Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]#[N:25])[CH:3]=3)[O:8][CH:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:10]2)[N:12]=1
Reactant: CN1OC2(CC(c3ccncc3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(c3ccncc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 14.2 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(pyridin-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (20 mg, 0.053 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (14.8 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(3′-amino-2′-methyl-2-(pyridin-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (3 mg, 10%). 1H-NMR (MeOD): 2.24 (m, 1H), 3.01 (m, 1H), 3.39 (t, 3H), 5.54 (d, 1H), 7.19 (m, 1H), 7.60 (m, 1H), 7.62 (t, 1H), 7.69 (m, 1H), 7.89 (m, 3H), 8.02 (, 2H), 8.70 (s, 2H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH3:10][CH:11]([OH:15])[CH2:12][C:13]#[CH:14].C(N(CC)CC)C>C(OCC)C>[OH:15][CH:11]([CH3:10])[CH2:12][C:13]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:14]=1
Reactant: C#CCC(C)O
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CC(C)O)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl chlorooximidoacetate (4 g, 26.4 mmol) and 4-pentyn-2-ol (10.00 ml, 107 mmol) were dissolved in diethyl ether (30 ml). A solution of triethylamine (3.68 ml, 26.4 mmol) in diethylether (20 ml) was added dropwise to the reaction mixture. After 1 h of stirring at RT the reaction mixture was washed with brine and water, dried with MgSO4 and evaporated to dryness. The residue was purified with flash chromatography using a gradient of methanol in methylene chloride affording 2.51 g (48%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ, 1.11 (d, 3H), 1.31 (t, 3H), 2.82-2.94 (m, 2H), 3.93-4.03 (m, 1H) 4.35 (q, 2H), 4.89 (d, 1H), 6.67 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[N:15]=[C:14]2[NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>CN1C(=O)CCC1.CO>[N:4]1([CH2:3][CH2:2][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH2:32])=[O:31])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(O)cc12
Reactant: ClCCN1CCCCC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN1CCCC1=O
Solvent: CO
Product: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(OCCN3CCCCC3)cc12
Temperature: 90 °C

Procedure:
To 1-(2-chloroethyl)piperidine (45 μmol) was added the solution of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (30 μmol) in NMP (200 μL) PS-BEMP (90 μmol) was added to the vials by resin dispenser. After the reaction mixture was heated at 90° C. for 12 h, the residue was diluted with methanol and purified by mass triggered PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:11]=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:3]([CH2:11][NH:16][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: NC1CC1
Reactant: O=Cc1cc2c(cc1Cl)OCO2
Product: Clc1cc2c(cc1CNC1CC1)OCO2

Procedure:
Synthesized according to typical procedure J from 6-chlorobenzo[1,3]dioxole-5-carbaldehyde and cyclopropylamine.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][C@@H:11]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH2:20][C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[O:18])=[O:14])[CH3:12])=[O:9])[CH3:7])=[O:4].[ClH:38]>C(O)(=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][C@@H:11]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[O:14])[CH3:12])=[O:9])[CH3:7])=[O:4].[ClH:38]
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: C[C@H](NC(=O)CN)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To Boc-Gly-Ala-DAla-Gly-Gly-OBzl prepared as in Example 33C (17.2 g, 33.0 mmol) in glacial acetic acid (480 ml) was added 6N HCl (120 ml) and the reaction mixture was stirred at room temperature for 24 h. Concentration in vacuo followed by coevaporation with water (2×250 ml) and toluene (2×250 ml) afforded 12.9 g (100% yield) of the product as a white powder: 1H NMR (D20) δ 1.36 (d, J=6.9 Hz, 3 H), 1.38 (d, J=7.2 Hz, 3 H), 3.84 (s, 2 H), 3.96 (s, 2 H), 3.99 (s, 2 H), 4.30-4.36 (m, 2 H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=O)[CH2:23][CH:24]([CH3:26])[CH3:25].[OH-].[NH4+:30].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH2:23]([C:22]1[N:10]([CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:30])[C:12]=2[N:21]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: Nc1cnc2ccccc2c1NCCOc1ccccc1
Reactant: [NH4+]
Reactant: CC(C)CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Cc1nc2c(N)nc3ccccc3c2n1CCOc1ccccc1
Temperature: 25 °C

Procedure:
N4-(2-Phenoxyethyl)quinoline-3,4-diamine (1.5 g, 5.4 mmol) and isovaleryl chloride (0.8 ml, 6.4 mmol) were combined and treated according to the general procedures of Parts C-E of Example 129. The resulting product, 2-isobutyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline-5N-oxide (1.6 g, 4.5 mmol) was dissolved in dichloromethane (200 ml) and ammonium hydroxide (50 ml) was added. The reaction was chilled (ice bath) and p-toluenesulfonyl chloride (0.85 g, 4.5 mmol) was slowly added over a period of 20 minutes. The cooling bath was removed and the reaction was maintained at ambient temperature overnight. The phases were separated and the organic phase was sequentially washed with 1% aqueous sodium carbonate (3×), water, brine; dried (Na2SO4); and concentrated to near dryness in vacuo. Hexane was added to provide a precipitate. The solid was collected and purified by recrystallization from acetonitrile to yield 0.96 g of 2-isobutyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan powder, m.p. 176.6-177.8° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].Br[CH2:14][CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]([Cl:30])[CH:17]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:22][C:20]1[CH:21]=[C:16]([CH2:15][CH2:14][NH:1][C@@H:2]([CH3:12])[C@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)[CH:17]=[C:18]([Cl:30])[C:19]=1[NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CNc1c(Cl)cc(CCBr)cc1Cl
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1c(Cl)cc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Cl
Temperature: 70 °C
Reaction time: 7 h
Yield: 58.6 %

Procedure:
To a solution of (1R,2S)-2-amino-1-(4-hydroxyphenyl)-propan-1-ol (495 mg) and ethyl N-[4-(2-bromoethyl)-2,6-dichloro-phenyl]aminoacetate (700 mg) in N,N-dimethylformamide (6 ml) was added N,N-diisopropylethylamine (343 μl), and the mixture was stirred for 7 hours at 70° C. The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloro-methane/ethanol=20/1) gave ethyl N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]-ethyl]phenyl]aminoacetate (510 mg).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]2=[N+:13]=[N-:14].[CH2:17]([OH:20])[C:18]#[CH:19]>CCOCC>[OH:20][CH2:17][C:18]1[CH:19]=[C:8]2[N:13]([C:9](=[O:12])[NH:10][C:11]3[C:3]([C:2]([F:16])([F:15])[F:1])=[CH:4][CH:5]=[CH:6][C:7]=32)[N:14]=1
Reactant: C#CCO
Reactant: [N-]=[N+]=C1C(=O)Nc2c1cccc2C(F)(F)F
Solvent: CCOCC
Product: O=c1[nH]c2c(C(F)(F)F)cccc2c2cc(CO)nn12
Reaction time: 0.5 h

Procedure:
2.0 g (0.0088 mole) of 7-(trifluoromethyl)-3-diazooxindole and 10.2 g (0.176 mole or 20 equivalents) of 97% propargyl alcohol are refluxed under N2 for 4 hours, cooled, diluted with ether (200 ml) and stirred for 30 minutes. The light pink solid that forms is filtered off. Yield: 1.3 g; 52.2% crude yield.
Reaction SMILES: [C:1](O)(=[O:4])C=C.OS(O)(=O)=O.[OH2:11].[C:12]1(C)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Cu-]=O>[CH3:1][O:4][C:12]1[CH:17]=[CH:16][C:15]([OH:11])=[CH:14][CH:13]=1
Reactant: O
Reactant: Cc1ccccc1
Reactant: C=CC(=O)O
Agent: O=[Cu-]
Agent: O=S(=O)(O)O
Product: COc1ccc(O)cc1

Procedure:
A mixture of 40 g of the above propoxylated pentaerythritol, 30.2 g acrylic acid, 0.4 g of copper (I) oxide and 1.2 cm3 conc. H2SO4 in toluene (150 cm3) was heated with stirring in the presence of a Dean and Stark trap. The reaction was allowed to continue until 6.1 cm3 of water had been liberated. The mixture was then cooled and washed with 20% w/v aqueous sodium chloride (2×50 cm3 aliquots), then with 15% w/v aqueous potassium bicarbonate (2×100 cm3 aliquots) and finally a further wash with 20% w/v aqueous sodium chloride (2×50 cm3 aliquots). The resulting solution was then filtered and dried over anhydrous sodium sulphate. The solvent was then removed leaving the polyacrylate product as a colourless oil to which 0.2% w/w of 4-methoxyphenol, a polymerisation inhibitor, was then added.
Reaction SMILES: OC1C([N+]([O-])=O)([N+]([O-])=O)C(O)=[N:5][C:4](=[C:15]([N+:19]([O-:21])=[O:20])[N+:16]([O-:18])=[O:17])[N:3]=1.OC1C=C(O)N=C(C)N=1>>[NH2:3][C:4]([NH2:5])=[C:15]([N+:19]([O-:21])=[O:20])[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])C(=C1N=C(O)C([N+](=O)[O-])([N+](=O)[O-])C(O)=N1)[N+](=O)[O-]
Agent: Cc1nc(O)cc(O)n1
Product: NC(N)=C([N+](=O)[O-])[N+](=O)[O-]
Yield: 70 %

Procedure:
The 4,6-dihydroxy-5,5-dinitro-2-(dinitromethylene)-2,5-dihydropyrimidine produced by the nitration reaction of 4,6-dihydroxy-2-methylpyrimidine in this comparative example was hydrolyzed to give 1,1-diamino-2,2-dinitroethylene with the combined yield of 70%.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([CH3:4])=[O:3].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].[C:25](=[O:28])([O-:27])[O-].[K+].[K+]>C(#N)C>[C:2]([OH:3])(=[O:18])[C:25]([OH:27])=[O:28].[NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([CH3:4])=[O:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)Nc1cccc(CC(C)N)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1cccc(CC(C)NCC(=O)c2ccccc2)c1
Product: O=C(O)C(=O)O
Yield: 60 %

Procedure:
A mixture consisting of 9.6 gm of 1-(3'-acetaminophenyl)-2-amino-propane (see Example 2), 10 gm of α-bromoacetophenone, 7 gm of potassium carbonate and 200 ml of acetonitrile was refluxed for three hours. Thereafter, the inorganic precipitate which had formed was removed by suction filtration, and 5 gm of oxalic acid were added to the filtrate. The precipitate formed thereby was collected by suction filtration, yielding 6 gm of 1-(3'-acetamino-phenyl)-2-(phenacyl-amino)-propane oxalate, m.p. 136-140° C. The oxalate was added to 60 ml of ethanolic 10% hydrochloric acid, and the mixture was refluxed for four hours. Thereafter, the reaction solution was evaporated, the residue was caused to crystallize by treating it with acetonitrile and a little water, and the crystallization was purified by dissolving it in a little water, filtering the solution through activated charcoal, and adding acetonitrile to the filtrate. The dihydrochloride of the formula ##STR25## having a melting point of 169°-173° C. (decomp.) was obtained.
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[OH:10])[CH2:2][CH:3]=[CH2:4].CCN(C(C)C)C(C)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:32][C:33]([CH3:40])([CH3:39])[C@@H:34]([C:36]([OH:38])=[O:37])[NH2:35].[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[O:10][C:21]([NH:35][C@H:34]([C:36]([OH:38])=[O:37])[C:33]([CH3:40])([CH3:39])[CH3:32])=[O:23])[CH2:2][CH:3]=[CH2:4]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC[C@@H]1CCC[C@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC[C@@H]1CCC[C@H]1OC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (1R,2S)-2-(but-3-en-1-yl)cyclopentanol (see International Patent Application Publication No. WO2009/134624) (2.1 g) and DIPEA (5.3 mL) in anhydrous 1,4-dioxane (51 ml), at 10° C. and under nitrogen, was added a solution of triphosgene (1.5 g) in dioxane (51 ml). This reaction was stirred at 22° C. for 1.5 hour and 3-methyl-L-valine (2 g) and NaOH (1M, 30.5 mL) were added, then stirred at 70° C. for 15 hours. At 22° C., the reaction solution was acidified to pH 3 with 1 N HCl and extracted with (3×100 ml) ether. The combined organic layer were washed with water (100 ml), brine (70 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, eluting with 10 to 100% EtOAc in hexane) to give the desired product (3.26 g). LRMS (ES+) M/Z (M+Na)+ 320.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:28][C:29](OC)([O:31]C)[CH3:30]>CN(C=O)C>[CH3:24][N:12]([CH2:13][C:14]1[N:15]([CH3:23])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[N:7][C:2]([NH:1][CH2:28][C:29](=[O:31])[CH3:30])=[CH:3][CH:4]=1
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Reactant: COC(C)(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2cc3ccccc3n2C)cn1
Reaction time: 18 h
Yield: 9.6 %

Procedure:
To a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.12 g, 0.32 mmol), from Example 1, in DMF (1 mL) was added NaH (14 mg, 60% dispersion in oil, 0.35 mmol) and 1-bromo-2,2-dimethoxy-propane (0.05 mL, 0.37 mmol). After 18 h at RT, the reaction was complete by TLC analysis. The solvent ws removed under vacuum and the residue was purified by reverse phase preparative HPLC (YMC CombiPrep® ODS-A, 10% to 90% CH3CN/H2O+0.1% TFA) to give the title compound (11.6 mg) as a pale yellow oil: 1H NMR (400 MHz, MeOH-d4, 2:1 mixture of rotamers, minor rotamer in italics) δ 9.28 and 9.22 (s, 1H), 8.60 and 8.52 (s, 1H), 8.25 and 8.15 (d, 1H), 7.68 (d, J=16 Hz, 1H), 7.50 (m, 1H), 7.35 (m, 3H), 7.15 (m, 1H), 7.02 (m, 1H), 6.55 and 6.25 (s, 1H), 5.05 and 4.95 (s, 2H), 3.72 and 3.68 (s, 3H), 3.50 and 3.48 (s, 3H), 3.35 (s, 2H), 3.15 and 3.10 (s, 3H). MS (ES+) m/e 376.3 (M+H)+. Unreacted (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (68 mg) was also recovered.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:10]=1[OH:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S([O-])(=O)(=O)C.[CH3:35][C:36]1([CH3:43])[O:40][CH:39]([CH2:41]O)[CH2:38][O:37]1>CN(C)C=O>[CH2:3]([C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:10]=1[O:29][CH2:41][CH:39]1[CH2:38][O:37][C:36]([CH3:43])([CH3:35])[O:40]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCCCCCCCCCCCCc1ccc(O)c(CCCCCC)c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(OCC2COC(C)(C)O2)c(CCCCCC)c1

Procedure:
To a suspension of 2.27 g of prewashed 50% sodium hydride in 65 ml of dimethylformamide was added dropwise a solution of 11.78 g of 2-hexyl-4-tetradecylphenol in 65 ml of dimethylformamide. This mixture was heated for 1/2 hour, then 8.61 g of the mesylate of solketal was added. The mixture was heated at reflux for 3 hours, cooled, quenched carefully with water and extracted several times with ether. The ether extracts were combined, dried and the solvent evaporated, giving 15 g of the desired compound.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=O.C1(N=C=O)C=CC=CC=1.[C:15]([C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:24][N:25]=2)[N:22]=1)#[CH:16].C(N(CC)CC)C>C1C=CC=CC=1>[C:30]([O:29][C:28](=[O:34])[NH:27][CH2:26][C:23]1[N:21]2[N:22]=[C:17]([C:15]3[O:3][N:1]=[C:4]([CH3:5])[CH:16]=3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC[N+](=O)[O-]
Reactant: C#Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Product: Cc1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)on1
Temperature: 50 °C

Procedure:
To a solution of nitroethane (1.02 ml, 14.3 mmol) in benzene (50 mL) was added phenyl isocyanate (3.12 ml, 28.5 mmol). The mixture was stirred at 50° C. for twenty minutes followed by the addition of tert-butyl (6-ethynyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.00 g, 11.0 mmol) and triethylamine (0.0765 ml, 0.549 mmol). The mixture was stirred at 50° C. for six hours then at room temperature overnight. The mixture was cooled to room temperature, filtered and the resulting brown precipitate was washed with additional benzene. The filtrate was concentrated to yield the product as a black solid. MS m/z=331.1 [M+1]+. Calc'd for C15H18N6O3: 330.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:4][C:5]([CH2:8]O)=[CH:6][CH:7]=1.[BrH:16].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)C>[CH3:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:4][C:5]([CH2:8][Br:16])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CO)nc1-c1ccccn1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(CBr)nc1-c1ccccn1

Procedure:
0.9 g (4.5 mmols) of 3-methyl-6-hydroxymethyl-2,2'-bipyridine are boiled under reflux for 6 hours, together with 5 ml of 62% hydrobromic acid. After cooling, 10 ml of water and 20 ml of diethyl ether are added. The water phase is rendered alkaline with potassium carbonate, separated from the ether phase and washed with a further 10 ml of diethyl ether. The combined ether phases are dried over sodium sulfate and concentrated to dryness in vacuo (maximum bath temperature: 30° C.). 1.16 g (98% of theory) of 3-methyl-6-bromomethyl-2,2'-bipyridine remains as an oily product which decomposes at room temperature, giving a red colouration, and crystallises at 0° C. The 3-methyl-6-bromomethyl-2,2'-bipyridine is immediately used further.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH2:29][C:30]#[C:31][CH3:32])[C@H:3]([O:22]C1CCCCO1)/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][C@H:7]1[OH:21]>C(O)(=O)C.O.C1COCC1>[CH3:1][C:2]([CH3:33])([CH2:29][C:30]#[C:31][CH3:32])[C@H:3]([OH:22])/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][C@H:7]1[OH:21]
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
290 mg. of (13E)-(11R,15R)-16,16-dimethyl-11-hydroxy-9-oxo-15-(tetrahydropyran-2-yloxy)-13-prosten-18-ynoic acid is agitated for 16 hours at room temperature with 8 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), evaporated under vacuum, and the residue purified by column chromatography on silica gel. With methylene chloride/5% methanol, 185 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=[CH:12][C:7]=2[N:6]=[N:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C(NC(C)C)(C)C.Cl.[CH3:30][NH:31][O:32][CH3:33]>C(Cl)Cl.CN(C=O)C>[CH3:33][O:32][N:31]([CH3:30])[C:13]([C:10]1[CH:11]=[CH:12][C:7]2[N:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:8]=2[CH:9]=1)=[O:15]
Reactant: CC(C)n1nnc2ccc(C(=O)O)cc21
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2nnn(C(C)C)c2c1
Reaction time: 72 h
Yield: 95.5 %

Procedure:
To a stirred mixture of 3-isopropyl-3H-benzotriazole-5-carboxylic acid (9 g) in 150 mL of methylene chloride and 0.15 mL of DMF was added 5.0 mL of oxalyl chloride. The solution was stirred overnight before 27 mL of N,N-diisopropylamine and 5.6 g of N,O-dimethylhydroxylamine hydrochloride was added. The mixture was stirred for 3 days before mixture was washed with a solution of sodium dihydrogenphosphate, aqueous bicarbonate, dilute hydrochloric acid, brine, dried (sodium sulfate), filtered, and the filtrate was concentrated to a dark oil. This oil was purified by flash chromatography (eluting with 3:2 ethyl acetate/hexanes) to afford 10.4 g of 3-isopropyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide as brown oil.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[CH:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH:17]=4)[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[OH-:40].[Na+].OO>C1COCC1.C(OCC)C.O>[C:1]([O:9][CH:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[CH:12]([CH2:13][CH2:14][C:15]3[C@H:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH:17]4[OH:40])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CCC(OC(=O)c2ccccc2)C(C)(C)C1CC3
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC(O)[C@H]2C3=C(CC[C@@]21C)[C@@]1(C)CCC(OC(=O)c2ccccc2)C(C)(C)C1CC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.04 g of 3-benzoyloxy-4,4-dimethylcholesta-8,14-diene (Step A) was dissolved in 50 ml of THF, and 360 ml of 1M borane in THF was added dropwise at 0° C. The mixture was stirred at ambient temperature overnight, cooled to 0° C., and 140 ml of water was added dropwise, followed by 360 ml of 10% sodium hydroxide and 378 ml of 30% hydrogen peroxide. After stirring for 90 mutes, 100 ml of diethyl ether was added to the mixture and the aqueous phase extracted twice with diethyl ether. The combined organic phases were washed twice with sodium bisulphite solution and then with water. After evaporation, the product was purified by chromatography on SiO2 (2% diethyl ether in toluene) to yield 0.62 g of 3-benzoyloxy-4,4-dimethylcholest-8-en-15-ol.