Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:19][C:18]2[CH:20]=[CH:21][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.7 %

Procedure:
To a solution of 4-dimethylaminobenzaldehyde (11 g) in toluene (200 mL) were added 4-isopropylaniline (10 g) and molecular sieves 4A (20 g) under ice-cooling, and the mixture was stirred at room temperature for one day. The molecular sieves 4A was filtered off from the reaction mixture, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (200 mL) and sodium borohydride (2.3 g) was added under ice-cooling. The mixture was stirred at room temperature for 5 hr. After methanol was distilled away, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give (4-dimethylaminophenylmethyl)(4-isopropylphenyl)amine (13.6 g). melting point: 71-73° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[N:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:20][CH:19]=2)=[CH:16][CH:17]=1>CN(C=O)C>[CH2:3]([O:10][C:12]1[N:13]=[N:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)nn1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(-c3ccc(OCCCN4CCCCC4)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
Sodium hydride (0.007 g, 0.18 mmol) was stirred in anhydrous DMF (4 mL) under a nitrogen atmosphere, and benzyl alcohol (0.016 g, 0.15 mmol) was added. After 15 min., 3-chloro-6-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyridazine (0.05 g, 0.15 mmol) was introduced, and the reaction mixture was stirred at room temperature for 5 h. The precipitate was collected by filtration, washed with H2O (10 mL) and dried in vacuo to provide the title compound as a white solid (0.050 g, 83%), m.p. 138° C.; 1H NMR (CDCl3) 2.00 (m, 2H, —CH2—), 2.50 (m, 2H, —CH2—), 4.10 (m, 2H, —CH2—), 7.00 (d, 1H, C—H), 7.05 (d, 2H, Ar—H), 7.75 (d, 1H, C—H), 7.95 (d, 2H, Ar—H) HPLC retention time 2.612 mina.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl.Cl[CH2:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:17][CH:16]=1>CN(C=O)C>[N:1]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]3)=[O:20])=[CH:29][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)C1CCN(C(=O)c2ccc(CCl)cc2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)c2ccc(Cn3ccc4ccccc43)cc2)C1
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
A solution of indole (29 mg, 0.25 mmol) in DMF (5 mL) at room temperature is treated with sodium hydride (30 mg), stirred for 10 minutes, treated with 1-(4-chloromethylbenzoyl)-3-(N,N-dimethylamino)pyrrolidine hydrochloride (113 mg, 0.37 mmol) stirred at room temperature overnight and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse-phase semi-preparative HPLC to give the title product as a white powder (63 mg), identified by HPLC and mass spectral analyses. MS [348.2 m/e (M+H)], retention time 2.58 min.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH3:6][O:7][CH:8]([O:11][CH3:12])[CH2:9]Br.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[C:1]([O:4][CH2:9][CH:8]([O:11][CH3:12])[O:7][CH3:6])(=[O:3])[CH3:2]
Reactant: COC(CBr)OC
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(COC(C)=O)OC
Temperature: 134 °C
Reaction time: 16 h

Procedure:
A mixture of sodium acetate (1.0 g, 12.19 mmol), bromoacetaldehyde dimethyl acetal (1.43 mL, 12.19 mmol), and tetrabutylammoniumbromide (1.96 g, 6.09 mmol) in 8 mL of anhydrous CH3CN was stirred at 134° C. for 16 h in a sealed tube. It was cooled to room temperature, water was added and the mixture extracted with Et2O (3×100 mL). The combined organic phases were washed with saturated NaCl (1×75 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 40-60% ethyl acetate/hexanes to give the product 43b (product is volatile, some of the product is lost during the evaporation of solvents). 1H NMR (400 MHz, CDCl3) δ 2.03 (s, 3H), 3.36 (s, 6H), 4.08 (d, J=5.3 Hz, 2H), 4.54 (t, J=5.3 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[N:20]1[C:21]([C:29](O)=[O:30])=[CH:22][N:23]2[CH:28]=[CH:27][CH:26]=[N:25][C:24]=12.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:21]3[N:20]=[C:24]4[N:25]=[CH:26][CH:27]=[CH:28][N:23]4[CH:22]=3)=[O:30])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: O=C(O)c1cn2cccnc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1cn2cccnc2n1

Procedure:
The title compound was prepared using the method of Example 34(d) from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.3 g, 1.07 mmol), imidazo[1,2-a]pyrimidine-2-carboxylic acid (0.17 g, 1.07 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) and EDCI (0.31 g, 1.61 mmol) using DMF (10 mL) as solvent. Yield 0.29 g. 1H NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.30 (dd, 1H), 4.49 (dd, 1H), 4.65 (m, 1H), 6.81 (dd, 1H), 6.98 (dd, 1H), 7.53 (d, 1H), 7.73 (dd, 1H), 8.08 (s, 1H), 8.48 (dd, 1H), 8.67 (m, 3H).
Reaction SMILES: O[CH:2]1[CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[Cl:14][CH:2]1[CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: OC1CCC2CCCCN2C1
Solvent: c1ccccc1
Product: ClC1CCC2CCCCN2C1

Procedure:
A solution of 14 g. (0.11 mole) of 3-hydroxyquinolizidine in 75 ml. of thionyl chloride and 50 ml. of benzene was refluxed for one hour. The solvent was completely evaporated, and the residue dissolved in chloroform. The solution was passed through an alumina column and evaporation of the chloroform gave crude 3-chloroquinolizidine. The crude material was chromatographed on an alumina column eluting with ether-petroleum ether, 1:19 to yield pure 3-chloroquinolizidine.
Reaction SMILES: [Na].O[C:3]([CH3:10])([CH3:9])[C:4]([O:6]CC)=O.[NH2:11][C:12]([NH2:14])=[O:13]>C(O)C>[CH3:9][C:3]1([CH3:10])[NH:14][C:12](=[O:13])[NH:11][C:4]1=[O:6]
Reactant: CCOC(=O)C(C)(C)O
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: CC1(C)NC(=O)NC1=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
In a 5-liter three neck distillation flask were placed 1.5 l of ethanol, 92 g of metallic sodium, 472 g of ethyl α-hydroxyisobutyrate (4 mole), and 240 g of urea (4 mole). The mixture was heated and stirred on hot oil bath at 100° C. for 18 hours. After ethanol and methanol were distilled off from the reaction mixture and then 2 l of water was added therefor, the mixture was made acid with aqueous hydrochloric acid solution and then extracted twice with ethyl acetate. The extract was dried with Glauber's salt, and then filtered. The solvent was distilled off from the extract to obtain 270 g of 5,5-dimethylhydantoin having a melting point of 75° C.
Reaction SMILES: [CH3:1][C:2]([S:28]([CH3:31])(=[O:30])=[O:29])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.CO>C(Cl)Cl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(CCc1ccc(Oc2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(CCc1ccc(Oc2ccccc2)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (247.2 mg, 0.552 mmol) was dissolved in methylene chloride (10 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 4.14 mL, 16.6 mmol) and the solution was stirred at RT for 5 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanamide as a solid. 94.4 mg. LCMS: (M−1) 362.3
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([CH3:27])[CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[S:7][C:6]=2[CH:35]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([CH3:27])[CH2:22]4)=[CH:16][CH:17]=3)[OH:11])=[C:8]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[S:7][C:6]=2[CH:35]=1
Reactant: CC1CCCN(CCOc2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CCCN(CCOc2ccc(C(O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)C1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 96 %

Procedure:
A solution of [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(3-methyl-1-piperidinyl]ethoxy]phenyl]methanone, as described in United Kingdom Patent Application GB 2097 788 H (0.300 g, 0.633 mmol), was stirred in THF (40 mL) at ambient temperature. Lithium aluminum hydride (0.100 g, 2.64 mmol) was added gradually over a 15 minute period and the reaction mixture was stirred at ambient temperature for 1.75 hours. Subsequently, the reaction was quenched with cold ethyl acetate. The mixture was evaporated and then taken up in methanol (10 mL) an ethyl acetate (30 mL). The organic layers were washed with sodium bicarbonate (25 mL of a saturated aqueous solution), potassium sodium tartrate (3×20 mL, saturated aqueous solution), and dried (magnesium sulfatel. Concentration gave 0.290 g (96%) of the title compound which was used without further purification: 1H NMR (300 MHz, MeOD-d4) δ7.50 (d, 1H, J=8 Hz), 7.34 (d, 2H, J=8 Hz), 7.28 (d, 2H, J=8 Hz), 7.16 (d, 1H, J=2 Hz), 6.83-6.90 (m, 4H), 6.68 (dd, 1H, J=8 Hz, J=2 Hz), 6.10 (s, 1H), 4.13 (t, 2H, J=6 Hz), 3.00-3.25 (m, 4H), 2.85-2.92 (m, 1H), 2.32-2.43 (m, 2H), 2.08-2.19 (m, 1H), 1.42-1.51 (m, 1H), 1.05 (d, 2H, J=6 Hz); IR (KBr) 3251, 2958, 1610, 1509, 1238 1171, 838 cm−1; MS (FD) m/z 476 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-:18].[Na+]>CO>[NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[NH2:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccc(COc2cccnc2N)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(COc2cccnc2N)cc1

Procedure:
A mixture of 2-amino-3-(4-cyanobenzyloxy)pyridine (2.25 g) and lN sodium hydroxide solution (22 ml) in methanol (45 ml) was refluxed for 4.5 hours and then cooled. The resulting precipitates were collected by filtration and dried to give 2-amino-3-(4-carbamoylbenzyloxy)pyridine (1.84 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]([C:12]1([CH3:15])[CH2:14][CH2:13]1)#[CH:11]>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:11]#[C:10][C:12]2([CH3:15])[CH2:14][CH2:13]2)[CH:3]=1
Reactant: C#CC1(C)CC1
Reactant: Nc1cnc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C#Cc2cc(Cl)ncc2N)CC1
Yield: 51.8 %

Procedure:
To a solution of 6-chloro-4-iodopyridin-3-amine (7.0 g, 28 mmol) in Et3N (100 mL) was added 1-ethynyl-1-methyl-cyclopropane (11.0 g, 137 mmol), CuI (0.53 g, 2.8 mmol) and Pd(PPh3)2Cl2 (1.9 g, 2.8 mmol) under N2 atmosphere. The mixture was refluxed overnight and quenched with H2O (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and purified by chromatography on silica gel (3% EtOAc in Petroleum ether as eluant) to afford 6-chloro-4-((1-methylcyclopropyl)ethynyl)pyridin-3-amine (3.0 g, 53%). 1H-NMR (CDCl3, 300 MHz) δ 7.84 (s, 1H), 7.08 (s, 1H), 4.11 (br s, 2H), 1.37 (s, 3H), 1.03 (t, J=2.4, 2H) 0.76 (t, J=2.4, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:6][N:5]=1)[CH3:2].C1C(=O)N([Br:22])C(=O)C1>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:9][C:8]1[C:4]([O:3][CH2:1][CH3:2])=[N:5][O:6][C:7]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1onc(OCC)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(OCC)c1CBr
Yield: 96.8 %

Procedure:
Ethyl 3-Ethoxy-4-methylisoxazole-5-carboxylate (18 g, 91 mmol), NBS (17.5 g, 100 mmol), dibenzoyl peroxide (1 g, 4.1 mmol) in tetrachloromethane (500 mL) was boiled under reflux for 16 h. The mixture was cooled, filtered and concentrated in vacuo to afford the crude title compound (24.5 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 74360080 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoate (910 mg, 2.0823 nmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (10.4 ml) and 1,4-dioxane (25 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (200 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (655 mg, 1.5484 mmol, 74%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:10][C:9](=[O:11])[C:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)([CH3:13])[CH3:12])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: CC(C)(OCc1ccc(F)cc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)OCc3ccc(F)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 770 mg of 2-(4-fluorobenzyloxy)-2-methylpropionic acid and 1.0 gof (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.17 g of the title compound as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH:1]1([C:4]2(O)[CH2:7][CH:6]([C:8]3[O:12][N:11]=[C:10]([C:13]4[CH:14]=[CH:15][C:16]([CH3:31])=[C:17]([NH:19][C:20]([C:22]5[N:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:25]6=[N:24][CH:23]=5)=[O:21])[CH:18]=4)[N:9]=3)[CH2:5]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=[O:36]>>[OH:36][CH2:2][CH2:3][CH:1]=[C:4]1[CH2:5][CH:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH3:31])=[C:17]([NH:19][C:20]([C:22]4[N:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]5=[N:24][CH:23]=4)=[O:21])[CH:18]=3)[N:9]=2)[CH2:7]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(-c2noc(C3CC(O)(C4CC4)C3)n2)cc1NC(=O)c1cnc2ccccn12
Product: Cc1ccc(-c2noc(C3CC(=CCCO)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reaction time: 0.25 h

Procedure:
A stirring solution of N-(5-(5-(3-cyclopropyl-3-hydroxycyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F113) (130 mg, 0.303 mmol) in trifluoroacetic acid (1 mL) was stirred at room temperature for 1.5 hours. The solvent was concentrated and dried under high vacuum. The crude product was taken in MeOH (1 mL) and a saturated solution of sodium bicarbonate (0.2 mL). The reaction mixture was stirred for 15 minutes. The crude product was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the desired product N-(5-(5-(3-(3-hydroxypropylidene)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F32). 1H NMR (400 MHz, d6-DMSO) δ 10.04 (s, 1H), 9.48-9.45 (m, 1H), 8.59 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.82 (dd, J=1.6 Hz, 7.6 Hz, 1H), 7.81-7.77 (m, 1H), 7.55-7.52 (m, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 1H), 5.28-5.23 (m, 1H), 4.50 (s, 1H), 3.98-3.89 (m, 1H), 3.40-3.37 (m, 2H), 3.23-3.14 (m, 2H), 3.09-3.03 (m, 2H), 2.36 (s, 3H), 2.08-2.02 (m, 2H). MS m/z 430.47 (M+1)+.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:6]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH2:2][C@H:3]([OH:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:6]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC(CCC)COc1cccc(C[C@@H](O)CCl)c1
Agent: [Na+]
Product: CCCC(CCC)COc1cccc(C[C@@H](O)CN=[N+]=[N-])c1

Procedure:
Treatment of (R)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol with sodium azide following the method used in Example 66 gave (R)-1-azido-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[N:11]2[C:12](=[O:20])[C:13](=[O:19])[NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:9]([C:10]=32)[CH2:8][CH2:7]1)=[O:4].[N+:21]([O-])([O:23]C(C)C)=[O:22]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]([CH2:5][CH:6]1[N:11]2[C:12](=[O:20])[C:13](=[O:19])[NH:14][C:15]3[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=[C:9]([C:10]=32)[CH2:8][CH2:7]1)=[O:4]
Reactant: COC(=O)CC1CCc2cccc3[nH]c(=O)c(=O)n1c23
Reactant: CC(C)O[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)CC1CCc2cc([N+](=O)[O-])cc3[nH]c(=O)c(=O)n1c23
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 43.1 %

Procedure:
To a solution of 5-methoxycarbonylmethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (66 mg, 0.24 mmol) in concentrated sulfuric acid (1.5 mL) was added isopropyl nitrate (30 μL, 0.3 mmol) at 0° C. The mixture was stirred for 45 min at 0° C., poured into ice-water, and extracted with ethyl acetate (100 mL×2). The extracts were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 0.1% acetic acid/ethyl acetate to give 33 mg of the title compound (43%): mp 254°~256° C.; 1H NMR (270 MHz, DMSO-d6) δ12.23 (bs, 1H), 7.91 (d, 1H, J=2.6 Hz), 7.85 (d, 1H, J=2.6 Hz), 5.05~5.21 (m, 1H), 3.64 (s, 3H), 2.85~3.10 (m, 2H), 2.56~2.72 (m, 2H), 2.17 (dm, 1H, J=13.5 Hz), 1.80~2.00 (m, 1H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])=[CH:25][CH:24]=1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 68B and (4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.67-8.69 (m, 1H), 8.43 (d, J=8.0 Hz, 1H), 8.22-8.24 (bs, 1H), 8.00-8.04 (m, 2H), 7.90-7.97 (m, 1H), 7.82-7.87 (m, 1H), 7.66-7.70 (m, 1H), 7.54-7.58 (m, 2H), 7.33-7.36 (m, 2H), 7.24-7.30 (m, 2H), 3.71-3.74 (bs, 2H); MS (APCI+) M/Z 454 (M+H)+.