Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7].C(N)CCC.[C:21]([C:25]#[CH:26])([CH3:24])([CH3:23])[CH3:22]>[Cu]I.O1CCCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[C:25]#[C:26]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7]
Reactant: C#CC(C)(C)C
Reactant: CCN(C/C=C/Cl)Cc1cccc(O)c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To 30 ml of tetrahydrofuran were added 4.51 g (20 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-hydroxybenzylamine, 190.5 mg (1 mmol) of copper (I) iodide and 324 mg (0.28 mmol) of tetrakis (triphenylphosphine)palladium, and further, 3.95 ml (40 mmol) of n butylamine and 2.94 ml (24 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=7/3). The desired fractions were put together and concentrated under reduced pressure to oil. The oil was cooled to crystallize and the crystals were suspended in cooled n-hexane. The crystals were collected by filtration and then dried to obtain 4.20 g (yield: 77%) of the above identified compound as slightly yellow crystalline powder.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:19][O:20][CH3:21])=[C:8]([C:22](OCC)=[O:23])[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:19][O:20][CH3:21])=[C:8]([CH2:22][OH:23])[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cnc(C(=O)OCC)c1-c1ccc(OC)cc1OCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCn1cnc(CO)c1-c1ccc(OC)cc1OCOC
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of ethyl 1-n-butyl-5-(2-methoxymethoxy-4-methoxyphenyl)-1H-imidazole-4-carboxylate (0.06 g, 0.17 mmol) in THF (5 mL) was added LAH (0.20 mL) at room temperature. The mixture was stirred for 2 h. After an aqueous work up, extracting with ethyl acetate (3×20 mL), the combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ethyl acetate/hexane) of the residue afforded the title compound as an oil (0.05 g, 96%). 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.19 (d, 1H), 6.85 (d, 1H), 6.65 (dd, 1H), 5.05 (d, 2H), 4.41 (dd, 2H), 3.85 (s, 3H) 3.80 (t, 2H), 3.45 (s, 3H) 3.23 (b, 1H), 1.55 (quintet, 2H), 1.25 (quintet, 2H), 0.83 (t, 3H).
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH3:5][C:6]([CH3:11])([CH2:9]O)[CH2:7][OH:8].Cl>>[CH:3]([CH:1]1[O:8][CH2:7][C:6]([CH3:11])([CH3:9])[CH2:5][O:2]1)=[CH2:4]
Reactant: CC(C)(CO)CO
Reactant: C=CC=O
Agent: Cl
Product: C=CC1OCC(C)(C)CO1
Temperature: 30 °C

Procedure:
2-Ethenyl-5,5-dimethyl-1,3-dioxane was prepared by adding 15.4 g. of acrolein (9.275 mole) and 26.0 g. (0.25 mole) 2,2-dimethyl-1,3-propanediol to a 100 ml. round bottom flask equipped with magnetic stir bar and thermocouple. Hydrochloric acid (0.1 ml. 37%) was added to the reaction and the temperature dropped to about 5° C. After all of the diol was dissolved, the reaction exothermed to approximately 45° C. After the reaction was cooled to 30° C., the mixture was placed in a separatory funnel. The lower aqueous layer was removed and the organic layer simultaneously neutralized and dried with excess sodium carbonate (anhydrous). The material was filtered and distilled (Bp 40° C. at 10 mm/Hg) to give a water clear liquid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[C:25]#[N:26])[C:15]([O:27][CH3:28])=[CH:14][N:13]=2)=[N:6]1.S(=O)(=O)(O)[OH:34].[OH-].[Na+]>>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[C:25]([NH2:26])=[O:34])[C:15]([O:27][CH3:28])=[CH:14][N:13]=2)=[N:6]1
Reactant: COc1cnc(-c2cc(OC)n(Cc3ccccc3F)n2)nc1Nc1ccncc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cnc(-c2cc(OC)n(Cc3ccccc3F)n2)nc1Nc1ccncc1C(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 126 mg of 4-({2-[1-(2-fluorobenzyl)-5-methoxy-1H-pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine-3-carbonitrile 2-1-7 (0.294 mmol, 1.0 eq.) were given at rt with caution 0.446 mL of sulfuric acid. The mixture was stirred for 24 hours at rt. Then the reaction mixture was dropped into ice water and set with aqueous 2 M sodium hydroxide solution to an alkaline pH. This aqueous layer was extracted three times with DCM/propan-2-ol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crystallization from methanol provided 37.0 mg (0.08 mmol, 28%) of analytically pure target compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([N+:33]([O-:35])=[O:34])[CH:26]=2)[CH:20]=1.O>O1CCCC1>[CH2:3]([O:5][C:6](=[O:16])[CH:7]=[CH:29][C:28]1[CH:31]=[CH:32][C:25]([C:21]2[CH:20]=[C:19]([O:18][CH3:17])[CH:24]=[CH:23][N:22]=2)=[CH:26][C:27]=1[N+:33]([O-:35])=[O:34])[CH3:4]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(-c2cc(OC)ccn2)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 101 mg) in tetrahydrofuran (10 ml) was added a solution of diethylphosphonoacetic acid ethyl ester (0.535 ml) dropwise at 0° C., and the mixture was stirred at 5° C. for 30 minutes. Then to the resultant mixture was added a solution of 4-(4-methoxypyridin-2-yl)-2-nitrobenzaldehyde (543 mg) in tetrahydrofuran (10 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried to give 4-(4-methoxypyridin-2-yl)-2-nitrocinnamic acid ethyl ester (557 mg).
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:10]=[CH:11][CH:12]=1)=O.NC1[C:25]([C:26]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)=[O:27])=[CH:24][NH:23][N:22]=1>C(O)(=O)C>[O:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:26]([C:25]1[CH:24]=[N:23][N:22]2[C:5]([C:7]3[CH:8]=[C:9]([CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:19]=12)=[O:27]
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Reactant: COC(=O)NCc1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: COC(=O)NCc1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1
Yield: 77.1 %

Procedure:
A reaction mixture comprising 2.62 g of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]methylcarbamic acid, methyl ester, 1.77 g of 3-amino-4-furoylpyrazole and 100 ml of glacial acetic acid was reacted as described in Example 29, giving 2.90 g of the desired product, mp 152°-154° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)=[CH:6][CH:5]=1)(O)=[O:2].C(=O)([O-])O.[NH4+:26].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.Cl>CN(C)C=O.N1C=CC=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)=[CH:6][CH:5]=1)(=[O:2])[NH2:26]
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(CCc2coc3cccc(O)c23)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1ccc(CCc2coc3cccc(O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a mixture of 3-[2-(4-carboxyphenyl)ethyl]-4-hydroxybenzofuran (80 mg), ammonium hydrogen carbonate (90 mg) and pyridine (0.091 mL) in N,N-dimethylformamide (3 mL) was added ditert-butyl dicarbonate (0.25 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (5 mL). To the solution was added sodium methoxide (28% methanol solution, 0.1 mL), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was cooled to room temperature. To the mixture was added 1 mol/L hydrochloric acid (0.52 mL), and the resulting mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=30/1) and VARIAN BOND ELUT-SAX (eluent: methanol) successively to give the title compound (50 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=O)[C:11]([C:16]#[N:17])=[CH:12][NH:13]2)=[CH:8][CH:7]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:10]1[C:9]2[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[N:13]=[CH:12][C:11]=1[C:16]#[N:17]
Reactant: O=S(Cl)Cl
Reactant: COCCOc1ccc2c(=O)c(C#N)c[nH]c2c1
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(Cl)c(C#N)cnc2c1

Procedure:
Following the procedure of Reference Example 32, 7-(2-methoxyethoxy)-4-oxo-1,4-dihydroquinoline-3-carbonitrile (800 mg, 3.28 mmol), thionyl chloride and a catalytic amount of N,N-dimethylformamide provides 748 mg of 4-chloro-7-(2-methoxyethoxy)quinoline-3-carbonitrile as an off-white solid solid, mp 143-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH2:16][CH2:15][CH2:14]2)=O.C([SiH](CC)CC)C>C(#N)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=C(c1ccc2c(c1)CCCO2)c1cc(I)ccc1Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: Brc1ccc(I)cc1Cc1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a stirred solution of (2-bromo-5-iodo-phenyl)-chroman-6-yl-methanone (2.0 g, 4.51 mmol) in acetonitrile:dichloromethane (2:1 mixture, 9 mL) was added triethylsilane (2.52 mL, 15.78 mmol) and boron trifluoride diethyl etherate complex (1.11 mL, 9.02 mmol) at 0° C. After stirring overnight at room temperature, reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution. Volatiles were evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (2×20 mL). Ethyl acetate layer was washed with water, brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 6-(2-bromo-5-iodo-benzyl)-chroman (1.5 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.N[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>C(O)C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH:32]2[CH2:31][CH2:30][O:29][CH2:28][CH2:33]2)=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NC1CCCCO1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
5-(Benzoxazol-2-yl)-2-fluoronitrobenzene (see Working Example 15-2) (0.55 g, 2.13 mmol), triethylamine (0.26 g, 2.57 mmol), and aminotetrahydropyran (0.24 g, 2.34 mmol) were added to ethanol (10 mL), and this reaction mixture liquid was heated to reflux with stirring for 2 hours. The reaction mixture was cooled to room temperature and was concentrated under reduced pressure, and 0.1N aqueous hydrochloric acid solution (50 mL) was added to the residue obtained, this was successively extracted with ethyl acetate (approx. 50 mL, 4 times), washed with water (30 mL), and dried over anhydrous sodium sulfate, and the solvent was distilled off at reduced pressure. The residue obtained was purified by silica gel column chromatography to yield the title compound (440 mg, 60.9% yield) as light brown crystals.
Reaction SMILES: [CH:1]1([CH:4]2[S:9][CH2:8][CH2:7][NH:6][CH2:5]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[CH:23][C:24]([C:28]#[N:29])=[N:25]2)=[CH:20][CH:19]=1>CC#N.CCOC(C)=O>[CH:1]1([CH:4]2[CH2:5][N:6]([CH2:17][C:18]3[CH:27]=[C:26]4[C:21]([C:22]([C:30]5[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=5)=[CH:23][C:24]([C:28]#[N:29])=[N:25]4)=[CH:20][CH:19]=3)[CH2:7][CH2:8][S:9]2)[CH2:3][CH2:2]1
Reactant: C1CSC(C2CC2)CN1
Reactant: Cn1cc(-c2cc(C#N)nc3cc(CBr)ccc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(C#N)nc3cc(CN4CCSC(C5CC5)C4)ccc23)cn1
Temperature: 60 °C
Yield: 45.2 %

Procedure:
To a solution of crude 2-cyclopropylthiomorpholine (4-14, 100 mg, 0.698 mmol) in CH3CN (3 ml) was added K2CO3 (289 mg, 2.094 mmol) then 7-(bromomethyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile (251 mg, 0.768 mmol) all at once as solid. The resulting mixture was heated to 60° C. overnight. The mixture was cooled to rt, diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. The crude product was subjected to silica gel chromatography (25 g, 0-100% EtOAc/hexanes, 10 minute gradient) to afford 7-((2-Cyclopropylthiomorpholino)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile (4-15, 123 mg, 45%) as a light orange foam. 1H NMR (399 MHz, CDCl3): δ 8.19 (d, J=8.7 Hz, 1 μl); 8.09 (s, 1 μl); 7.85 (s, 1 μl); 7.77 (s, 1H); 7.71 (d, J=8.8 Hz, 1H); 7.61 (s, 1H); 4.07 (s, 3H); 3.85-3.70 (m, 2 μl); 3.16 (dd, J=11.6, 2.7 Hz, 1H); 3.01 (d, J=11.6 Hz, 1H); 2.83 (ddd, J=13.4, 10.6, 2.7 Hz, 1H); 2.61-2.53 (m, 1H); 2.45-2.34 (m, 2H); 2.20-2.13 (m, 1H); 0.88-0.80 (m, 1H); 0.61-0.44 (m, 2H); 0.36-0.27 (m, 1H); 0.23-0.16 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17].[CH:18](OC(=O)C)=[O:19]>ClCCl.C(OCC)(=O)C>[CH:18]([NH:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17])=[O:19]
Reactant: CC(=O)OC=O
Reactant: C=CC[C@@H]1[C@@H](N)C(=O)N1C(C(=O)OC)=C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CC[C@@H]1[C@@H](NC=O)C(=O)N1C(C(=O)OC)=C(C)C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (500 mg) in dichloromethane (5 ml) was added acetic formic anhydride (0.34 ml) at 0°. After stirring at the same temperature for one hour, the mixture was diluted with ethyl acetate (35 ml) and washed with a dilute aqueous sodium bicarbonate. The aqueous layer was saturated with sodium chloride and extracted with dichloromethane. The extracts were combined, washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (2.5 g) eluting with 10-30% acetone in dichloromethane afforded methyl 2-[(3R,4R)-3-formamido-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (485 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1>CN(C=O)C>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][N:11]1[C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:13]=[C:12]1[CH3:14]
Reactant: COc1cccc(CBr)c1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(C)cc3c2ccc2nnc(C)n23)c1
Reaction time: 0.17 h

Procedure:
To a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50.0 mg, 0.268 mmol, from Example 2, Step 5) in DMF (4 mL) was added sodium hydride (0.032 g, 0.81 mmol, 60% in mineral oil). After stirring for 10 minutes, 1-(bromomethyl)-3-methoxybenzene (0.038 mL, 0.27 mmol, Aldrich) was added and the reaction was stirred for 45 minutes and was quenched by the addition of water and diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (0.04 g, 50%).
Reaction SMILES: [F:1][CH2:2][C:3](OCC)=[O:4].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl>C(Cl)Cl>[F:1][CH2:2][C:3]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:4]
Reactant: CCOC(=O)CF
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Product: O=C(CF)N1CCOCC1
Temperature: 70 °C
Yield: 74.4 %

Procedure:
A mixture of ethyl fluoroacetate (50 g, 472 mmol) and morpholine (82 g, 944 mmol) was heated at 70° C. for 20 h. After cooling to ambient temperature, the mixture was added to a stirred mixture of 2 N HCl (240 mL) and methylene chloride (200 mL) over 20 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (200 mL×2). The combined organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to give 51.7 g (74.6%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 4.96 (d, J=47.2 Hz, 2H), 3.70 (bs, 4H), 3.64 (bs, 2H), 3.47 (bs, 2H).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH3:22])[C:18](OC)=[O:19])[N:11]=1)([CH3:3])[CH3:2].O.[NH2:24][NH2:25]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH3:22])[C:18]([NH:24][NH2:25])=[O:19])[N:11]=1)([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)[C@H](C)Nc1nccc(N2C(=O)OC[C@@H]2C(C)C)n1
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C(=O)NN)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of (S)-methyl 2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanoate (120 mg, 0.39 mmol in 5 ml of MeOH) was added 99% hydrazine hydrate, the reaction solution was stirred at room temperature overnight (24 hours), the solvent was removed to yield the desired product (99 mg) in 78% yield, and was used for next step without purification. LCMS m/z 309.1 (M+H)+ RT=1.25 min.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([SH:7])([CH3:6])[CH3:5].Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH2:18][CH3:19])=[C:11]([CH3:20])[N:10]=1>CN(C)C=O>[C:4]([S:7][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH2:18][CH3:19])=[C:11]([CH3:20])[N:10]=1)([CH3:6])([CH3:5])[CH3:3]
Reactant: CC(C)(C)S
Reactant: CCc1cc([N+](=O)[O-])c(Cl)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc([N+](=O)[O-])c(SC(C)(C)C)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.2 %

Procedure:
To a suspension of sodium hydride (0.23 g, 9.8 mmol) in dimethylformamide (DMF, 20 mL) under an atmosphere of nitrogen, 2-methyl-2-propanethiol (1 mL, 8 mmol) was added. After stirring at room temperature for 15 minutes, a clear solution was obtained. Then a solution of 2-chloro-5-ethyl-6-methyl-3-nitropyridine (1.5 g, 7.5 mmol) in DMF (2 mL) was added, and the reacting mixture turned dark green to black in color. After addition was completed, the mixture was stirred for an additional 15 minutes, and then concentrated under reduced pressure (0.1 torr). The residue was subjected to column chromatography on silica gel, eluted with 60% chloroform in hexane. Collection and concentration of appropriate fractions yielded 0.5 g (26%) of the corresponding 2-tert-butylthiopyridine as a bright yellow solid.
Reaction SMILES: [C:1]([N:8]1[C@@H:13]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:22])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>[Pd].C(O)C>[C:1]([N:8]1[C@@H:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:22])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@H]1CCC[C@H](C=Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CCC[C@H](CCc2ccccc2)N1C(=O)OC(C)(C)C

Procedure:
A solution of trans-N-Boc-2-methyl-6-(2-phenylethenyl)piperidine (3.8, 12.54 mmol) in 6 m/L of ethanol was shaken under 58 psi of H2 pressure over 0.70 g Pd/C catalyst overnight, and then the mixture was filtered through Celite and concentrated to give 3.81 g (quantitative) of the product. No further purification was necessary. 1H NMR (250 MHz) 87.30-7.14 (m, 5H), 3.93-3.89 (m, 2H), 2.64-2.59 (t, 2H), 1.98-1.20 (m, 20H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[N:3]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[N:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1ccnc1-c1cccc(F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A mixture of 2-Fluoro-6-(1H-imidazol-2-yl)pyridine (410 mg; 2.51 mmol), tert-butyl bromoacetate (539 mg; 2.76 mmol), potassium carbonate (520 mg; 3.77 mmol), and N,N-dimethylformamide (20 mL) is stirred at room temperature for 16 h. Water (60 mL) is added and the mixture extracted with ethyl acetate (3×70 mL). The organic extracts are washed with water (3×40 mL) and brine (1×40 mL), dried (MgSO4), and concentrated to give [2-(6-Fluoropyridin-2-yl)-imidazol-1-yl]acetic acid tert-butyl ester as an orange oil (630 mg). 1H NMR (CDCl3) δ 8.12 (dd, 1H), 7.82 (q, 1H), 7.16 (s, 1H), 6.98 (s, 1H), 6.81 (dd, 1H), 5.14 (s, 2H), 1.44s, (9H), LCMS: 276.1 (M−).
Reaction SMILES: [CH:1]1([NH:5][CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:17](C)=O.[Na+]>C1COCC1>[CH:1]1([N:5]([CH3:17])[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)/C=C/CNC1CCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CN(C)C1CCC1
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of (E)-methyl 4-(cyclobutylamino)but-2-enoate (19) (1.7 g, 10 mmol) in THF (30 mL) was added HCHO solution (3 g, 40 mmol, 40% solution in water). The resulting mixture was stirred for 30 min before introducing NaBH(OAc)3 (3.18 g, 15 mmol). Stirring was continued at RT overnight. After quenching with sat. aq. NaHCO3 solution, the reaction mixture was extracted with EA (3×). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (0-5% methanol in DCM) to provide (E)-methyl 4-(cyclobutyl(methyl)amino)but-2-enoate (20) (1.47 g, 80%) as an oil. LC-MS (ESI): m/z (M+1) 184.3.