Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([CH:27]1[CH2:32][NH:31][CH2:30][CH2:29][N:28]1[CH:33](O)[CH3:34])=O)(C)(C)C.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:54]1[C:62]2[C:57](=[CH:58][C:59]([C:63]3[N:67]=[CH:66][N:65](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:64]=3)=[CH:60][CH:61]=2)[C:56]([C:87]2[CH:88]=[C:89]([OH:93])[CH:90]=[CH:91][CH:92]=2)=[N:55]1.Cl>O1CCCC1>[NH:64]1[C:63]([C:59]2[CH:58]=[C:57]3[C:62](=[CH:61][CH:60]=2)[NH:54][N:55]=[C:56]3[C:87]2[CH:92]=[CH:91][CH:90]=[C:89]([O:93][CH2:34][CH2:33][N:28]3[CH2:27][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:88]=2)=[N:67][CH:66]=[N:65]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(O)N1CCNCC1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCNCC2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 51.2 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 2-(tert-butyloxycarbonyl)piperazinylethanol (0.610 g, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6N hydrochloric acid (25 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (25 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (5–70% acetonitrile/water). The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (0.132 g, 52% yield) as the bis-trifluoroacetic acid salt. 1H NMR (D2O) δ 8.26 (s, 1H), 8.12 (s, 1H), 7.61 (d, 1H), 7.37 (d, 1H), 7.31 (m, 2H), 7.19 (m, 1H), 6.90 (m, 1H), 4.35 (m, 2H), 3.62 (m, 6H), 3.52 (m, 4H). ES-MS (m/z) 390 [M+1]+
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].C=O.[C:9]([O:13][C:14](=[O:36])[CH:15](P(OCC)(OCC)=O)[CH:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH3:17])([CH3:12])([CH3:11])[CH3:10]>C1COCC1>[C:9]([O:13][C:14]([C:15](=[CH2:1])[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=1)[CH3:17])=[O:36])([CH3:10])([CH3:11])[CH3:12]
Reactant: CCOP(=O)(OCC)C(C(=O)OC(C)(C)C)C(C)c1ccc(C(=O)OC)cc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C(=O)OC(C)(C)C)C(C)c1ccc(C(=O)OC)cc1

Procedure:
Potassium carbonate (9.16 g, 66.2 mmol) and paraformaldehyde (2.48 g, 82.7 mmol) were added to a solution of methyl 4-(4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutan-2-yl)benzoate (13.7 g, 33.1 mmol) in anhydrous THF (250 mL), respectively. The reaction mixture was heated at reflux for 20 h, then cooled, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in petroleum ether to give the title compound. MS: m/z=235.0 (M−tBu); 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H, J=8.5 Hz), 7.28 (d, 2H, J=8.5 Hz), 6.26-6.32 (m, 1H), 5.56-5.61 (m, 1H), 4.01 (q, 1H, J=7.1 Hz), 3.92 (s, 3H), 1.42 (d, 3H, J=7.0 Hz), 1.33 (s, 9H).
Reaction SMILES: CN1CCN(CC2C=CC(C(NC3C=CC(C)=C(C=3)C(OC)=O)=O)=CC=2)CC1.[F:29][C:30]([F:58])([F:57])[C:31]1[CH:32]=[C:33]([CH:48]=[C:49]([N:51]2[CH:55]=[C:54]([CH3:56])[N:53]=[CH:52]2)[CH:50]=1)[C:34]([NH:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:47])=[C:41]([CH:46]=1)[C:42](OC)=[O:43])=[O:35]>>[F:58][C:30]([F:29])([F:57])[C:31]1[CH:32]=[C:33]([CH:48]=[C:49]([N:51]2[CH:55]=[C:54]([CH3:56])[N:53]=[CH:52]2)[CH:50]=1)[C:34]([NH:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:47])=[C:41]([CH:42]=[O:43])[CH:46]=1)=[O:35]
Reactant: COC(=O)c1cc(NC(=O)c2cc(-n3cnc(C)c3)cc(C(F)(F)F)c2)ccc1C
Agent: COC(=O)c1cc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)ccc1C
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(C=O)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The compound is obtained by using the procedures of examples 83 (steps 1 and 2) replacing the methyl 5-(4-((4-methylpiperazin-1-yl)methyl)benzamido)-2-methylbenzoate with the methyl 5-(3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl)benzamido)-2-methylbenzoate.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH:1](=[N:17][NH:18][C:19]([NH2:21])=[NH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: N=C(N)NN
Reactant: CCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC=NNC(=N)N

Procedure:
1 mol (170.3 g) of undecanol, 1.1 mol (150 g) of aminoguanidine hydrogen carbonate and 1 g of p-toluenesulphonic acid are mixed with 500 ml of toluene and refluxed with stirring. As soon as 2 mol of water have been separated using the water separator, the mixture is allowed to cool, concentrated by rotary evaporation and the dark red oil is taken up in 250 ml of petroleum ether 40/60°. The precipitate formed is suction filtered and washed again with petroleum ether. For recrystallisation the precipitate is dissolved in ethyl acetate and mixed with petroleum ether at boiling temperature (boiling range 40 to 60° C.) until beginning to turn cloudy. Fine crystals are obtained, m.p. 101° C. The structure and purity of the compound were confirmed by analytical and spectroscopic data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:25](=O)[CH3:26])=[CH:4][CH:3]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29].CO.[BH4-].[Na+]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[CH:25]([NH:31][CH:28]([CH3:30])[CH3:29])[CH3:26])=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: CC(=O)c1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)NC(C)c1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
A solution of 1-[9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purin-6-yl]-ethanone I-(15A-1)a (16 mg, 0.038 mmol) and isopropylamine (6.5 μl, 0.076 mmol) in methylene chloride (0.3 ml) was stirred at room temperature and to it was added titanium(IV) isopropoxide (34 μl, 0.114 mmol). The reaction mixture was stirred for 3 hours and then methanol (0.5 ml) was added followed by sodium borohydride (5 mg). When the reaction was shown to be complete by LC/MS it was purified by TLC preparative plate using 10% methanol/methylene chloride with 1% ammonium hydroxide as the solvent to obtain title compound 15A-1. A solution of the material in methylene chloride was treated with excess 1 N HCl in diethyl ether, stirred, evaporated to dryness, and then triturated in diethyl ether to afford the hydrochloride salt of compound 15A-1 (5.9 mg): +ESI MS (M+1) 460.5; 1H NMR (500 MHz, CD3OD) δ 9.08 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.64 (s, 1H), 7.59–7.48 (m, 3H), 7.41 (d, J=8.8 Hz, 2H), 5.38 (q, J=6.2 Hz, 1H), 3.45 (septuplet, J=6.5 Hz, 1H), 1.84 (d, J=6.7 Hz, 3H), 1.43 (d, J=6.7 Hz, 3H), 1.41, (d, J=6.2 Hz, 3H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH:25]([CH:26]=[CH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23][CH:22]1[OH:35]>CC(C)=O.O.[Cr]>[O:35]=[C:22]1[CH2:23][CH2:24][CH:25]([CH:26]=[CH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:21]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([OH:3])=[O:14]
Reactant: CC(C)=O
Reactant: CCCCCC(=O)C=CC1CCC(O)C1CCCCCCO
Agent: O=[Cr](=O)=O
Agent: [Cr]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCC(=O)C=CC1CCC(=O)C1CCCCCC(=O)O
Reaction time: 1 h
Yield: 20 %

Procedure:
8N Jones' reagent (19.4 ml.) was added to a stirred solution of 2-(6-hydroxyhexyl)-3-(3-oxo-1-octenyl)cyclopentanol (8.0 g., 0.026 mole) in acetone (60 ml.) at 15°-25°C. at a rate such that the deep red coloration caused by the addition of one drop of reagent had changed to green before addition of the next drop. The reaction mixture was diluted with sufficient water to dissolve the precipitated chromium salts and was then extracted three times with diethyl ether. The combined ether extracts were washed with 2N aqueous sulphuric acid and then added to 10% aqueous sodium carbonate (350 ml.) and stirred for 1 hour. The aqueous layer (containing the desired acid as the sodium salt) was separated and worked with diethyl ether. The solution was then covered with a layer of diethyl ether, cooled to below 20°C. and acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid. The ether layer was separated and the aqueous layer was again extracted with diethyl ether. The combined extracts were dried over magnesium sulphate, and the ether was removed in vacuo to give the crude acid (4.62 g.). This was purified by preparative thin layer chromatography on silica gel using a 65:15:1 mixture of benzene, dioxane and acetic acid as solvent. Evaporation gave pure 6-[2-oxo-5-(3-oxo-1-octenyl)cyclopentyl]hexanoic acid (1.66 g., 20%)λmax 228 mμ, ε 13,200 (ethanol), νmax 1730 cm-1, 1700 cm-1, 1670 cm-1 and 1625 cm-1 (liquid film). N.M.R. (approximately 10% solution in deuterochloroform) 0.89 δ (triplet J=51/2c/s, terminal CH3), 1.4 δ (multiplet, chain CH2), 2-2.7 δ (multiplets), 6.15 and 6.75 δ (doublet J=16c/s and doublet of doublets J=16c/s and 71/2c/s, CH=CHCO), 10.15 δ (singlet, COOH). (Found: C, 70.4; H, 9.3. C19H30 04 requires C, 70.8; H, 9.3%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[OH:19][CH:20]([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][C:5]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH2:21][CH:20]([OH:19])[CH2:30][N:31]([CH3:32])[CH3:33])=[CH:24][CH:25]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(Oc2nc(Cl)ncc2Br)cc1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2nc(Nc3ccc(OCC(O)CN(C)C)cc3)ncc2Br)cc1
Yield: 63.1 %

Procedure:
A solution of 5-bromo-2-chloro-4-(4-methoxyphenoxy)pyrimidine (Method 1, 200 mg, 0.63 mmol) and 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 8, 156 mg, 0.56 mmol) in NMP (4 ml) was heated at 100° C. for 6 hours. Silica (1 g) was added and volatile material was removed by evaporation. The residue was purified by column chromatography, eluting with 0-10% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (173 mg, 56%). MS (MH+): 489, 491; HPLC (RT): 4.68.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:13]=[CH:12][C:11]2[CH:10]=[CH:9][C:8]3[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][N:16]([CH3:17])[C:7]=3[C:6]=2[N:5]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>CN(C)C=O>[CH2:23]([NH:25][C:26]([NH:3][C:4]1[N:13]=[CH:12][C:11]2[CH:10]=[CH:9][C:8]3[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][N:16]([CH3:17])[C:7]=3[C:6]=2[N:5]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1nn(C)c2c1ccc1cnc(N)nc12
Reactant: CCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ncc2ccc3c(C(=O)OCC)nn(C)c3c2n1
Reaction time: 0.08 h
Yield: 50.5 %

Procedure:
To a suspension of 18 mg (0.44 mmol) of sodium hydride 60% in mineral oil (0.37 mmol) in dry dimethylformamide, a solution of 100 mg of ethyl 8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (0.37 mmol) in 5 mL of the same solvent was added dropwise at 0° C. under stirring. After 5 minutes, 0.070 mL (0.88 mmol) of ethylisocyanate were added to the mixture and the reaction allowed to come to room temperature. After 8 hours the solvent was evaporated under reduced pressure, the residue redissolved with dichloromethane and washed with water. After drying over Na2SO4 the solvent was removed and the product purified by chromatography on a silica gel column (eluant dichloromethane/acetone) leading 64 mg (50% yield) of the title compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:35])(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:36]1([NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH2:42]>C(Cl)Cl>[C:16]([NH:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH2:43])(=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Nc1ccccc1N
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1N
Yield: 76.3 %

Procedure:
N,N'-Dicyclohexylcarbodiimide (2.27 g) was added to a solution of 2.82 g of oleic acid and 1.62 g of o-phenylenediamine in 50 ml of methylene chloride with stirring under ice cooling. The mixture was stirred at room temperature for one night. After completion of the reaction insoluble matter was filtered, followed by removal of the solvent by evaporation. The residue obtained was purified by silica gel column chromatography to obtain 2.84 g of the objective compound (yield: 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:1]=[C:17]([CH3:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: N#Cc1c(N)cccc1OCC1CCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclobutylmethoxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as an orange solid (26%). 1H NR (400 MHz, DMSO-d6) δ 1.32 (t, J=8.0 Hz, 3H), 1.83-1.90 (m, 4H), 2.10-2.13 (m, 2H), 2.59 (s, 3H), 2.86 (m, 1H), 4.16 (d, J=4.0 Hz, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.05 (brs, 2H). MS 315 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:33]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([Cl:33])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2ccc3nc(C)[nH]c(=O)c3n2)cc1OC
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3nc(C)nc(Cl)c3n2)cc1OC
Yield: 74.7 %

Procedure:
To a solution of 2-methyl-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (416 mg, 1.4 mmol) in toluene (28 ml) was added 2,6-lutidine (490 μl, 4.2 mmol) and POCl3 (4.2 mmol, 385 μl). The mixture was refluxed under nitrogen atmosphere for 5 hours. The reaction mixture was cooled down, diluted with ethyl acetate (50 ml) and extracted with a saturated sodium bicarbonate solution. The combined organic layers were evaporated in vacuo and the residue was purified by silica gel column chromatography (the mobile phase being an ethyl acetate/hexane mixture in a ratio of 15:85), resulting in the pure title compound (330 mg, yield 75%) which was characterised by its mass spectrum as follows: MS (m/z): 316, 318 ([M+H]+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:11]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N=C=NC(C)C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1Nc1ccccc1)c1cncc(Br)c1
Temperature: 50 °C
Yield: 83.2 %

Procedure:
A mixture of 5-bromonicotinic acid (20.0 g, 99 mmol), N-phenyl-o-phenylenediamine (19.32 g, 105 mmol), diisopropylcarbodiimide (DIC) (26.5 g, 210 mmol), and triethylamine (Et3N)(2.65 g, 27 mmol) in DCM (anhydrous, 350 mL) was heated to about 50° C. and degassed overnight under argon. After cooling to RT, the solids were then filtered off. The filtrate was washed with water (2×200 mL), dried over sodium sulfate and loaded onto silica gel. A flash column (gradient of 3% to 10% ethyl acetate in DCM) gave 30.32 g of 1E; 83% yield, pure by HNMR.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:31][CH:32]=[CH2:33])=[C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.B.[O:35]1CCCC1.C(=O)(O)[O-].[Na+].OO>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH2:31][CH2:32][CH2:33][OH:35])=[C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=CCc1c(OCc2ccccc2)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: B
Agent: O=C([O-])O
Agent: OO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(OCc4ccccc4)c(CCCO)c3O2)cc1
Reaction time: 72 h

Procedure:
To a solution of 4.46 g (9.6 mmole) of [(2R)-8-allyl-7-(benzyloxy)-2,3-dihydro-1,4-bezodioxin-2-yl]methyl 4-methylbenzenesulfonate in 30 mL of tetrahydrofuran at −10° C. was added 21 mL (21 mmole) of 1 M borane/tetra-hydrofuran. The solution was allowed to come to room temperature and stir under nitrogen for 3 days. Saturated aqueous sodium bicarbonate (50 mL) was cautiously added, followed by 2.5 mL of 30% hydrogen peroxide. The mixture was stirred at room temperature under nitrogen for 2 hours, then it was extracted with three 60 mL portions of ether. The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuum to give 4.87 g of the (R)-enantiomer of the title compound as a colorless oil. 1H-NMR (CDCl3): doublet 7.8 δ (2H); multiplet 7.4 δ (5H); doublet 7.35 δ (2H); doublet 6.65 δ (1H); doublet 6.45 δ (1H); singlet 5.0 δ (2H); multiplet 4.45 δ (1H); multiplet 4.2 δ (3H); doublet of doublets 4.0 δ (1H); triplet 3.5 δ (2H); doublet of triplets 2.73 δ (2H); singlet 2.45 δ (3H); multiplet 1.75 δ (2H).
Reaction SMILES: [Br-:1].[CH2:2]([N+:4]1[N:5]=[CH:6][N:7]([NH2:9])[CH:8]=1)[CH3:3].[C:10](#N)[CH3:11]>[N+]([O-])([O-])=O.[Ag+].CO>[Br-:1].[CH3:3][C:2]1([N+:4]2[N:5]=[CH:6][N:7]([NH2:9])[CH:8]=2)[CH2:11][CH2:10]1
Reactant: CC[n+]1cn(N)cn1
Reactant: CC#N
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Br-]
Solvent: CO
Product: CC1([n+]2cn(N)cn2)CC1

Procedure:
To a preweighed Erlenmeyer flask, 1.0303 g, 4.7 mmol, of 1-ethyl-4-amino-1,2,4-triazolium bromide was measured out under nitrogen conditions. Methanol, 25 ml, was added to dissolve the salt, resulting in a clear solution, homogeneous. In a second preweighed Erlenmeyer flask, 0.8045 g, 4.7 mmol, of silver nitrate was measured out. Acetonitrile, 4 ml, was added along with 15 ml of methanol to dissolve the salt, resulting in a clear, homogeneous solution. The silver nitrate solution was added, dropwise, to the 1-methylcyclopropyl-4-amino-1,2,4-triazolium bromide solution, resulting in an immediate clouding and precipitation in the solution. The reaction mixture was allowed to stir at ambient temperature for thirty minutes. At the end of the thirty minutes the reaction mixture was filtered through a filter of celite removing the silver halide. The reaction vessel was rinsed three times, 10 ml each, with fresh methanol and the solution transferred to a 500 ml round bottom flask. The flask was placed on a rotary evaporator, the solvent was removed, leaving an oil. The oil was dissolved in a minimal amount of methanol and transferred to a preweighed Schlenk flask, placed in an oil bath at 60° C., and vacuum dried for 24 hours. The product was an oil which solidified upon standing, yield 0.9285 grams, 4.7 mmoles. Melting point 53° C., DSC onset 210° C.
Reaction SMILES: C1(C(SCCC(Cl)=O)=O)CCCCC1.C(SCC(C)C(Cl)=O)(=O)C.[C:25]([S:33][CH2:34][CH:35](C)[C:36]([N:38]1[CH2:42][CH2:41][CH:40]=[C:39]1[C:43]([OH:45])=[O:44])=[O:37])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(SCC(C)C(N1CCC=C1C(O)=O)=O)(=O)C>>[CH:26]1([C:25]([S:33][CH2:34][CH2:35][C:36]([N:38]2[CH2:42][CH2:41][CH:40]=[C:39]2[C:43]([OH:45])=[O:44])=[O:37])=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1CCC=C1C(=O)O
Agent: CC(=O)SCC(C)C(=O)Cl
Agent: CC(=O)SCC(C)C(=O)N1CCC=C1C(=O)O
Agent: O=C(Cl)CCSC(=O)C1CCCCC1
Product: O=C(O)C1=CCCN1C(=O)CCSC(=O)C1CCCCC1

Procedure:
Following the procedure of Example 1 but substituting an equivalent amount of 3-[(cyclohexylcarbonyl)thio]propanoyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in part (b) and subjecting the product to the procedure of Example 1 (c), one obtains 4,5-dihydro-1-[3-[(cyclohexylcarbonyl)thio]-1-oxopropyl]-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:20])=[N-]>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:20][CH:12]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)/C=C/c1ccc(C(C)(C)C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C1CC1c1ccc(C(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a −40° C. solution of (E)-ethyl 3-(4-tert-butylphenyl)acrylate (1.0 g, 4.3 mol) in ether (20 mL), freshly prepared diazomethane was added dropwise over 10 minutes. Pd(OAc)2 (30 mg, 0.133 mol) was then added. The reaction mixture was stirred for another 10 min at −40° C., and then filtered through a pad of Celite® and precipitate washed with ether. The filtrate was concentrated in vacuo and the crude material was then purified via silica gel column chromatography to afford ethyl 2-(4-tert-butylphenyl)cyclopropanecarboxylate (0.9 g, 84%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cccnc3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyridin-3-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11m, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.69 (d, 1H), 8.59 (d, 1H), 7.98 (m, 1H), 7.88 (m, 2H), 7.49-7.38 (m, 4H), 7.24 (m, 2H), 7.11 (m, 1H), 7.02 (d, 1H), 6.95 (d, 1H), 6.90 (s, 1H), 4.54 (s, 2H), 4.49 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 502 (M+1).