Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.O.[OH-].[Li+].O1CCOCC1>O>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: COC(=O)c1cc(Cl)nn1-c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)nn1-c1cccnc1

Procedure:
In step c of Scheme 2, methyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (6d) is saponified in the presence of an inorganic base, preferably metal hydroxides or their hydrates such as lithium hydroxide hydrate (LiOH.H2O) in water and a polar solvent such as dioxane at temperatures from about 0° C. to about 30° C. to yield 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (6e). Alternatively, this process can also be accomplished by hydrolysis by exposing methyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (6d) to a concentrated acid such as hydrochloric acid in water at temperatures from about 30° C. to about 100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].C(N(CC)CC)C.[C:23](Cl)(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[OH-].[K+].Cl>O1CCCC1.O.CO>[C:23]([NH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8])(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)cc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Dimethyl 5-aminoisophthalate (Aldrich, 3.28 g, 15.7 mmol) and triethyl amine (3.4 mL, 24.7 mmol) were dissolved in dry tetrahydrofuran (90 mL) under inert atmosphere and cooled to 0° C. for at least 30 min. A solution of palmitoyl chloride (5 mL, 16.5 mmol) in THF (25 mL) was then added slowly, dropwise. The reaction was then allowed to warm slowly to room temperature and stirred for at least 1 h before deionized water (10 mL) was added and the tetrahydrofuran was removed by rotary evaporation. The crude residue was then suspended in deionized water (50 mL), filtered, washed with deionized water, and dried to give a white solid. The crude solid was then dissolved in refluxing methanol (200 mL). Potassium hydroxide (˜85%, 5.76 g, 0.102 mol) and deionized water (50 mL) were then added. After 1 h, the reaction was cooled to room temperature to give a cloudy white suspension. 5M HCl (25 mL) was added until the pH of the slurry was acidic, and the solid was filtered, washed with deionized water, and dried in vacuo to give a white solid (6.45 g, 98%). The product was identified by 1H and 13C NMR spectroscopy and ESI-MS and was of satisfactory purity. The product was believed to be of the formula
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: N#CCCCCCCl
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCC#N)ccc(C(C)=O)c1O

Procedure:
A solution of 44.4 g. of 2,4-dihydroxy-3-propylacetophenone, 42.2 g. of 6-chlorocapronitrile, 33.2 g. of potassium carbonate and 4.0 g. of potassium iodide in one liter of methyl ethyl ketone was allowed to reflux for three days. The reaction mixture was filtered and the filtrate was evaporated in vacuo. Chromatography of the residue over silica gel (0-30% ethyl acetate gradient in hexane) gave 53.6 g. of the title product as an oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.Cl.Cl.[CH3:28][N:29]1[C:33]([CH3:34])=[C:32]([NH2:35])[CH:31]=[N:30]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)([O-])C.[Na+]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:35][C:32]3[CH:31]=[N:30][N:29]([CH3:28])[C:33]=3[CH3:34])[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1c(N)cnn1C
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cnn1C
Temperature: 140 °C
Yield: 28 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 mol), 1,5-dimethyl-1H-pyrazol-4-amine dihydrochloride (96.9 mg, 526 mol), BINAP (10.9 mg, 17.5 mol), palladium (II) acetate (19.7 mg, 87.7 mol) and sodium tert-butoxide (118 mg, 1.23 mmol) in DMF (1 mL) and toluene (500 L) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (50-100% ethyl acetate in hexanes) gave N-tert-butyl-2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 98.3 mol, 28%) as a yellow gum. (EI/CI) m/z: 458.3 [M+H].
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6]C)=[O:5].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li+].[OH-]>C(Cl)Cl.O>[CH3:9][N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2](=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(=O)Cl
Reactant: CNc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of methyl 3-chloro-3-oxopropanoate (1 mL, 9.32 mmol) and N-methyl aniline (1.01 mL, 9.32 mmol) in DCM (18.6 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue (N-methyl-N-phenyl-malonamic acid methyl ester, 2.55 g) was dissolved in THF (9 mL). A solution of LiOH×H2O (0.7 g, 18.64 mmol) in water (9 mL) was added and the mixture stirred for 1 h at room temperature. The THF was removed under reduced pressure and the remaining aqueous solution was acidified with 1N HCl (until pH˜3) then extracted with EtOAc. The organic phase was concentrated under reduced pressure to afford the acid 31 (1.67 g, 93% yield) as a brown foam. MS (m/z): 194.0 (M+H).
Reaction SMILES: CN(C)CCN(C)C.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([Li])CCC.CON(C)[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C1CCCCC1>[SH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:31]
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Sc1ccccc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: O=C(c1ccccc1)c1ccccc1S
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a solution of N,N,N',N'-tetramethylethylene diamine (4.4 g, 0.038 mol) and thiophenol (2 g, 0.018 mol) in cyclohexane (40 mL) was added dropwise n-butyllithium (24 mL, 0.038 mol) at room temperature. The suspension was stirred under nitrogen for 16 hours, followed by the dropwise addition of N-methoxy-N-methylbenzamide (3.3 g, 0.019 mol). After stirring for 20 minutes, the reaction mixture was added to cold aqueous HCl (1N). The product was partitioned between ethyl acetate and the acidic solution. The layers were separated and the organic portion was washed with brine, dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The liquid obtained was purified using silica gel chromatography (75% hexane/25% ethyl acetate) to give 2.3 g of the title compound a as a viscous yellow liquid.
Reaction SMILES: [NH2:1][C:2]([CH3:39])([CH3:38])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[Cl:40][CH:41]([Cl:45])[C:42](Cl)=[O:43].CCN(C(C)C)C(C)C>>[Cl:40][CH:41]([Cl:45])[C:42]([NH:1][C:2]([CH3:39])([CH3:38])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])=[O:43]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(C)N)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(C)NC(=O)C(Cl)Cl)CC1
Yield: 48.4 %

Procedure:
2,2-Dichloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-acetamide was obtained from treating 2-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.610 g, 0.97 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.510 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, 2,2-Dichloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-acetamide (0.028 g, 48%) as an oil. ES-LCMS m/z 642 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:5]([N:28]2[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[NH:30][C:29]2=[O:36])[O:4]1.N1C(C)=CC=CC=1C.[C:45]([S:49][S:50][CH2:51][CH:52]([NH:66][C:67](=[O:73])[O:68][CH2:69][CH:70]([CH3:72])[CH3:71])[C:53]([NH:55][CH:56]1[CH2:61][CH2:60][N:59]([P:62](Cl)([Cl:64])=[O:63])[CH2:58][CH2:57]1)=[O:54])([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:45]([S:49][S:50][CH2:51][CH:52]([NH:66][C:67](=[O:73])[O:68][CH2:69][CH:70]([CH3:71])[CH3:72])[C:53]([NH:55][CH:56]1[CH2:57][CH2:58][N:59]([P:62]([Cl:64])([O:1][CH2:2][C@H:3]2[O:4][C@@H:5]([N:28]3[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[NH:30][C:29]3=[O:36])[CH2:6][N:7]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:8]2)=[O:63])[CH2:60][CH2:61]1)=[O:54])([CH3:48])([CH3:47])[CH3:46]
Reactant: Cc1cn([C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)NC1CCN(P(=O)(Cl)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1cn([C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](COP(=O)(Cl)N3CCC(NC(=O)C(CSSC(C)(C)C)NC(=O)OCC(C)C)CC3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 1-((2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (moT(Tr)) (5.576 g, 10.98 mmol) in DCM (100 ml) at 0° C., was added lutidine (1.92 ml, 16.47 mmol) and DMAP (669 mg, 5.5 mmol), followed by the addition of the compound from Example 62 (6.13 g, 12.08 mmol). The reaction was left stirring at RT for 18 h. The title compound was obtained after ISCO purification (50% EtAc/Hexane).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:7][N:8]=1.[CH2:14]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)/[CH:15]=[C:16](/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])\[CH3:17].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:14]([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:7][N:8]=2)=[O:30])=[CH:32][CH:33]=1)/[CH:15]=[C:16](/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])\[CH3:17]
Reactant: CC(C)CSc1nnc(N)s1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2nnc(SCC(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
Sodium hydride (0.4 g) and 2-amino-5-isobutylthio-1,3,4-thiadiazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.6 g) and carbonyldiimidazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.9 g of the aimed compound.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:28]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:36][CH2:37][OH:38]>>[CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:28]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH2:36][CH2:37][OH:38])[CH2:24][CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 45.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mL, 0.43 mmol) and 2-bromo ethanol (37 mg, 0.52 mmol) to give 7-cyclopentyl-2-{5-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 48%). MS (ESI) m/z 478.3 (M+H)|
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([NH:9][C:10]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[CH:7][CH:6]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[O:11])=[CH:18][CH:19]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Nc1ccc(OCCO)cc1)C1CCOCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(NC(=O)C3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.4 %

Procedure:
4′-(2-Hydroxyethoxy)-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (5.7 g) solution in pyridine (50 ml) was added with p-toluenesulfonylchloride (4.92 g). The mixture was stirred for 6 hours at room temperature and allowed to stand for one night. The reaction mixture was concentrated under vacuum and dissolved into chloroform (50 ml). This solution was washed water (50 ml) two times. After concentrated under vacuum, the organic layer was added with methanol (50 ml) and mixed. Crystals formed were collected by filtration, washed with water and then dried under vacuum at 60° C. to obtain 4′-[2-(p-toluenesulfonyloxy)ethoxy]-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (5.17 g) as yellowish crystal.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([O:8][C:9](=[O:33])[N:10]([C:22]1[CH:27]=[C:26](Br)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:11][C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)[CH3:7]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:6]([O:8][C:9](=[O:33])[N:10]([C:22]1[CH:27]=[C:26]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:11][C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=1)[CH3:7]
Reactant: c1cocn1
Reactant: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(-c2ncco2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using oxazole (30 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg) and palladium bis(triphenylphosphine)dichloride (30 mg), giving the product (61 mg) as a yellow solid
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].C(OCC)C.C([Li])CCC.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>CCCCCC.O>[CH3:18][Si:17]([CH3:20])([CH3:19])[C:4]#[C:3][CH:2]([OH:5])[CH3:1]
Reactant: C[Si](C)(C)Cl
Reactant: C#CC(C)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CC(O)C#C[Si](C)(C)C
Temperature: 25 °C

Procedure:
A solution of 107.1 parts by weight of 3-butyne-2-ol (I) in 1000 parts by volume of dry ethyl ether is chilled to -50° C. (internal temperature) and 1390 parts by volume of 2.17 M n-butyl lithium in hexane is added over a 2 hour period. The internal temperature is allowed to reach 10° C. during the latter part of the addition to facilitate stirring. The mixture is then cooled again to -30° C. (internal) and 400 parts by volume of chlorotrimethylsilane in 200 parts by volume of ethyl ether is added over a 15 minute period. The mixture is allowed to warm slowly to room temperature overnight. After a brief period of reflux the mixture is again cooled to 25° C. and 100 parts by volume of water is added causing the internal temperature to rise to 37° C. After stirring for 1 hour, more water is added. The organic layer is separated and washed with 5% aqueous hydrochloric acid and water. The solution is dried over sodium sulfate, then concentrated to approximately 400 parts by volume. After adding 500 parts per volume of methanol and 200 parts per volume of 5% hydrochloric acid the solution is stirred at room temperature for one hour then diluted with 1000 parts per volume of water and extracted with ether. The ether extract is washed with water, dried over sodium sulfate and concentrated to afford 4-(trimethylsilyl)-3-butyn-2-ol (II) which distills at 49°-50° C./0.25 mm and has the following structural formula ##STR8##
Reaction SMILES: C(S)CS.C([O:12][C:13]1[CH:14]=[C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)[C:16]([CH:19]2[CH2:24][CH:23]=[CH:22][CH2:21][CH:20]2[NH:25][C:26](=[O:28])[CH3:27])=[CH:17][CH:18]=1)C1C=CC=CC=1>C(Cl)Cl>[F:35][C:31]1[CH:30]=[C:29]([C:15]2[C:16]([CH:19]3[CH2:24][CH:23]=[CH:22][CH2:21][CH:20]3[NH:25][C:26](=[O:28])[CH3:27])=[CH:17][CH:18]=[C:13]([OH:12])[CH:14]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)NC1CC=CCC1c1ccc(OCc2ccccc2)cc1-c1cccc(F)c1
Agent: SCCS
Solvent: ClCCl
Product: CC(=O)NC1CC=CCC1c1ccc(O)cc1-c1cccc(F)c1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
1,2-Ethanedithiol (0.22 mL, 2.66 mmol) and BF3OEt2 (0.176 mL, 1.4 mmol) were added to benzyl ether 18a (64 mg, 0.14 mmol) in DCM (1.8 mL). After 8 h, reaction mixture was concentrated and purified by column chromatography (SiO2, 10:100, MeOH:DCM) to afford phenol 19a as an amorphous solid (45 mg, 0.12 mmol, 86%)1H NMR (500 MHz, CDCl3) δ 8.98 (s, 1H), 7.40-7.34 (q, J=7.1, 6.2 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.10-7.01 (m, 2H), 6.96 (d, J=9.4 Hz, 1H), 6.84-6.79 (dd, J=8.5, 2.6 Hz, 1H), 6.68 (d, J=2.6 Hz, 1H), 5.73-5.52 (m, 2H), 4.51-4.38 (dt, J=9.9, 5.0 Hz, 1H), 2.88-2.77 (q, J=9.5, 7.9 Hz, 1H), 2.43 (d, J=17.3 Hz, 1H), 2.34 (m, 2H), 2.18 (s, 1H), 1.77 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.5, 163.6-161.7 (d, J=244.0 Hz), 155.2, 144.2 (d, J=7.6 Hz), 142.3, 130.8, 130.1 (d, J=8.4 Hz), 128.2, 127.0, 125.0 (d, J=2.2 Hz), 124.7, 116.5, 116.3 (d, J=20.3 Hz), 115.9, 114.2 (d, J=20.3 Hz, 49.6, 40.8, 35.5, 33.5, 23.2; HRMS (FAB) m/z: [M+Na+] for C21H25FNO2Na, 348.1376. found, 348.1379.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:11]2=[O:26])[S:5][C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:40][C:41](=[NH:43])[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[C:11]2=[O:26])[S:5][C:6]=1[C:7]1[O:8][N:43]=[C:41]([CH3:42])[N:40]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(-c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid (0.39 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added 1,1′-carbonyldiimidazole (0.24 g, 1.50 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes, and N-hydroxyacetamidine (0.08 g, 1.1 mmol) was added. The stirring was continued at ambient temperature for 6 hours, and another portion of N-hydroxyacetamidine (0.08 g, 1.1 mmol) was added. The reaction mixture was heated for 23 hours at 110° C. and cooled to ambient temperature, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, and filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in 15% yield (0.06 g): mp 163-164° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 4.55 (s, 2H), 4.15-4.09 (m, 2H), 3.51-3.45 (m, 2H), 2.68 (s, 3H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.8, 167.3, 160.5, 155.3, 154.5, 139.6, 128.5, 125.9, 125.8, 122.1, 109.0, 47.6, 42.1, 41.9, 17.5, 11.6; MS (ES+) m/z 424.1 (M+1).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[OH:12][CH:13]1[CH2:17][C:16](=[O:18])[CH:15]=[CH:14]1>O1CCCC1>[CH2:1]([C:16]1([OH:18])[CH2:17][CH:13]([OH:12])[CH:14]=[CH:15]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1C=CC(O)C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC1(O)C=CC(O)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
30 ml of tetrahydrofuran was put in a reaction tube and cooled to -78° C., and n-butyllithium (as a 1.6M hexane solution; 13.8 ml, 22.08 mmmoles) was added dropwise. Then a solution of 4-hydroxy-2-cyclopentenone (987 mg; 10.1 mmoles) in 20 ml of tetrahydrofuran was added dropwise over about 20 minutes. The reaction mixture was washed with 8 ml of tetrahydrofuran. After 60 minutes, 40 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was vigorously shaken. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 ml×6). The extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column (Merck silica gel 30 g; hexane:ethyl acetate=4:1) to obtain 1.55 g (yield about 90%) of 4-butylcyclopent-2-ene-1,4-diol.