Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:47]>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.O1CCOCC1>[NH2:47][C:33]1[C:32]([CH3:31])=[C:37]([C:2]2[N:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cn1cc(Br)nc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1=O
Reactant: Cc1c(N)cccc1B1OC(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
Product: Cc1c(N)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Temperature: 100 °C
Yield: 84.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 101d (9.23 g, 23.5 mmol), 1,4-dioxane (250 mL) and aqueous 0.71M sodium carbonate (50 mL, 35.5 mmol). After bubbling argon through the resulting solution for 15 minutes, 101f (6.58 g, 28.2 mmol) and tetrakis(triphenylphosphine)palladium (4.06 g, 3.51 mmol) were added and the reaction mixture then heated at 100° C. for 38 h. After this time the reaction was cooled to room temperature and partitioned between water (1 L) and methylene chloride (300 mL). The aqueous phase was separated and re-extracted with methylene chloride (2×300 mL). A white precipitate of the product present in the combined organic extracts was filtered and retained. The organic phase was extracted with 2N hydrochloric acid (2×200 mL) and then discarded. The acidic aqueous phase was made basic with 2N sodium hydroxide to pH 8-10 and extracted with methylene chloride (3×300 mL). The combined organic extracts were dried over sodium sulfate, filtered, then combined with the white precipitate (vide supra) and concentrated under reduced pressure. The resulting white solid was triturated with hot ethanol (100 mL), filtered, and washed with ethanol (2×40 mL). The filter cake was dissolved in chloroform, the solution was concentrated under reduced pressure and dried to a constant weight under high vacuum at 50° C. to afford an 84% yield of 101g (8.31 g) as an off-white solid: mp 274-275° C.; 1H NMR (500 MHz, CDCl3) δ 9.40 (s, 1H), 8.09 (d, 2H, J=8.5 Hz), 7.34 (d, 2H, J=8.5 Hz), 7.14 (s, 1H), 6.93 (t, 1H, J=7.5 Hz), 6.66 (d, 1H, J=7.5 Hz), 6.57 (d, 1H, J=7.5 Hz), 4.92 (bs, 2H), 3.58 (bs, 4H), 3.54 (s, 3H), 3.48 (bs, 4H), 2.09 (s, 3H); MS (ESI+) m/z 420 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]=1[NH2:23])(=[O:3])[CH3:2].[C:24](OCC)(OCC)(OCC)[CH3:25]>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:8]2[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]=2[N:23]=[C:24]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNc1c(C)c(C)nc(Oc2ccccc2)c1N
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OCCn1c(C)nc2c(Oc3ccccc3)nc(C)c(C)c21
Temperature: 95 °C
Yield: 97.4 %

Procedure:
1-[(3-Amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]eth-2-yl acetate (10.5 g, 33.29 mmol), toluene (100 mL), pyridine hydrochloride (0.077 g, 0.6659 mmol), and triethyl orthoacetate (9.1 mL, 49.94 mmol) were combined with stirring and the resulting mixture was heated to a gentle reflux (about 95° C.) for 1.5 hours. The reaction was complete. The resulting reaction mixture was concentrated under reduced pressure to white solids, which were dissolved in ethyl acetate. The ethyl acetate solution was washed with water (3×) and brine (2×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether, filtered off, and dried at 60° C. overnight to provide 11 g of pure product, which was carried on to the next step.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13].[F:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[C:19]([F:21])[CH:20]=1>>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=2)[N:11]=1
Reactant: Nn1nc(Cl)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(Cl)c2ccccc2c1=O

Procedure:
The product from Example 19A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.77 (s, 2H) 7.06-7.22 (m, 3H) 7.98-8.20 (m, 3H) 8.37 (d, J=7.32 Hz, 1H) 11.82 (s, 1H); MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7].Cl.[NH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O>[CH2:26]([O:25][C:23]([CH2:22][O:21][N:20]=[C:14]([C:12]1[N:13]=[C:9]([NH:8][CH:6]=[O:7])[S:10][CH:11]=1)[C:15]([OH:17])=[O:16])=[O:24])[CH3:27]
Reactant: CCOC(=O)CON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
Sodium bicarbonate (0.84 g.) was added to a suspension of 2-(2-formamidothiazol-4-yl)glyoxylic acid (2 g.) in water (120 ml.) to prepare a solution. Ethyl 2-aminooxyacetate hydrochloride (4.56 g.) was added to the solution and stirred at ambient temperature for 3 hours while adjusting to pH 6 with sodium bicarbonate. The resultant solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted with ethyl acetate three times. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 2-ethoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.44 g.), mp. 112° C. (dec.).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]3[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)=[C:9](S(C)(=O)=O)[CH:10]=[CH:11][C:12]=2C)C=CC=CC=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[C:36]([OH:38])=[O:37].Cl>C(O)C>[C:7]1([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([N:24]([CH3:25])[CH3:26])=[CH:22][CH:23]=2)[C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:27][C:28]=2[C:36]([OH:38])=[O:37])[CH:1]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(C)(=O)=O)c(-c2ccc(N(C)C)cc2)c1-c1ccccc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc(C(c2ccccc2)c2c(C(=O)O)[nH]c3ccccc23)cc1

Procedure:
Proceeding in a manner similar to that described in Example 2 above, 20.5 g of [(phenyl)(4-dimethylaminophenyl)(4-methylphenylsulfonyl)]methane was interacted with 10.0 g of indole-2-carboxylic acid in the presence of 5.6 ml of concentrated hydrochloric acid in 140.0 ml of ethanol to obtain 3.34 g of [(phenyl)(4-dimethylaminophenyl)(2-carboxyindol-3-yl]methane (Formula XI: R1 =R2 =R3 =R4 =R11 =B"=H; R5 =N(CH3)2), a blue solid which melted at 213°-215° C. The nuclear magnetic resonance spectrum was consistent with the assigned structure. A toluene solution of the product spotted on an acid clay-coated paper slowly developed a purple-colored image and on a phenolic resin-coated paper slowly developed a dark blue-colored image.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[N:13]=[CH:12][C:11]=3[N:24]=2)=[CH:4][CH:3]=1.[N+](C1C=CC(S(O[CH2:38][C@H:39]2[CH2:41][C:40]2([F:43])[F:42])(=O)=O)=CC=1)([O-])=O>>[F:42][C:40]1([F:43])[CH2:41][C@@H:39]1[CH2:38][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[N:13]=[CH:12][C:11]=3[N:24]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Reactant: CC(=O)N[C@@H](C)COc1cc2sc(-c3ccc(O)cc3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2sc(-c3ccc(OC[C@H]4CC4(F)F)cc3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-hydroxyphenyl)[1,3]thiazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[C:23]4[O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:31])[CH:5]=[CH:4][N:3]=1.[CH3:32][N:33]([CH3:40])[CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37]>>[CH:21]1[C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]=2[C:18]([C:16]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([CH3:31])=[C:9]([CH:14]=2)[NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][N:33]([CH3:40])[CH3:32])[N:7]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: CN(C)CC(C)(C)CO
Reactant: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(Cl)n1
Product: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(OCC(C)(C)CN(C)C)n1

Procedure:
Using an analogous procedure to that described in Example 8, 2-chloro-4-[5-(4-dibenzofuranylcarbonylamino)-2-methylanilino]pyrimidine was reacted with 3-dimethylamino-2,2-dimethylpropanol. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent followed by increasingly polar mixtures of methylene chloride and methanol containing 1% aqueous ammonium hydroxide solution. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 0.85 (s, 6H), 2.14 (s, 6H), 2.18 (s, 2H), 3.94 (s, 2H), 6.22 (d, 1H), 7.23 (d, 1H), 7.4-7.58 (m, 4H), 7.78 (d, 1H), 7.84 (d, 1H), 7.96 (m, 2H), 8.2 (d, 1H), 8.31 (d, 1H); Mass Spectrum: M+H+ 524.
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C(N1C=CN=C1)([N:35]1C=CN=C1)=O.CN(C1C=CC=CN=1)C.[OH-].[NH4+]>O1CCCC1>[C:1]1(=[O:32])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[CH2:7][C:8]([NH2:35])=[O:9])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
A mixture of 3-phthalimido-3-(4'-benzyloxy-3'-methoxyphenyl)propionic acid (1.00 g, 2.32 mmol), carbonyldiimidazole (0.406 g, 2.50 mmol) and a catalytic amount of dimethylaminopyridine in 20 mL of dry tetrahydrofuran under nitrogen was stirred for 1 hour. To the reaction solution was then added 0.25 mL of concentrated ammonium hydroxide. After 15 minutes, the reaction mixture was concentrated in vacuo to an oil which was diluted with 20 mL of water and stirred overnight. The resulting slurry was filtered and the solid dried to afford 0.645 g (65%) of 3-phthalimido-3-(4'-benzyloxy-3'-methoxyphenyl)propionamide as a white powder: 1H NMR (DMSO-d6) δ 7.84 (m, 4 H, Ar), 7.60-7.25 (m, 5 H), 7.53 (br s, 1 H, CONH), 7.15-6.8 (m, 4 H), 5.67 (t, 1 H, J=7.8 Hz), 5.04 (s, 2 H, OCH2), 3.75 (s, 3 H, OMe), 3.19 (d, 2 H, J=9, 16.5 Hz); 13C NMR (DMSO-d6) δ 171.1, 167.6,148.8, 147.2, 137.0, 134.5, 132.0, 131.2, 128.3, 127.7, 127.6, 123.0, 119.3, 113.2, 111.4, 69.8, 55.5, 50.3, 36.9. Anal. Calcd for C25H22N2O5. Theory: C, 69.76; H, 5.15; N, 6.51. Found: C, 69.54; H, 5.13; N, 6.28.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:28][C:29](=[N:35]O)[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:25]3[O:27][N:35]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CCOC(=O)C(N)=NO
Product: CCOC(=O)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
200 mg (about 0.47 mmol) of the compound from Example 49A and 54 mg (0.41 mmol) of ethyl amino(hydroximino)ethanoate were reacted according to the General Method 1. Yield: 17 mg (8% of theory).
Reaction SMILES: [CH3:1][C:2]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][C:6](=O)[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: [H][H]
Reactant: CCOC(=O)C1(C)CC(=O)c2ccccc2O1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C)CCc2ccccc2O1
Yield: 80.3 %

Procedure:
A mixture of 126 parts of ethyl 3,4-dihydro-2-methyl-4-oxo-2H-1-benzopyran-2-carboxylate and 560 parts of ethanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was distilled, yielding 95.5 parts (80.3%) of ethyl 3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylate; bp. 71°-73° C. at 0.5 mm. pressure (intermediate 27).
Reaction SMILES: C[C:2](C)(P(O)(O)=O)[C:3]#[N:4].[Li+].[Cl-].C1CCN2C(=NCCC2)CC1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)([CH:36]=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([CH:36]=[CH:2][C:3]#[N:4])([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C#N)P(=O)(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(C2CCCCC2)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC#N)(C2CCCCC2)CC1
Reaction time: 1 h

Procedure:
To a solution of dimethyl phosphono acetonitrile (0.78 mL, 4.02 mmol), LiCl (184 mg, 4.02 mmol), and DBU (0.55 mL, 4.02 mmol) in anhydrous acetonitrile (25 mL) is added 4-cyclohexyl-4-formylpiperidine-1-carboxylic acid tert-butyl ester, 7, (992 mg, 3.35 mmol) under an atmosphere of argon at room temperature. The mixture is stirred for 1 hour and the solvent removed in vacuo. The resulting crude product is purified over silica gel eluting with dichloromethane/methanol 15:1 to afford the desired product in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O[C:29](OCC)(OCC)[CH2:30][CH2:31][CH2:32][CH3:33])C.Cl.[NH+]1C=CC=CC=1.C>C1(C)C=CC=CC=1.CO>[CH2:30]([C:29]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Reactant: CCCCC(OCC)(OCC)OCC
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (3.46 g, 10.0 mmol) in 50 mL of toluene was treated with triethylorthovalerate (2.5 mL, 14.5 mmol) and the reaction mixture was heated to reflux. A 25 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 4 h. The reaction was then concentrated to dryness under reduced pressure. The residue was dissolved in 50 mL of CH2Cl2 and washed with saturated NaHCO3, H2O and brine. The organic portion was dried over Na2SO4 and concentrated to give a green oil. The green oil was dissolved in 50 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 4.12 g of tert-butyl 2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=O.Cl.[NH2:19][OH:20].O>CO>[OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[N:19][OH:20]
Reactant: NO
Reactant: Cc1cc2c(c(C)c1O)C(=O)CC1(CCC1)O2
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc2c(c(C)c1O)C(=NO)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 98.6 %

Procedure:
A mixture of 1 g of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one and 0.91 g of hydroxylamine hydrochloride was dissolved in 5 mL of MeOH by way of brief heating. After all solids had dissolved, the solution was sealed in a microwave reaction vial and placed in a microwave reactor for 25 min at 125° C. The reaction was cooled to room temperature, added to H2O and extracted with EtOAc, washed with brine and dried over Na2SO4. Evaporation of solvent yielded 1.05 g of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one oxime as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:21])[CH:3]=1.[C:22]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][CH:7]3[CH2:11][CH2:10][N:9]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[C:8]3=[O:18])=[C:4]([Cl:21])[CH:3]=2)=[CH:31][CH:30]=1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCCCC1
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Yield: 78.3 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (500 mg, 1.35 mmol) and 4-(tert-butoxycarbonyl)phenylboronic acid (900 mg, 4.0 mmol) affords 495 mg (78%) of the title compound: Mass spectrum (apci) m/z=468.2 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1.[OH-].[Li+]>O1CCOCC1.O>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:34])([F:35])[F:36])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]4[CH2:17][CH2:18][N:13]([C:11]([N:8]5[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:43])=[O:2])[CH2:10][CH2:9]5)=[O:12])[CH2:14][CH2:15]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)CC1CCN(C(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1CCN(C(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1
Temperature: 25 °C

Procedure:
To a mixture of [1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-acetic acid methyl ester (70 mg, 0.117 mmol) in dioxane (3 mL) and water (3 mL) at room temperature was added lithium hydroxide (0.01 g, 0.24 mmol). The mixture was stirred at room temperature for about an hour. The mixture was acidified to pH of about 2 and then blown to dryness. Purification by reversed-phase HPLC gave [1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-acetic acid. LCMS calcd for C30H31F3N4O5 (m/e) 584, obsd 585 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cccnc3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[O:35][C@H:18]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][CH:38]([O:41][CH3:42])[CH2:39][NH2:40].ClCCl>C(O)C>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]([C@H:18]([OH:35])[C@@H:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[NH:40][CH2:39][CH:38]([O:41][CH3:42])[O:37][CH3:36])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: COC(CN)OC
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc([C@@H](NCC(OC)OC)[C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1

Procedure:
Mixture: 187.2 g (0.4 mol) of rel-(S,S)-3,3'-dibenzyloxy-4,4'-dimethoxystilbene oxide, 210 g (2 mol) of aminoacetaldehyde dimethyl acetal, 5 l of dichloromethane, 3 l of ethanol.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br-].O>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Sc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.11 g of 2-mercaptopyridine and 0.48 of 50% sodium hydride were dissolved in 25 ml of dimethyl formamide, and the mixture was stirred at room temperature for 1 hour. A solution of 6.5 g of polyprenyl bromide of general formula (II) in which n is 15 and A2 is Br in 5 ml of N,N-dimethylformamide was added dropwise. After the addition, the mixture was stirred overnight at room temperature. The reaction mixture was poured into about 50 ml of water, and extracted with diethyl ether. Then, the diethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The ether was distilled off to give a yellow liquid. The liquid was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent to give 3.9 g of a slightly yellow liquid. The NMR analysis of this liquid showed that the signal (doublet, δ=3.91) assigned to --CH2Br of the starting polyprenyl bromide disappeared, and a signal (doublet, δ=3.78) assigned to --CH2S and a signal (multiplet, δ=6.75-8.35) assigned to --S--C5H4N newly appeared. The FD-MASS analysis of this liquid gave m/e=1335.