mmol) and carbon tetrabromide (3.40 g, 10.25 mmol) in dry CH2Cl2 (50 mL) was added triphenylphosphine (2.70 g, 10.30 mmol) in portions. The reaction mixture was stirred for 40 min and MeOH (1 mL) was added. Concentration on a rotary evaporator, followed by flash chromatography using 50:1 hexane/EtOAc as eluent, gave 40 as a colorless oil (1.98 g, 96%): IR (neat) 3020 (w), 2945, 2860 (w), 1740 (s), 1435, 1370, 1200, 1165 cm-1 ; 1H NMR (CDCl3) δ 5.77 (m, J1 =10.5 Hz, J2 =8.3 Hz, J3 =1.4 Hz, 1H), 5.56 (m, J1 =10.6 Hz, J2 =7.5 Hz, 1H), 3.98 (d, J=8.1 Hz, 2H), 3.67 (s, 3H), 2.34 (t, J=7.4 Hz, 2H), 2.19 (dq, J1 =7.5 Hz, J2 =1.4 Hz, 2H), 1.74 (p. J=7.3 Hz, 2H); 13C NMR (CDCl3) δ 173.55, 134.48, 126.26, 51.37, 33.06, 26.60, 26.01, 24.28. A minor amount (ca. 5%) of methyl trans-7-bromo-5-heptenoate could be seen in the 1H NMR spectrum at δ 3.93.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[C:17]2[O:16][C:15]([CH2:18][CH2:19][C:20]#[CH:21])=[N:14][C:13]=2[CH:12]=[C:11]([F:22])[CH:10]=1>>[Br:8][C:9]1[C:17]2[O:16][C:15]([CH2:18][CH2:19][C:20]#[C:21][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:14][C:13]=2[CH:12]=[C:11]([F:22])[CH:10]=1
Reactant: C#CCCc1nc2cc(F)cc(Br)c2o1
Reactant: Brc1ccccn1
Product: Fc1cc(Br)c2oc(CCC#Cc3ccccn3)nc2c1
Yield: 45.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (131 mg, 0.83 mmol) and 7-bromo-2-(but-3-ynyl)-5-fluoro-benzo[d]oxazole (223 mg, 0.83 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 130 mg (0.38 mmol, 45%) of 7-bromo-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[N:10]([C:12]1[CH:17]=[C:16]([CH2:18][C@H:19]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:20](=[O:32])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=[CH:14][C:13]=1[OH:43])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:51]([O:53][C:54](=[O:58])[CH:55](Br)[F:56])[CH3:52]>CN(C=O)C>[CH2:51]([O:53][C:54](=[O:58])[CH:55]([O:43][C:13]1[CH:14]=[CH:15][C:16]([CH2:18][C@H:19]([NH:33][S:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[C:20](=[O:32])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:17][C:12]=1[N:10]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:44])[CH3:11])[F:56])[CH3:52]
Reactant: CN(C(=O)OCc1ccccc1)c1cc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)ccc1O
Reactant: CCOC(=O)C(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)Oc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{5-[(2S)-2-Benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-hydroxy-phenyl}-methyl-carbamic acid benzyl ester of Step B (100 mg, 0.16 mmol) is dissolved in DMF (2 mL). Potassium carbonate (23 mg, 0.16 mmol) and bromo-fluoro-acetic acid ethyl ester (20 μl, 0.16 mmol) are added. The mixture is stirred at RT overnight. 40 μl (0.32 mmol) more of bromo-fluoro-acetic acid ethyl ester is added and stirred overnight. The mixture is purified through a silica plug to provide [4-[(2S)-2-benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-(benzyloxycarbonyl-methyl-amino)-phenoxy]-fluoro-acetic acid ethyl ester which is used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:55][CH2:56][C:57]1[CH:62]=[CH:61][C:60]([S:63]([NH2:66])(=[O:65])=[O:64])=[CH:59][CH:58]=1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:55][CH2:56][C:57]1[CH:58]=[CH:59][C:60]([S:63](=[O:65])(=[O:64])[NH2:66])=[CH:61][CH:62]=1)=[O:11])#[N:2]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: N#Cc1cccc(Oc2ncccc2C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ncccc2C(=O)NCc2ccc(S(N)(=O)=O)cc2)c1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
To a solution of 2-(3-Cyano-phenoxy)-nicotinic acid (0.140 g 0.600 mmole), BOP (0.260 grams, 0.600 mmole) and DIEA (0.310 μl, 1.8 mmole) in dimethylformamide (5 ml) was added 4-Aminomethyl-benzenesulfonamide (0.135 grams, 0.600 mmole) and stirred at room temperature over night. The reaction was quenched with water and extracted with ethyl acetate. The combined organics were washed with alternating portions of 5% citric acid and sat'd bicarb, dried over Na2SO4, filtered and concentrated to a product which was recrystalized from ethyl acetate to give a white solid (0.100 g). M.P. 179-180° C.; Anal. calcd. for C20H16N4O4S; C, 58.81; H, 3.95; N, 13.72. Found: C, 57.47; H, 4.15; N. 13.45.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([NH:26][C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CCCCNC(=O)C(C)c1ccc(O)c(O)c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 5 g of ethyl 3,4-diacetoxyphenylpropionate and 3.5 g of n-butylamine was heated to 150° C. with stirring for 2 hours in an autoclave. After cooling, the reaction mixture was concentrated and the residue was purified by silica gel chromatography. A solvent mixture of chloroform:methanol=20:1 was used as eluent. Pure N-n-butyl-3,4-dihydroxyphenylpropionamide was obtained as colorless viscous oil. The yield was 5.45 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[C:14](=[O:19])[N:13]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[CH:12]=[CH:11]2)([CH3:4])([CH3:3])[CH3:2].[C:30](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[N:7]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[C:14](=[O:19])[N:13]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[CH:12]=[CH:11]2)[CH3:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.4 %

Procedure:
To a solution of [7-Fluoro-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-carbamic acid tert-butyl ester (0.36 g, 0.9 mmol) in dry DMF (9 mL) was added cesium carbonate (1.04 g, 3.19 mmol) followed by neat methyl iodide (0.064 mL, 1.03 mmol). The mixture was stirred at room temperature for 3.5 hr, extracted into ethyl acetate (150 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, filtered, concentrated in vacuo and dried to give 0.34 g (93%) of pure [7-Fluoro-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester. RP-HPLC: 5.89 min; ES-MS (M+H)+=414.0; 1H-NMR (DMSO-d6) δ (ppm): 1.33 (s, 9), 3.20 (s, 3), 6.75 (d, 1), 7.52 (d, 1), 7.80 (d, 2), 7.83 (d, 1), 7.93 (d, 1), 8.35 (d, 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([I:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]([C:13]([O:15]CC)=O)[C:7]2=[O:18].CCCCCC.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:13]([C:8]2[C:7](=[O:18])[C:6]3[C:11](=[C:2]([F:1])[CH:3]=[C:4]([I:19])[CH:5]=3)[N:10]([CH3:12])[CH:9]=2)=[O:15])=[CH:29][CH:28]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C)c2c(F)cc(I)cc2c1=O
Solvent: CCCCCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)cc(F)c21
Temperature: 25 °C

Procedure:
A solution of ethyl 8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate from Preparation No. 13 (15.8 g) in p-chlorobenzylarnine (15.4 mL) is warmed to 190° C. The mixture is then cooled to room temperature, and hexane is added. The resulting precipitate is collected by filtration to give the title compound as a solid. An analytical sample is prepared by recrystallization from EtOH.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na].Cl[C:20]1[N:25]=[C:24](Cl)[C:23]([F:27])=[CH:22][N:21]=1>CCOCC>[CH2:1]([O:17][C:20]1[N:25]=[C:24]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:23]([F:27])=[CH:22][N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCCCCCCCCCCCCCCCO
Agent: [Na]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOc1ncc(F)c(OCCCCCCCCCCCCCCCC)n1
Yield: 63.1 %

Procedure:
A 36.3 g quantity of n-hexadecanol is dissolved in 200 ml of absolute ether, 3.3 g of metal sodium is added to the solution and the mixture is refluxed until the sodium has been completely dissolved. Subsequently 8.5 g of 2,4-dichloro-5-fluoropyrimidine is added to the solution, and the mixture is refluxed for 3 hours. The resulting reaction mixture is washed with a small amount of water, and the ethereal layer is concentrated to separate out crystals, which are recrystallized from ethanol to give 18.6 g of white crystalline 2,4-di(n-hexadecyloxy)-5-fluoropyrimidine in a yield of 63.1 %, m.p. 62°-63° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[CH3:39][NH:40][C:4](=[O:3])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Yield: 62 %

Procedure:
N-Methyl-3-(3-methyl-1H-indol-5-yl)-3-phenyl-acrylamide LXXII (386 mg, 62% yield) was prepared from 3-(3-methyl-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester XVIII (see Example 4).
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:19]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:17]([CH3:38])[O:16][C@H:11]1[O:12][CH2:13][CH:14]=C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:43]CC1>CC(C)=O.O.O=[Os](=O)(=O)=O>[C:1]([O:9][C@H:10]1[C@H:19]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:17]([CH3:38])[O:16][C@H:11]1[O:12][CH2:13][CH:14]=[O:43])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1O[C@@H](OCC=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of prop-2-en-1-yl 2,3,4-tri-O-benzoyl-α-L-fucopyranoside (6.06 g, 11.73 mmol) in acetone (94 mL) and water (23.5 mL) was added 4-methylmorpholine 4-oxide (2.75 g, 23.46 mmol) followed by the addition of 2.5% OsO4 in water (5.97 g, 0.587 mmol). The mixture was allowed to stir at rt for 16 hr. To the resulting mixture was then added a solution of NaIO4 (5.40 g, 23.46 mmol) in water (100 mL). After stirring for additional 6 hr, the precipitate was filtered and washed with acetone (200 mL). The volume of the filtrate was reduced to approximately ⅓ of the initial volume and then extracted with EtOAc (200 mL). The organic phase was separated, washed with sat. NaHCO3 (200 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The organic phases were combined and washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (220 g), eluting with 0-100% EtOAc in hexanes to give the title compound. 1H NMR (CDCl3) δ 1.33-1.29 (3H, m), 3.27 (1H, s), 3.41 (1H, s), 4.35-4.31 (1H, m), 5.51-5.45 (1H, m), 5.75-5.69 (1H, m), 5.81 (1H, dd, J=13.91, 3.57), 6.05-5.98 (1H, m), 7.42 (2H, d, J=7.76), 7.53 (5H, d, J=8.61), 7.67-7.63 (2H, m), 7.84-7.81 (2H, m), 8.01 (2H, t, J=8.82), 8.14-8.12 (2H, m), 9.77-9.77 (1H, m).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13])=O.[Cl-].[OH:17][NH3+:18].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13])=[N:18][OH:17]
Reactant: Cc1cc(C)c(C(=O)C(F)(F)F)c(C)c1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C(=NO)C(F)(F)F)c(C)c1
Temperature: 0 °C
Yield: 28.3 %

Procedure:
6.3 g (0.029 mol) of 2,2,2-trifluoro-1-(2,4,6-trimethylphenyl)-ethanone are dissolved in 30 ml of ethanol at 80° C. To the solution are added dropwise 2.0 g (0.029 mol) of hydroxylammonium chloride and 4.1 g (0.050 mol) of sodium acetate dissolved in 15 ml of water. The reaction mixture is refluxed overnight, poured into ice water, and extracted with ethyl acetate. The organic phase is washed with brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from 20 ml of hexane, yielding 1.9 g of 2,2,2-trifluoro-1-(2,4,6-trimethylphenyl)-ethanone oxime in the form of white crystals, mp. 119-125° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12]([Br:14])[C:11]([OH:15])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12]([Br:14])[C:11]([O:15][CH2:26][O:27][CH3:28])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(Br)c(O)c(C(=O)OC)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)cc(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 5-bromo-4-hydroxyisophthalic acid dimethyl ester (12.3 g) in chloroform (130 mL) were successively added diisopropylethylamine (8.24 g) and methoxymethyl chloride (4.11 g) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was washed successively with 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1, v/v) to give the title compound (8.52 g).
Reaction SMILES: C(NCC1C=CN=C(NCC2[N:17]3[CH:18]=[C:19](C)[CH:20]=[CH:21]C3=NC=2C2C=CC(F)=CC=2)N=1)C.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([C:37]([CH2:47][NH:48][C:49]3[N:54]=[C:53]([CH:55]=O)[CH:52]=[CH:51][N:50]=3)=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[N:39]=2)[CH:36]=1.N1CCCC1>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([C:37]([CH2:47][NH:48][C:49]3[N:54]=[C:53]([CH2:55][N:17]4[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH:52]=[CH:51][N:50]=3)=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[N:39]=2)[CH:36]=1
Reactant: O=Cc1ccnc(NCc2c(-c3ccc(F)cc3)nc3ccc(Cl)cn23)n1
Reactant: CCNCc1ccnc(NCc2c(-c3ccc(F)cc3)nc3ccc(C)cn23)n1
Solvent: C1CCNC1
Product: Fc1ccc(-c2nc3ccc(Cl)cn3c2CNc2nccc(CN3CCCC3)n2)cc1
Yield: 33 %

Procedure:
The title compound was prepared in the same fashion as that described for compound 196 from 2-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidine-4-carbaldehyde and pyrrolidine. (0.040 g, 33% yield). M/e+ 437.1 for C23H22ClFN6 (M+H)+; 1H-NMR (500 MHz, CDCl3, δ) 8.54 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.77-7.75 (m, 2H), 7.57 (dd, J=9.5. 0.5 Hz, 1H), 7.20-7.15 (m, 3H), 6.81 (d, J=5.0 Hz, 1H), 5.32-5.26 (m, 1H), 5.05 (d, J=5.5 Hz, 2H), 3.64 (s, 2H), 2.64 (br s, 4H), 1.84 (br s, 4H).
Reaction SMILES: Br[C:2]1[C:12]2[C:13]3[C:5]([CH:6]=[CH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.[O:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.[Cl-].[NH4+]>C1COCC1>[CH2:7]1[C:8]2=[C:13]3[C:12](=[CH:11][CH:10]=[CH:9]2)[C:2]([C:20]2([OH:19])[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]2)=[CH:3][CH:4]=[C:5]3[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc2c3c(cccc13)C=C2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3c4c(cccc24)CC3)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromoacenaphthylene (1.00 g, 4.29 mmol) in dry THF (20 mL), under nitrogen at −78° C., was added a solution of n-butyllithium (2.5M in hexanes) (1.89 mL, 4.72 mmol) over a period of 30 min. The resulting deep red solution was left to stir for a further 30 minutes at −78° C. A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (0.94 g, 4.72 mmol) in dry THF (10 mL) was then added over 30 min. After 2.5 h a cooled solution of saturated ammonium chloride (30 mL) was added, the reaction mixture allowed to warm to room temperature and then extracted with diethyl ether. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to yield a thick, yellowish tan oil. This oil was purified by flash chromatography on silica, eluting with a methanol/dichloromethane gradient, to yield tert-butyl 4-(1,2-dihydro-5-acenaphthylenyl)-4-hydroxy-1-piperidinecarboxylate as a sticky yellow residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[F:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a stirred solution of 1-chloro-2,5-difluorobenzene (0.770 g, 5.18 mmol) in concd H2SO4 (8.0 mL) at 0° C., KNO3 (0.525 g, 5.19 mmol) was added in one lot. The resulting yellow solution was allowed to warm to room temperature and stirred overnight at room temperature. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum and the residue was dried further under vacuum to afford 0.845 g (85%) of title compound as a yellow liquid; 1H NMR (CDCl3) δ 7.43 (dd, 1 H, J1 =9.6 Hz, J2 =6.0 Hz), 7.93 (t, 1 H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=3[F:23])[C:9]=2[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:14]=3[F:23])[C:9]=2[CH:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[OH:25])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cccnc1)c1c(-c2cc(C(F)(F)F)ccc2F)noc1-c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC(c1cccnc1)c1c(-c2cc(C(F)(F)F)ccc2F)noc1-c1cccc(Cl)c1
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 56 mg (0.13 mmol) of 5-(3-chlorophenyl)-3-(2-fluoro-5-trifluoromethyl-phenyl)-4-[(3-pyridyl)carbonyl]isoxazole in 2 mL of ethanol was added 24 mg (0.63 mmol) of sodium borohydride. After 2 hrs at room temperature, the reaction mixture was diluted with ethyl acetate. The solution was washed with saturated sodium chloride and was dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation. The residue was purified by prepTLC to give 44 mg (0.098 mmol) of 5-(3-chlorophenyl)-3-(2-fluoro-5-trifluoromethylphenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 6.01 (s, 1), 7.01 (m, 1), 7.83 (m, 1), 8.27 (m, 1), and 8.35 ppm (br s, 1). MS m/z: 449.0 (M+H).