Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC[O:22]C(/N=N/C(OCC)=O)=O.C([O:34][C:35](=[O:53])[CH:36]([O:51][CH3:52])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]#[C:45][CH2:46][CH2:47][CH2:48][CH2:49][OH:50])=[CH:40][CH:39]=1)C.[C:54]1([C:60]2[CH:65]=[CH:64][C:63](O)=[CH:62][CH:61]=2)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[C:60]1([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:61]=[CH:62][C:63]([O:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][C:44]([C:41]2[CH:40]=[CH:39][C:38]([CH2:37][C@H:36]([O:51][CH3:52])[C:35]([OH:34])=[O:53])=[CH:43][CH:42]=2)=[O:22])=[CH:64][CH:65]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCCO)cc1)OC
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(C(=O)CCCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (0.474 g, 1.8 mmol) in 50 mL of dry THF was treated at 0° C. with diethylazodicarboxylate (1.8 mmol) and stirred for 20 min. A solution of 3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 49, Step A) (0.365 g, 1.2 mmol) and 4-phenylphenol (0.307 g, 1.8 mmol) in 10 mL of dry THF was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 10:1 to 3:1). Fractions with Rfs 0.48 and 0.45 (hexanes/ethyl acetate 2:1) corresponding to the coupled compound and starting phenol, respectively, were combined and concentrated. The mixture was dissolved in 5 mL of methanol and was treated with a mixture of 0–712 mg of mercury (II) oxide and 12 ml of 4% sulfuric acid in water. The solution was stirred at 55° C. for 3 hours, cooled to room temperature, diluted with saturated aqueous NaHCO3 (20 mL), and extracted with dichloromethane (4×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was dissolved in 6 mL of methanol and 2 mL of 1N NaOH and stirred for 2 hours. The methanol was evaporated under vacuum, and the aqueous solution was diluted with brine (6 mL) and washed with diethyl ether (3×15 mL). The aqueous layer was acidified with 1N HCl (pH 1–2) and extracted with ethyl acetate (3×15 mL). The combined extracts were dried (MgSO4) and concentrated to give the title compound. MS(ES) for C28H30O5[M+H]+: 447.2.
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[O:26]=O>>[OH:26][C:9]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:23]
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCCCC1
Reactant: O=O
Agent: [H-]
Agent: [Na+]
Product: O=C1N(N2CCCCC2)c2ccccc2C1(O)Cc1ccncc1
Yield: 25 %

Procedure:
1,3-dihydro-1-(1-piperidinyl)-3-(4-pyridinyl methyl)-2H-indol-2-one could be reacted with sodium hydride and oxygen as reported in Example 22. After column chromatography, the product was recrystallized from hexane-chloroform to give the product as a brown solid, m.p. 156°-158° C. in 25% yield. High Res. Mass Spec. Calcd. for C19H21N3O2 : 324.1712(M+H). Found: 324.1709.
Reaction SMILES: C(OC([N:8]1[CH2:44][CH2:43][C:11]2([O:15][C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=4)=[C:30]([CH3:42])[CH:29]=3)=[N:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:45]([OH:51])([C:47](F)(F)F)=O.C(OC(=O)C)(=O)C>C(Cl)Cl.N1C=CC=CC=1>[CH3:42][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:14]4[O:15][C:11]5([CH2:43][CH2:44][N:8]([C:45](=[O:51])[CH3:47])[CH2:9][CH2:10]5)[CH2:12][N:13]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][C:35]1[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NCC6(CCN(C(=O)OC(C)(C)C)CC6)O5)cc34)cc2C)cn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC2(CC1)CN=C(Nc1ccc3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(C)c4)c3c1)O2

Procedure:
1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diaza-spiro[4.5]dec-2-en-8-yl)-ethanone is prepared from 2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diazaspiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride followed by standard acetylation methods using acetic anhydride in a mixture of pyridine and methylene chloride. MS ESI (+) m/z 538 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 8.68 (s, 1H), 8.28 (d, 1H), 7.83 (d, 1H), 7.64 (s, 1H), 7.52 (d, 2H), 7.48 (d, 2H), 7.12 (m, 3H), 6.93 (d, 1H), 3.69 (m, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 2.14 (s, 3H), 2.02 (m, 2H), 1.78 (m, 2H), 1.30 (m, 2H), 0.87 (m, 2H).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([Mg]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:7]1([C:1]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([OH:6])[CH2:2][CH2:3][CH2:4][OH:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCO1
Solvent: C1CCOC1
Product: OCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
4-Butyrolactone (11.93 mL, 0.155 mol) was dissolved in anhydrous THF and cooled to 0° C. Phenylmagnesium bromide (3 M in ether, 112 mL) was added dropwise over 30 minutes to the reaction under N2. After the addition, the reaction was warmed to room temperature overnight. Additional phenylmagnesium bromide (3 M in ether, 103 mL) was added, and the reaction stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl (150 mL). Ether (200 mL) and 10% HCl (100 mL) were added. The organic layer was separated and washed with 10% HCl (100 mL), brine (100 mL), and then dried over MgSO4. The solution was filtered, concentrated, and the crude material chromatographed on silica gel eluting with 50% EtOAc/Hexanes to give 26.94 g (72%) of desired product as an off-white solid.
Reaction SMILES: [OH-:1].C([N+:6]([CH2:15]CCC)([CH2:11][CH2:12]CC)[CH2:7]CCC)CCC.[CH2:19]([OH:22])[CH2:20][OH:21]>O1CCOCC1>[CH3:15][N:6]([CH3:7])[C:11](=[O:1])[CH2:12][O:21][CH2:20][CH2:19][OH:22]
Reactant: OCCO
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: [OH-]
Solvent: C1COCCO1
Product: CN(C)C(=O)COCCO
Yield: 32.1 %

Procedure:
The process of Example 6 is carried out with the difference that instead of ethylene glycol, dioxane is used as solvent and that 1 g of tetrabutylammonium hydroxide are added to the reaction mixture. In this case, the yield is 4.73 g (32.1%) of the title compound having purity higher than 98% as determined by gas chromatography.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:22]([NH:24][CH3:25])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[F:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1)[C:22]([NH:24][CH3:25])=[O:23]
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 105 °C
Yield: 64.3 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (125 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-fluoro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (128.5 mg, 0.293 mmol, 64.2% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-2.03 (m, 3H) 2.09-2.25 (m, 1H) 2.50 (m, 4H) 2.75 (d, J=4.29 Hz, 3H) 2.96-3.14 (m, 4H) 3.35-3.45 (m, 3H) 3.53-3.65 (m, 1H) 3.93-4.05 (m, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.04 (t, J=8.59 Hz, 1H) 7.51-7.67 (m, 3H) 8.27-8.38 (m, 1H) 10.44 (s, 1H). [M+H] calc'd for C23H27FN6O2, 439; found, 439.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[C-:13]#[N:14].[Na+]>C(O)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:13]#[N:14]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccccc1C(F)(F)F
Yield: 93 %

Procedure:
To a solution of 2-(trifluoromethyl)benzyl bromide (1.50 g) in ethanol (15 mL) was added a solution of sodium cyanide (461 mg) in water (15 mL) at ambient temperature, and the mixture was heated for 3 hours under reflux . After evaporation of the organic solvent, the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give [2-(trifluoromethyl)phenyl]acetonitrile (1.08 g) as an oil.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>C(O)(=O)C>[N:11]1([C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[CH:1]=[N:25][N:24]=[N:23]1
Reactant: CC(C(=O)O)c1ccc(N)cc1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc(-n2cnnn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Triethyl orthoformate (5.29 ml, 31.8 mmol) and 2-(4-aminophenyl) propionic acid (3.26 g, 19.73 mmol) were suspended in acetic acid (50 ml) then added sodium azide (1.924 g, 29.6 mmol). The mixture was refluxed for 3 hours then let stirred at room temperature overnight. The reaction was poured into water (60 ml) and extracted with ethyl acetate (60 ml). The organic layer was separated and dried over MgSO4. The mixture was filtered and concentrated to yield 2-[4-(1H-tetrazol-1yl)phenyl]propanoic acid (4.2 g, 98%). LC-MS (IE, m/z): 219 [M+1]+.
Reaction SMILES: [CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][N:7]([C:10](=O)[C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O1CCOCC1>[CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][N:7]([C:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)=[S:30])[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(C(=S)N2CCC3(CC2)OCCO3)cc1
Yield: 42.2 %

Procedure:
A solution of 1-(4-cyanobenzoyl)-4-piperidone ethylene ketal (1.00 g, 3.68 mmol) and Lawesson's reagent (1.2 g, 2.9 mmol) in dioxane (20 ml) was heated to reflux for 1 h, cooled and evaporated. The residue was pre-absorbed on silica gel and purified by flash chromatography eluting with 25% ethyl acetate/hexane, increasing the gradient to 40% ethyl acetate/hexane, to afford the product as a yellow solid (353 mg), MS (+EI) 288 (M+), 1H NMR(CDCl3) 7.67 (2H, d, J 7 Hz), 7.36 (2H, d, J 7 Hz), 4.5-4.45 (2H, m), 4.06-3.98 (4H, m), 3.58 (2H, dd, J 6, 4.2 Hz), 1.94 (2H, t, J 6 Hz), 1.69 (2H, t, J 6 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1C(O)=O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:27])C(Cl)=O.CN(C)C=O.[N+:34]([C:37]1[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=1[NH2:39])([O-:36])=[O:35]>C(OCC)(=O)C.N1C=CC=CC=1>[N+:34]([C:37]1[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=1[NH:39][C:23](=[O:27])[C:20]1[CH:19]=[CH:15][C:14]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][CH:21]=1)([O-:36])=[O:35]
Reactant: O=C(CCOCc1ccccc1)Nc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(CCOCc1ccccc1)Nc1ccc(C(=O)Nc2ccccc2[N+](=O)[O-])cc1

Procedure:
N-(2'-Nitrophenyl)-4-(3-benzyloxypropanoylamino)-benzamide is prepared analogously to Example 1 using 12 g (40.1 mMole) 4 (3 benzyloxypropanoylamino)-benzoic acid, 6.6 g (0.13 mMole) oxalyl chloride, 9.7 g (0.13 mole) dimethylformamide, 2×4.5 g pyridine, 6.1 g (44.1 mMole) o-nitroaniline, and 280 mL dry ethyl acetate. The crude product is purified by column chromatography (silica gel; ethyl acetate/n hexane 1:5-1:1 v/v). Yield 3.5 g (21% of theory); m.p. 140° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)N3CCOCC3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid (570 mg, 2.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and the solution was mixed with 1,1-carbonyldiimidazole (320 mg, 2.0 mmol) and stirred at room temperature for 1 hour. The reaction solution was mixed with morpholine (170 mg, 2.0 mmol) and the stirring was continued for 14 hours. The solvent was removed by evaporation from the reaction solution under a reduced pressure, and the residue was mixed with ethyl acetate and washed with water, hydrochloric acid (1 N), sodium hydroxide aqueous solution (1 N) and saturated brine. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation under a reduced pressure to obtain 610 mg (1.9 mmol, 94% in yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[S:25][C:26]([CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[N:27][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1[C:24]1[S:25][C:26]([CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[N:27][N:28]=1
Reactant: CC1(C)CC(Cc2nnc(Br)s2)CC(C)(C)N1
Reactant: COc1cc(-n2cccn2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-n2cccn2)ccc1-c1nnc(CC2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C

Procedure:
To a stirred suspension of 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole [Intermediate 4] [39 mg, 0.128 mmol) and 2-bromo-5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-thiadiazole (34 mg, 0.107 mmol) in dioxane (1 mL) was added Pd(PPh3)4 (6 mg, 0.005 mmol), followed by a solution of Na2CO3 (34 mg, 0.32 mmol) in water (0.25 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (10 mL). The organic phase was separated and concentrated in vacuo to afford the crude product as a brown oily residue. The crude material was purified by UV directed preparative HPLC under acidic conditions (formic acid modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a slightly off-white solid 28.6 mg, 65% yield). LC-MS: Rt 0.88 min; MS m/z 412.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, J=2.53 Hz, 1H), 8.39 (d, J=8.59 Hz, 1H), 7.83 (d, J=1.01 Hz, 1H), 7.73 (d, J=1.52 Hz, 1H), 7.67 (dd, J=8.59, 2.02 Hz, 1H), 6.64-6.61 (m, 1H), 4.11 (s, 3H), 3.01 (d, J=6.57 Hz, 2H), 2.17-2.28 (m, 1H), 1.53 (dd, J=12.63, 2.53 Hz, 2H), 1.09 (s, 6H), 1.00 (s, 6H), 0.86 (t, J=12.38 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][Li:8])=[O:6].N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C=O)C>[Si:18]([O:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][Li:8])=[O:6])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [Li]OC(=O)CCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: [Li]OC(=O)CCCO[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a suspension of 4-hydroxybutanoyloxylithium (5.17 g, 41.03 mmol) and 1H-imidazole (4.19 g, 61.55 mmol) in DMF (20 mL) was added TBSCl (7.42 g, 49.04 mmol) in portions at r.t. The reaction mixture was then stirred overnight. The reaction solution was poured into water and extracted with ethyl acetate three times. The organic phase separated and washed with water twice, brine and dried with anhydrous Na2SO4. It was then concentrated to give the title compound as colorless oil (8.0 g, 89%). [M+H] Calc'd for C10H21LiO3Si, 225; Found, 225.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:28])=[CH:20][CH:21]=1)=[O:26])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCC(=O)N(C)CCO
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: CCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccc(C)cc1

Procedure:
N-methyl-N-(2-p-toluoyloxyetyl)lauramide was prepared by the procedure of example 1 from 26 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)lauramide and 15 gms. (0.1 mole) of p-toluoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([N:16]([C:30]([C@H:32]3[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[C@H:17]3[CH2:22][CH2:21][C@H:20]([O:23]C4CCCCO4)[CH2:19][CH2:18]3)[CH:9]=2)=[CH:3]1>C(O)(=O)C.C1COCC1.O>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([N:16]([C@H:17]3[CH2:18][CH2:19][C@H:20]([OH:23])[CH2:21][CH2:22]3)[C:30]([C@H:32]3[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[CH:9]=2)=[CH:3]1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CC(O)CCC3)sc2C(=O)O)[C@H]2CC[C@H](OC3CCCCO3)CC2)CC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CC(O)CCC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1

Procedure:
A solution of 5-(3-hydroxy-cyclohex-1-enyl)-3-{(trans-4-methyl-cyclohexane-carbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid (4 mg, 0.007 mmol) in acetic acid:THF:H2O (4:2:1) (0.7 mL) was stirred at 45° C. for 3.5 h. The mixture was evaporated to dryness and triturated with CHCl3 and hexane yielding 5-(3-hydroxy-cyclohex-1-enyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (1.6 mg, 47%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1>>[CH3:18][CH:19]1[NH:20][CH2:21][CH2:22][N:23]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:24]1
Reactant: Clc1nccnc1OCCOc1ccccc1
Reactant: CC1CNCCN1
Product: CC1CN(c2nccnc2OCCOc2ccccc2)CCN1

Procedure:
The title compound was prepared according to the procedure described In Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.54 mmol; from Example 1, Step 1) and 2-methylpiperazine (250 mg, 2.5 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out This gave 138 mg (73%) of the title product. Anal. (C17H22N4O2) C, H, N.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[CH2:17]([O:19][C:20](=[O:34])[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:24](=[O:32])[C:23]1=[O:33])[CH3:18].O1C2C=CC(O)=CC=2OC1.[O:45]1[C:49]2[CH:50]=[C:51]([OH:54])[CH:52]=[CH:53][C:48]=2[CH2:47][CH2:46]1>>[CH2:17]([O:19][C:20](=[O:34])[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:24]([OH:32])([C:52]2[C:51]([OH:54])=[CH:50][C:49]3[O:45][CH2:46][CH2:47][C:48]=3[CH:53]=2)[C:23]1=[O:33])[CH3:18]
Reactant: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccc2c(c1)OCC2
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl(4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compound was obtained (68%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.66 (br, 1H), 7.31-7.19 (m, 3H), 6.73 (dd, 1H), 6.49-6.45 (m, 1H), 5.09-4.36 (m, 4H), 4.20 (q, 2H), 3.14-2.90 (m, 2H), 1.23 (t, 3H); MS (ES+) m/z 432.2 (M−17).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[OH:11][CH:12]1[CH2:15][NH:14][CH2:13]1.Br[CH2:17][C:18]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:19]=1[C:20]#[N:21]>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:18]([CH2:17][N:14]2[CH2:15][CH:12]([OH:11])[CH2:13]2)=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: OC1CNC1
Reactant: N#Cc1cc(Cl)ccc1CBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc(Cl)ccc1CN1CC(O)C1
Yield: 82.3 %

Procedure:
DIEA (3.57 mL, 20.50 mmol) was added to a stirred mixture of 3-hydroxyazetidine hydrochloride (1.00 g, 9.11 mmol) and 2-bromomethyl-5-chlorobenzonitrile (2.10 g, 9.11 mmol) in CH2Cl2 (75 mL). After 16 h the reaction mixture was concentrated and the residue was partitioned between ether and 1N HCl. The aqueous layer was washed with ether, made neutral with NaHCO3, saturated with NaCl and extracted into CH2Cl2. The organic layer was dried (Na2SO4) and evaporated to give 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzonitrile (1.67 g) as a gum: 1H NMR (CDCl3, 400 MHz) δ 3.03 (m, 2H), 3.68 (m, 2H), 4.49 (t, J=6.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.53 (d,d, J=2.2, 6.2 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H).