Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C@H:11]1CO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:19][CH:18]=1)=[C:15]=[O:16].[Br-].[Li+].CC(=[O:36])CC>>[O:16]=[C:15]1[N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[CH:19][CH:18]=2)[CH2:11][C@H:10]([CH2:9][NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:36]1
Reactant: CCC(C)=O
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: c1ccc(CNCC[C@H]2CO2)cc1
Agent: [Br-]
Agent: [Li+]
Product: O=C1COCCN1c1ccc(N2C[C@H](CNCc3ccccc3)OC2=O)cc1
Yield: 89.21 %

Procedure:
(S)—N-benzyl-1-(oxiran-2-ylmethyl)methylamine (3.10 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in butanone (70 mL) respectively, and heated to reflux. Then lithium bromide (0.15 g, 1.74 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (5.88 g, yield: 89.21%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:7][CH2:8][CH3:9].C(Cl)(Cl)Cl.CN(C)[CH:27]=[O:28]>>[CH2:6]([N:10]([CH2:6][CH2:7][CH2:8][CH3:9])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([CH:27]=[O:28])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCNc1cc(OC)cc(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)c1cc(OC)c(C=O)c(OC)c1
Temperature: 7.5 °C
Yield: 80 %

Procedure:
In a stream of argon, to 30 ml of N,N-dimethylformamide was added 16.0 g (104 mmol) of phosphorus oxychloride under cooling at 5 to 10° C. and stirring. After the mixture was well-stirred, 23.5 g (80.1 mmol) of 4-butylamino-2,6-dimethoxybenzene dissolved in 10 ml of N,N-dimethylformamide was added dropwise. The mixture was reacted with stirring for 1.5 hours. After the mixture was poured into 70 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 18.8 g (yield: 80%) of 4-dibutylamino-2,6-dimethoxybenzaldehyde as a dark purple crystal (mp: 55-56° C.)
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]1[CH:51]=[C:52]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)[CH:53]=[C:54]([F:56])[CH:55]=1>CN(C=O)C>[F:49][C:50]1[CH:51]=[C:52]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)[CH:53]=[C:54]([F:56])[CH:55]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cc(F)cc(F)c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 35.2 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′,5′-difluoro-biphenyl-3-ylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.009 g of product in 35% yield: LCMS (ESI) m/z 394 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[OH:9].[OH-:10].[K+].Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:10])[C:3]=1[OH:9]
Reactant: [OH-]
Reactant: Oc1c(F)cccc1I
Agent: Cl
Agent: [K+]
Product: Oc1cccc(F)c1O
Reaction time: 8 h
Yield: 78 %

Procedure:
To a 500 ml flask were added 119 g (0.5 mol) of 2-fluoro-6 -iodophenol and 200 ml of a 30% aqueous potassium hydroxide solution and they were reacted under vigorous stirring under a reflux temperature for 8 hours. After the termination of the reaction, the mixture was cooled to ordinary temperature and neutralized with hydrochloric acid to adjust pH between 2 and 3. After filtration, the filtrate was washed with water to obtain 49.9 g of a product [H]. The process yield was 78%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19].ON1C2C=CC=CC=2N=N1.[C:30]([C:33]1[N:34]=[CH:35][C:36]2[NH:37][C:38]3[C:43]([C:44]=2[CH:45]=1)=[CH:42][CH:41]=[CH:40][CH:39]=3)(O)=[O:31].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[CH:35]1[C:36]2[NH:37][C:38]3[C:43]([C:44]=2[CH:45]=[C:33]([C:30]([C:2]2([NH2:1])[CH2:8][CH2:7][C:6]4[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=4[N:4]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:3]2=[O:19])=[O:31])[N:34]=1)=[CH:42][CH:41]=[CH:40][CH:39]=3
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: NC1CCc2ccccc2N(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC1(C(=O)c2cc3c(cn2)[nH]c2ccccc23)CCc2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
In 15 ml of dimethylformamide were dissolved 0.252 g of 3-amino-1-phenyl-2,3,4,5-tetrahydro-1-benzoazepin-2(1H)-one, 0.127 g of 1-hydroxybenzotriazole, 0.223 g of 3-carboxy-β-carboline and 0.2 g of 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride and 0.5 ml of triethylamine was added to the solution, and the mixture was stirred at room temperature for one day. After the solvent was removed under reduced pressure, a 10% aqueous citric acid and chloroform were added to the residue and the mixture was stirred. Thereafter, the chloroform layer was separated, washed with a 10% sodium hydroxide aqueous solution and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and ethyl acetate was added to the residue. The precipitates were collected by filtration to obtain 0.312 g of the title compound as crystals. Melting point: 302° to 304° C., IR (Nujol) (cm-1): 3360, 3290, 1730, 1670, 1650, 1625, MS (m/z): 446 (M+), 264 (base)
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(O)C>[CH2:20]([N:22]([CH2:23][CH2:24][NH:25][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1)[CH2:26][CH3:27])[CH3:21]
Reactant: Cc1ccc(-n2c(=O)c(Cl)nc3cccnc32)cc1
Reactant: CCN(CC)CCN
Solvent: CCO
Product: CCN(CC)CCNc1nc2cccnc2n(-c2ccc(C)cc2)c1=O

Procedure:
Preparation as in Example 39 but using 2-chloro-3,4-dihydro-4-(4-methylphenyl)-3-oxopyrido[2,3-b]pyrazine and N,N-diethylethylene diamine in refluxing ethanol gave the title compound mp 131°-132° C.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1.[CH3:17][O:18][CH2:19]Cl.C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:17][O:18][CH2:19][O:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2O
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC1CCC(C)(C)c2cc(C(C)=O)ccc21
Yield: 61.7 %

Procedure:
A solution of (+/-) 1-hydroxy-6-acetyl-1,2,3,4-tetrahydro-4,4-dimethyl-naphthalene (Compound D25, 24.8 mg, 0.11 mmol), chloromethyl methyl ether (0.12 mmol), triethyl amine (0.02 ml, 0.13 mmol) and catalytic amount of tetrabutylammonium bromide in 2 ml of CH2Cl2 was stirred at room temperature for 5 h. Purification by column chromatography (silica) with ethyl acetate/hexane (1/10) afforded the title compound as an oil (17.8 mg).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C@@:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:21].C[O-].[Na+]>CO>[CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C@@:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:21]
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)N(C)C(=O)C3)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(C)C(=O)C3)c1
Temperature: 0 °C

Procedure:
A solution of N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline (4.6 g, 1.6 mmole) and sodium methoxide (1.84 g, 3.4 mmole) in 150 ml of methanol was stirred at room temperature under nitrogen for 20 hours. It was poured into 150 ml of ice-water and extracted with ether, and the combined extracts were washed with 3 N hydrochloric acid and sat. sodium bicarbonate, dried (Na2SO4) and evaporated. The crude product was a white viscous oil (3.8 g). Thin layer chromatography on silica gel, eluting with 10% ether/benzene, showed a major spot (Rf 0.31) and a minor component (Rf 0.07). The major component, N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline, was clearly separated by preparative thick layer chromatography and isolated as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2([OH:21])[CH2:20][N:17]([CH:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:18]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCOCC
Product: OC1(c2ccc(Cl)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-chlorophenylmagnesium bromide (9.1 mL, 10 M in diethyl ether) in diethyl ether (80 mL) at −78° C. under an argon atmosphere was added compound 3 (1.8 g, 7.6 mmol) in diethyl ether (50 mL) dropwise over 20 minutes. The reaction mixture was stirred at −78° C. for 2 hours, then slowly warmed to room temperature with stirring over 18 hours. The reaction mixture was then partitioned between aqueous ammonium acetate solution (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (3×50 mL) and the combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated in vacuo to give the crude product as a pale yellow viscous oil in quantitative yield. A sample purified for analysis by column chromatography on silica gel using 15-30% ethyl acetate-hexane as eluent and subsequent crystallisation from bexane gave 3-(4-chorophenyl)-1-(diphenyhnethyl)-3-azetidinol (4), m.p. 108° C. Found: C, 75.42; H, 5.79; N, 3.98. C22H20CINO requires C, 75.53; H, 5.76; N, 4.00%.
Reaction SMILES: C(O[C@H]1CN([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)C[C@H]1NC1C(CC)=NC(C2C(C)=NC(OC)=CC=2)=C(CC)N=1)C.[CH3:35][N:36]([CH3:63])[C:37]1[N:42]=[CH:41][C:40]([C:43]2[N:44]=[C:45]([CH2:60][CH3:61])[C:46]([NH:51][C@H:52]3[C@@H:56]([O:57][CH2:58][CH3:59])[CH2:55][NH:54][CH2:53]3)=[N:47][C:48]=2[CH2:49][CH3:50])=[C:39]([CH3:62])[CH:38]=1>>[CH3:63][N:36]([CH3:35])[C:37]1[N:42]=[CH:41][C:40]([C:43]2[N:44]=[C:45]([CH2:60][CH3:61])[C:46]([NH:51][C@H:52]3[C@@H:56]([O:57][CH2:58][CH3:59])[CH2:55][N:54]([C:9]4[N:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH2:53]3)=[N:47][C:48]=2[CH2:49][CH3:50])=[C:39]([CH3:62])[CH:38]=1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Reactant: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 8.36, 7.99, 6.53, 6.46, 5.19, 4.91, 4.22, 3.95, 3.73, 3.58–3.44, 3.13, 2.71, 2.54, 2.12, 1.32–1.26, 1.16; IR (diffuse reflectance) 2969, 2931, 2403 (w), 2351 (w), 2306 (w), 2212 (w), 2168 (w), 1606 (s), 1583 (s), 1568 (b), 1547 (s), 1508 (s), 1474 (s), 1393 (s), 798 cm−1 HRMS (ESI) calcd for C26H36N8O+H1 477.3090. found 477.3113.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[ClH:28].[CH:29](O)=O>C=O>[ClH:28].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:16]4[CH2:21][CH2:20][N:19]([CH3:29])[CH:18]([CH3:22])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: C=O
Agent: Cl
Product: COc1c(N2CCN(C)C(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
A solution of 1.5 g (0.004 mole) of 1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (free form) (prepared as described in Example 22, but omitting the final reaction with hydrochloric acid) in a mixture of 75 ml of 90% aqueous formic acid and 45 ml of 37% aqueous formaldehyde was heated under reflux for 15 hours. 8 ml of concentrated hydrochloric acid were then added to the reaction mixture, and the solvent (formic acid, formalin and water) was then removed by evaporation under reduced pressure. Methanol was then added to the residue, and the resulting solution was filtered to remove insoluble material. The filtrate was evaporated to dryness under reduced pressure, and the residue was washed with ethanol to afford 1.35 g of 1-cyclopropyl-6-fluoro-8-methoxy-7-(3,4-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride as a colorless powder melting at 218°-221° C. (with decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH3:14])([CH3:13])[C:5](=[O:12])[NH:6]2.[CH2:15](I)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH3:14])([CH3:13])[C:5](=[O:12])[NH:6]2)[CH:16]=[CH2:15]
Reactant: C=CCI
Reactant: Cc1ccc(O)c2c1NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2c1C(C)(C)C(=O)N2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
8.21 g (42.99 mmol) of 2,3-dihydro-4-hydroxy-3,3,7-trimethyl-1H-indol-2-one and 7.95 g (47.3 mmol) of allyl iodide were dissolved in 65 ml of N,N-dimethylformamide. After the addition of 12.0 g (87 mmol) of potassium carbonate, the mixture was stirred for 2 hours over a water bath at 70° C. After the reaction, the solvent was removed by evaporation under reduced pressure. Chloroform was added to the residue, and the mixture was washed with water, 2N sodium hydroxide aqueous solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 10:1 mixture of chloroform and ethyl acetate) and crystallized from n-hexane to obtain 5.67 g (yield, 57.1%) of colorless crystals of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[C:12]([S-])=[S:13])C.[K+].O.Cl>N1C=CC=CC=1>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[C:12]1[SH:13]
Reactant: Nc1ncccc1O
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: Sc1nc2ncccc2o1
Yield: 67.4 %

Procedure:
2-Amino-3-hydroxypyridine (5.51 g) was dissolved in pyridine (100 mL), and potassium ethylxanthate (8.82 g) was added thereto. The mixture was refluxed for 2 hr. Iced water (400 mL) was added to the reaction mixture, and concentrated hydrochloric acid (40 mL) was added thereto. The mixture was extracted with chloroform and the extract was washed with brine and concentrated under reduced pressure to give 1,3-oxazolo[4,5-b]pyridine-2-thiol (5.13 g) as a pale-brown powder.
Reaction SMILES: C([NH:8][CH2:9][CH:10]([CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:8][CH2:9][CH:10]([CH:16]([O:18][Si:19]([C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:21])[CH3:20])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(CNCc1ccccc1)C(C)O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(CN)C(C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of 70.2 g of ethyl 2-(N-benzylaminomethyl)-3-t-butyldimethylsilyloxybutanoate in methanol (100 ml) was added portionwise 10.0 g of 10% wet palladium on carbon under nitrogen atmosphere. The mixture was shaken vigorously under 3.5 atmospheric pressure of hydrogen. After 8 hours, palladium on carbon was filtered off and washed with chloroform. The filtrate was evaporated to dryness under reduced pressure to give 50.3 g of crude ethyl 2-aminomethyl-3-t-butyldimethylsilyloxybutanoate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[C:32](/[CH:33]=[CH:34]\[C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)=[CH:31][CH:30]=[C:29]([O:47][CH2:48][CH:49]=[CH2:50])[C:28]=1[O:51][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.C(O)(=O)C.O>C1COCC1>[OH:26][C:27]1[C:32](/[CH:33]=[CH:34]\[C:35]2[CH:36]=[C:37]([O:45][CH3:46])[C:38]([O:43][CH3:44])=[C:39]([O:41][CH3:42])[CH:40]=2)=[CH:31][CH:30]=[C:29]([O:47][CH2:48][CH:49]=[CH2:50])[C:28]=1[OH:51]
Reactant: C=CCOc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCOc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O)c1O
Temperature: 25 °C

Procedure:
Tetrabutylammonium fluoride (0.24 mL, 0.24 mmol, 1M in THF) was added to a solution of 1,2-di(t-butyldimethylsilyloxy)-3-allyloxy-6-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]-benzene (69 mg, 0.120 mmol) and glacial acetic acid (14 μL, 0.24 mmol) in THF 4 mL at 0° C. The reaction mixture was allowed to warm to rt overnight, then cooled to 0° C. and water was added. The reaction mixture was extracted with t-BuOMe (3×) and the organic phase was dried (Na2SO4) and evaporated to dryness. Purification by column chromatography (SiO2 3:7 EtOAc:cyclohexane) gave ZSB-84 (36 mg, 84%) as an 96:4 mixture of Z:E isomers:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19])[C:7]([OH:9])=O.[NH2:20][C:21](=[N:39]O)[C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][O:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:39]=[C:21]([C:22]3[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=3)[CH2:25][O:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[N:20]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19]
Reactant: CC(C)(C)OC(=O)CCOCc1cccc(C(N)=NO)c1
Reactant: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Product: COCc1cc(-c2nc(-c3cccc(COCCC(=O)OC(C)(C)C)c3)no2)ccc1N1CCCCC1C

Procedure:
Tert-butyl 3-[(3-{5-[3-(methoxymethyl)-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}benzyl)oxy]propanoate was prepared following the general procedure 3 starting from Intermediate 2 and Intermediate 20. It was hydrolyzed following general procedure 8 to afford the title compound as a pale yellow powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.19 (m, 1H), 8.06 (m, 3H), 7.57 (m, 2H), 7.39 (m, 1H), 4.60 (s, 2H), 4.57 (m, 2H), 3.70 (t, J=6.2 Hz, 2H), 3.42 (s, 3H), 3.24 (m, 1H), 3.03 (m, 1H), 2.63 (m, 1H), 2.54 (t, J=6.2 Hz, 2H), 1.85-1.30 (m, 6H), 0.86 (d, J=6.1 Hz, 3H). LC/MS (Method B): 466.4 (M+H)+, 464.4 (M−H)−. HPLC (Method A) Rt 3.30 min (Purity: 98.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)cc1
Reaction time: 7 h
Yield: 103.5 %

Procedure:
Morpholine-4-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (128 mg) was dissolved in tetrahydrofuran (3 ml), and 20% palladium hydroxide on carbon (26.3 mg) was added at room temperature under a nitrogen atmosphere, followed by stirring under a hydrogen atmosphere for 7 hr. The atmosphere in the reaction vessel was replaced with nitrogen, and the catalyst was removed by filtration and washed with tetrahydrofuran. The solvent was removed under reduced pressure to provide the titled compound as a pale yellow solid (121 mg).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[NH2:22]O>C(O)C>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:20][N:22]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Yield: 65.3 %

Procedure:
A mixture of ethyl 2,4-dioxo-4-(4-(trifluoromethyl)phenyl)butanoate (6.89 g, 23.9 mmol) and hydroxylamine hydrochloride (2.0 g, 28.7 mmol) in ethanol (120 mL) was stirred at reflux overnight. The volatiles were removed in vacuo, and the residue purified by silica gel chromatography, eluting with dichloromethane to obtain the title compound (4.5 g, 15.6 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]=2[CH3:18])=[CH:5][CH:4]=1.[CH2:19](Br)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[C:12]3[N:13]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:21])[CH:14]=[CH:15][CH:16]=[C:11]3[C:10]=2[CH3:18])=[CH:5][CH:4]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1ccc(-c2[nH]c3ncccc3c2C)cc1
Product: COc1ccc(-c2nc3n(CC(=O)c4ccccc4)cccc-3c2C)cc1

Procedure:
The title compound was prepared from 2-(p-methoxyphenyl)-3-methyl-pyrrolo[2,3-b]pyridine and phenacylbromide on a 10 mmol scale according to the procedure described in example 8 yielding 4.02 g (92% ).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:8][CH2:9][CH:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.53 mL, 6.80 mmol) was added to a −20° C. solution of tert-butyl 4-hydroxycyclohexanecarboxylate (1.05 g, 5.25 mmol) and triethylamine (1.46 mL, 10.5 mmol) in dichloromethane (21 mL). The reaction was stirred for 2 hours, then saturated aqueous sodium bicarbonate was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 4-[(methylsulfonyl)oxy]cyclohexanecarboxylate. 1H NMR (500 MHz, CDCl3) δ 4.96-4.55 (m, 1H), 3.00 (s, 3H), 2.23-2.12 (m, 2H), 2.03-1.98 (m, 2H), 1.93-1.81 (m, 1H), 1.79-1.66 (m, 1H), 1.66-1.48 (m, 3H), 1.42 (s, 9H).