Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[C:22]=1[O:23][CH3:24])[CH:18]=[O:19]>O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:19])[CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[C:22]=1[O:23][CH3:24]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccn2)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.76 ml of 2-bromopyridine dissolved in 30 ml of absolute tetrahydrofuran are treated -60° within 30 minutes with 19.2 ml of 1.6M n-butyl lithium solution (in hexane), whereupon the mixture is stirred at -60° for 30 minutes. 6.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 50 ml of tetrahydrofuran are then added dropwise thereto at -40° within 30 minutes. The reaction mixture is warmed to 0° within 2 hours, poured into ice-water and extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and evaporated, and the residue is chromatographed on 200 g of silica gel with ethyl acetate. There is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-pyridinemethanol as a brown oil.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20](=[O:22])[CH3:21])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:23])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C(Cl)Cl>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([OH:22])[CH3:21])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:23])(=[O:6])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)COc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(O)COc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
To a suspension of 1-((6-(tert-butylsulfonyl)-4-chloroquinolin-7-yl)oxy)propan-2-one (100 mg, 0.281 mmol) in MeOH (2810 μl) was added NaBH4 (13.29 mg, 0.351 mmol) at rt. This was stirred at rt for 20 min. Removed solvent in vacuo. Redissolved in DCM and quenched with sat aq NH4Cl. Separated and extracted twice more with DCM. Washed combined organics with brine, then dried on MgSO4, filtered and concentrated providing 1-((6-(tert-butylsulfonyl)-4-chloroquinolin-7-yl)oxy)propan-2-ol (98.8 mg, 0.276 mmol, 98% yield) as an off-white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (d, J=6.06 Hz, 3H) 1.33 (s, 9H) 4.00-4.20 (m, 3H) 4.81 (d, J=4.29 Hz, 1H) 7.74 (s, 1H) 7.76 (d, J=4.80 Hz, 1H) 8.65 (s, 1H) 8.94 (d, J=4.80 Hz, 1H). MS: m/z: 358.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14](N)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[BrH:18].N([O-])=O.[Na+].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>O.CC(C)=O.CO>[Br:18][CH:24]([CH2:25][C:14]1[CH:16]=[CH:17][C:11]([O:10][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[CH:12][CH:13]=1)[C:23]([O:27][CH3:28])=[O:26]
Reactant: C=CC(=O)OC
Reactant: Br
Reactant: Cc1ccc(CCOc2ccc(N)cc2)nc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(Br)Cc1ccc(OCCc2ccc(C)cn2)cc1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-[2-(5-methyl-2-pyridyl)ethoxy]aniline (12.0 g), 47% aqueous HBr solution (36.5 g) and methanol (40 ml)-acetone (80 ml) was added dropwise a solution of NaNO2 (4.0 g) in water (10 ml) at 5° C. or below. The whole mixture was stirred at 5° C. for 20 minutes, then methyl acrylate (27.0 g) was added thereto and the temperature was raised to 38° C. Cuprous oxide (1.0 g) was added to the mixture in small portions with vigorous stirring. After nitrogen gas evolution had ceased, the reaction mixture was concentrated under reduced pressure. The concentrate was made alkaline with concentrated aqueous ammonia and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was evaporated off to leave methyl 2-bromo-3-{4-[2-(5-methyl-2-pyridyl)ethoxy]phenyl}-propionate as a crude oil (17.5 g, 87.5%). IR(Neat)cm- 1 : 1735. NMR δ (ppm) in CDCl3 : 2.27 (3H, s), 3.10 (1H, dd, J=14 and 7), 3.22 (2H, t, J=6), 3.38 (1H, dd, J=14 and 7), 3.66 (3H, s), 4.29 (2H, t, J=6), 4.32 (1H, t, J=7), 6.7-7.5 (6H, m), 8.34 (1H, d, J=2).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:12]1([CH:18]([CH:22]([OH:24])[CH3:23])[CH2:19][CH2:20][OH:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CN=C1.C(OCC)(=O)C>CN(C)C=O.O>[C:12]1([CH:18]([CH2:19][CH2:20][O:21][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:22]([OH:24])[CH3:23])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(O)C(CCO)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)C(CCO[Si](C(C)C)(C(C)C)C(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1.25 mL of triisopropylsilyl chloride was added dropwise to a solution of 1.0 g of 3-phenylpentane-1,4-diol and 0.45 g of imidazole in 20 mL of N,N-dimethylformamide in a nitrogen atmosphere at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 19 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/19 to 1/10), so as to obtain 1.2 g of 3-phenyl-5-((tris(propan-2-yl)silyl)oxy)pentan-2-ol in the form of a colorless oily product.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:18][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(C)Oc1ccc(CO)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)C(C)Oc1ccc(CCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
12 gm (0.058 mol) of methyl 2-(4-hydroxymethyl-phenoxy)-propionate were dissolved in 60 ml of hexamethylphosphoric acid triamide, the solution was cooled to -10° C., and 4.4 ml (0.06 mol) of thionyl chloride were added dropwise thereto. The resulting mixture was stirred for 30 minutes at 0° C. and then for one hour at 10° C., and subsequently poured into water. The aqueous mixture was extracted with ether, and the extract solution was washed with water, sodium bicarbonate solution and again with water, and dried. The ether was subsequently removed in vacuo at room temperature, leaving methyl 2-(4-chloromethyl-phenoxy)-propionate as a residue.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH2:17][CH:18]=[CH2:19])[C:11]2=[O:20])=[N:7][N:6]=1)(=[O:4])=[O:3].Cl[C:22]([O:24][CH2:25][C:26]#[CH:27])=[O:23]>N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:22]([O:24][CH2:25][C:26]#[CH:27])=[O:23])[CH2:14][CH2:13][N:12]([CH2:17][CH:18]=[CH2:19])[C:11]2=[O:20])=[N:7][N:6]=1)(=[O:4])=[O:3]
Reactant: C#CCOC(=O)Cl
Reactant: C=CCN1CCC(O)N(c2nnc(S(C)(=O)=O)s2)C1=O
Solvent: c1ccncc1
Product: C#CCOC(=O)OC1CCN(CC=C)C(=O)N1c1nnc(S(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-3-allyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and propargyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-3-allyl-6-propargyloxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH:1]([OH:3])=O.CC(OC(C)=O)=O.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][CH:1]=[O:3])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=CNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
A solution of formic acid (24.3 g, 98%, 528 mmol) in Ac2O (43.94 g, 430 mmol) was heated to 55° C. for 2 hours, cooled to room temperature. The mixture was diluted with toluene (25 mL) followed by the addition of of 3-bromoaniline (28 g, 163 mmol) in toluene (40 mL). The solution was stirred cold for 30 minutes after which the solvents were removed under vacuo and the residue crystallized from hexane to give N-(3-bromophenyl)formamide (32.79 g). The material was added in portions to 1M. BH3 in THF (450 mL) at 0° C., heated to refluxing for 3 hours and cooled to ambient temperature. The solvents were removed under reduced pressure, the residue was treated with aqueous hydrochloric acid (1M, 200 mL) for for ½ hour, the pH was adjusted to 12 with the addition of sodium hydroxide (1M). The solution was extracted with diethyl ether (3×75 mL), the combined ether layers dried (MgSO4, filtered and concentrated under reduced pressure to give the titled compound (29.48).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12]>N1C=CC=CC=1>[CH3:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:7])[CH3:6])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(N)cc1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C)c(C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (38.9 mL, 412 mmol) was added to a stirred solution of 3,4-dimethylaniline 1-5 (10.0 g, 82.5 mmol) in pyridine (150 mL) at ambient temperature. After stirring at approximately 60° C. for 2 h, the volatiles were removed in vacuo, and the residue was partitioned between diethyl ether and aqueous 1 N hydrochloric acid. The organic phase was separated and washed with saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to afford 1-6 as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[C:32]([O:31][C:29](=[O:30])[CH2:28][N:16]1[C:15]2[CH:14]=[CH:13][C:12]([Cl:20])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[C:19]=2[N:18]=[N:17]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1nnc2c(Oc3cc(Cl)cc(C#N)c3)c(Cl)ccc21

Procedure:
3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (500 mg, 1.64 mmol) and cesium carbonate (534 mg, 1.64 mmol) were suspended in DMF (5 mL) under N2. To this was added tert-butyl bromoacetate (336 mg, 1.72 mmol) After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride (5 mL), diluted with water and the mixture extracted with ethyl acetate (2×25 mL). The combined organic fractions were washed with water (3×25 mL) and dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by automated column chromatography on silica gel (40 g) eluting with 0-15% EtOAc/hexanes to give the title product. LRMS (M+1)=418.9.
Reaction SMILES: S(Cl)(Cl)=O.O[N:6]=[CH:7][C:8]1[N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:11]=[CH:10][C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].O>CCOCC>[C:7]([C:8]1[N:12]([C:13]([CH3:15])([CH3:16])[CH3:14])[N:11]=[CH:10][C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:6]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C=NO
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C#N
Reaction time: 16 h
Yield: 83.5 %

Procedure:
Thionyl chloride (6.6 ml, 0.092 mole) was added to a cold solution of 5-(hydroxyiminomethyl)-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester (11 grams, 0.046 mole) in 75 ml of ether. The solution was stirred in the cold for thirty minutes, then at room temperature for 16 hours. Water was added to the reaction mixture to neutralize the remaining thionyl chloride, then the reaction mixture was poured into a separatory funnel. The phases were separated and the organic phase was washed with water and dried using sodium sulfate and filter paper. The solvent was removed in vacuo, yielding 8.5 grams of 5-cyano-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1.[OH-].[Na+]>O1CCCC1.O>[C:16]1([CH:15]=[CH:14][C:13]([NH:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][C:3]([OH:23])=[O:2])=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)COc1cccc(NC(=O)C=Cc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(NC(=O)C=Cc2ccccc2)c1
Temperature: 35 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a suspension of [3-(3-phenyl-acryloylamino)-phenoxy]-acetic acid methyl ester (8) (0.345 g, 1.1 mmol) in tetrahydrofuran (6 ml) a solution of NaOH (0.130 g, 3.3 mmol) in water (6 ml) was added and the resulting mixture was stirred for 3 hours at 35° C. Tetrahydrofuran was evaporated and the remaining water mixture was acidified with 2N HCl to pH 3. The precipitate was filtered off and dried to give 0.300 g (92%) of the title product 9, which was used in the next step without an additional purification.
Reaction SMILES: [CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[CH3:13])=[O:2].[CH2:14]([Si](C)(C)C)[CH:15]=[CH2:16].B(F)(F)F.CCOCC.C(N(CC)CC)C>C(Cl)Cl>[OH:2][CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[CH3:13])[CH2:16][CH:15]=[CH2:14]
Reactant: CCOC(=O)c1noc(C=O)c1C
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC(O)c1onc(C(=O)OCC)c1C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 5-formyl-4-methylisoxazole-3-carboxylate (Intermediate C) (350 mg, 1.911 mmol) in DCM (19 mL) was added allyltrimethylsilane (276 μl, 1.911 mmol) and the mixture was cooled to −78° C. A solution of boron trifluoride etherate (278 μl, 2.198 mmol) in DCM (5 mL) was cooled to −78° C. and added to the reaction mixture over 5 min. The reaction mixture was stirred for 15 mins and triethylamine (266 μl, 1.911 mmol) was added. The reaction mixture was maintained at −78° C. for 15 minutes and allowed to warm to room temperature. The resulting mixture was quenched by the addition of a saturated aqueous NaHCO3 solution (10 mL) and extracted with DCM (2×10 mL). The combined organic extracts were passed through a phase separating cartridge and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-40% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O.[F:22][C:23]([F:31])([F:30])[C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:26]([CH3:27])[C:25]=2[C:24](=[O:29])[C:23]([F:31])([F:30])[F:22])=[CH:16][CH:17]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccc(Cl)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccc(Cl)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 34 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(4-chloro-phenyl)-methanone [example A3] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 34%; MS: m/z=433 (M).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH:46](Br)[CH3:47]>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:46]([CH3:47])[CH2:45][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(Br)CBr
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1C
Temperature: 85 °C

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (300 mg, 0.572 mmol) and potassium carbonate (316 mg, 2.29 mmol) in butanone (4 ml) was added 1,2-dibromopropane (0.072 ml, 0.686 mmol). The reaction was heated to 85° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided a yellow solid. The solid was recrystallized from MeOH. The solid was filtered, washed with MeOH, and dried to provide the title compound as a yellow solid which was dissolved in acetone and concentrated (3×). The light yellow solid was collected and dried under to provide the title compound as a 1:1 mixture of rotational diastereoisomers (75.1 mg, 0.133 mmol, 23%): mp 201-204° C.; 1H NMR of mixture (400 MHz, CDCl3) δ 8.56 (s, 2H), 8.18 (dd, J=10.8, 7.4 Hz, 6H), 7.84-7.73 (m, 8H), 7.45-7.30 (m, 8H), 7.30-7.23 (m, 2H), 7.20 (d, J=6.7 Hz, 1H), 7.12 (dd, J=7.8, 1.2 Hz, 1H), 4.43-4.33 (m, 1H), 4.16 (dd, J=12.6, 6.3 Hz, 1H), 3.48 (dt, J=13.3, 6.7 Hz, 1H), 3.37 (dd, J=10.8, 6.2 Hz, 1H), 3.24 (dt, J=13.7, 6.9 Hz, 1H), 3.08-2.92 (m, 3H), 1.33-1.16 (m, 18H); ESIMS m/z 566 (M+H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2(CC(O)=O)[NH:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[NH:8]2)=[CH:4][CH:3]=1.[C:20](N1C=CN=C1)([N:22]1[CH:26]=[CH:25]N=C1)=O.CN.[O:34]1CCCC1>>[Br:1][C:2]1[O:6][C:5]([C:7]2[N:15]([CH2:25][C:26]([NH:22][CH3:20])=[O:34])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(c2ccc(Br)o2)Nc2cccnc2N1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Agent: CN
Product: CNC(=O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A suspension of 2-(5-bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine acetic acid (5.0 g, 0.0155 mole) and 1,1'-carbonyldiimidazole (2.52 g, 0.0155 mole) in dry tetrahydrofuran (100 ml) was stirred at room temperature for two hours with a stream of nitrogen bubbling through it. A solution of methylamine in tetrahydrofuran (31 ml of a 3.03M solution, 0.093 mole) was added, and the suspension was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure, and the residue was triturated in water. The resulting solid was collected by filtration and rinsed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol and filtered, and the solution was allowed to cool to room temperature. Addition of water caused a precipitate to form which was collected by filtration and dried under high vacuum to give 2.95 g (57%) of title compound, mp. 187°-191° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/OC)([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[CH:24][N:23]=1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[CH:24][N:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Reactant: NCc1cc(O)c(-c2ccoc2)cn1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(c1)C(=CNCc1cc(O)c(-c3ccoc3)cn1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
An amount of 40.0 mg (0.154 mmole) of (4E)-6-tert-butyl-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (based on a sample that is 39% pure by weight), is dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 29 mg (0.154 mmole) of 2-aminomethyl-5-furan-3-yl-pyridin-4-ol. All solids dissolved and after the mixture is stirred at room temperature for 2 hours, the solution is evaporated to dryness in vacuo, treated with acetonitrile, filtered and washed several times with fresh acetonitrile and dried to give 41 mg of the title compound as a pink solid (64% yield); mp 215-230° C. dec, MS data ES(+) 418.3
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([N:9]([CH3:21])[C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:4]1)[CH3:2].[H][H]>C(O)C.[Pt]=O>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([N:9]([C@H:5]2[C@H:6]([OH:8])[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4]2)[CH3:21])=[O:20])=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: O=[Pt]
Solvent: CCO
Product: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccc(N)cc2)C1
Yield: 40.9 %

Procedure:
A solution of 23 g (79 mmoles) of trans-N-(1-ethyl-4-hydroxy-3-pyrrolidinyl)-N-methyl-4-nitrobenzamide in 250 ml of absolute ethanol was treated with platinum oxide and shaken with hydrogen at ambient temperature in the Parr reduction apparatus for 3 hr. The mixture was filtered and the filtrate was concentrated to give 20.6 g (100%) of crude product. One-half of the residue was crystallized from acetone to give 8.5 g (82%) of white powder; m.p. 142°-145° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].O>CN(C=O)C>[CH3:1][C:2]1([CH3:23])[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC1(C)C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a suspension of 4,4-dimethyl-17β-hydroxyandrost-5-en-3-one (3.34 g) in DMF (30 ml), imidazole (1.40 g) and tert-butyldimethylsilyl chloride (3.15 g) were added. After stirring the mixture overnight at RT, water was added, and stirring was continued for 30 min at 0° C. The formed solid was filtered and, after drying, 4,4-dimethyl-17β-tert-butyldimethylsilyloxyandrost-5-en-3-one was obtained (4.0 g, 93% yield).