Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([NH2:39])[CH2:36][CH2:37][CH3:38]>>[NH:1]([C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11]([NH:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)cc1
Reactant: CCCCN
Product: CCCCNc1ccc(Nc2ccccc2)c2c1C(=O)c1ccccc1C2=O
Yield: 90 %

Procedure:
1-(anilino)-4-(n-butylamino)-anthraquinone was prepared by reaction of 1-(anilino)-4-tosyloxyanthraquinone with n-butylamine. The isolated and purified reaction product has the structure illustrated below. ##STR14## The yield was 90% and m.p. 118°-120° C. Mass spectrum, m/e 370 (M+), 327 (M-C3H7), 299 (327-CO); 1H-NMR (CD2Cl2)δ12.17 (br s, 1H), 10.78 (br s, 1H), 8.37-8.27 (m, 2H), 7.76-7.39 (m, 4H), 7.33-7.10 (m, 5H), 3.65-3.05 (m, 2H), 1.72-1.38 (m, 4H), 1.07-0.92 (t, 3H): UV/VIS max (Xylenes) 388 nm (ε4000), 598 (14 200), 642 (15 600).
Reaction SMILES: II.C1C=C2C(OC3(C4C(=C(I)C(O)=C(I)C=4)OC4C3=CC(I)=C(O)C=4I)C2=CC=1)=O.C1C(I)=C(O)C(I)=C2OC3C(C4(OC(=O)C5C(Cl)=C(Cl)C(Cl)=C(Cl)C4=5)C=12)=CC(I)=C(O)C=3I.[CH3:65][C:66]1[CH2:71][CH2:70][CH2:69][C:68]([CH3:73])([CH3:72])[C:67]=1/[CH:74]=[CH:75]/[C:76](/[CH3:86])=[CH:77]/[CH:78]=[CH:79]/[C:80](/[CH3:85])=[CH:81]\[C:82]([OH:84])=[O:83]>>[CH3:65][C:66]1[CH2:71][CH2:70][CH2:69][C:68]([CH3:72])([CH3:73])[C:67]=1/[CH:74]=[CH:75]/[C:76](/[CH3:86])=[CH:77]/[CH:78]=[CH:79]/[C:80](/[CH3:85])=[CH:81]/[C:82]([OH:84])=[O:83]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)C(C)(C)CCC1
Agent: II
Agent: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: O=C1OC2(c3ccccc31)c1cc(I)c(O)c(I)c1Oc1c2cc(I)c(O)c1I
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1

Procedure:
In general, a convergent approach, involving stereospecific coupling of the appropriate C15 (synthesized from β-ionone) and C5 synthons, has been utilized. (however, a linear sequence comprising of seven steps, starting from β-ionone, has also been described; J Org. Chem. 54, 2620-2628, 1989). For example, Patternden and Weedon, J. Chem. Soc.(C), 1984-97 (1968) have disclosed a procedure for the preparation of 13-cis retinoic acid by reacting a C15-triarylphosphonium salt (Wittig salt) and a C5-butenolide in diethylether to produce an isomeric mixture (of the cis and trans isomers at C-11 double bond) of 13-cis retinoic acid in 66-75% yield; the desired 11-trans-13-cis content is only about 36% and the rest being the corresponding 11,13-di cis isomer. Selective isomerization of the 11-cis double bond in the presence of 13-cis double bond proved extremely difficult to accomplish. A great deal of effort has been directed to affect selective isomerization of 11-cis double bond (without isomerizing the 13-cis double bond) in 11,13-di cis retinoic acid. The methods include photoisomerisation by using either iodine (J. Chem. Soc. (C) 1982, 1968), transition metal catalysts (U.S. Pat. No. 4,556,518) or photosensitizers such as erythrosin B, rose Bengal etc. (U.S. Pat. No. 5,424,465). These processes suffer from the following limitations and for various reasons are not suitable for commercial production of isotretinoin. For example, the process for selective photoisomerization using iodine under diffused light is extremely difficult to accomplish without affecting the 13-cis double bond. This results in the generation of all trans retinoic acid (tretinoin) as a major impurity in isotretinoin produced by this process. Although, U.S. Pat. No. 5,424,465 describe that use of photosensitizers enhances selectivity of photoisomerisation of C11-cis double bond, no data, however, is provided for the extent of tretinoin formation in this process.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][CH:15]=[N:14][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]1([C:7]2[N:6]=[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]3=[N:3][C:2]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1nc2cccnc2nc1-c1ccccc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc3cccnc3nc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
2-Chloro-3-phenylpyrido[2,3-b]pyrazine (step 3) (175 mg, 0.724 mmol) in dry dioxane (4 ml) under nitrogen was treated with p-tolylboronic acid (108 mg, 0.797 mmol), potassium carbonate (200 mg, 1.448 mmol) in water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (41.8 mg, 0.036 mmol). The resulting mixture was heated using microwave radiation at 150° C. for 1 hour. After cooling to RT, the mixture was diluted with water (100 ml) and extracted with DCM (×3). The combined organic extracts were washed with brine, dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica eluting with 0-30% EtOAc/iso-hexane to afford the title compound as a yellow solid; LCMS; Rt 1.19 mins MS m/z 298 [ M+H]+; Method 2minLC_v003
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C:16](=[O:19])[C:15]([C:20]#[N:21])=[CH:14]2)C.[OH-].[Na+].Cl>C(O)C>[C:20]([C:15]1[C:16](=[O:19])[O:17][C:18]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:22])=[O:3])#[N:21]
Reactant: CCOC(=O)CCCOc1cccc2cc(C#N)c(=O)oc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc2cccc(OCCCC(=O)O)c2oc1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
After 10 ml of ethanol was added to 6.0 g of 4-(3-cyano-2-oxo-8-chromenyloxy)butyric acid ethyl ester, 50 ml of 2N aqueous solution of sodium hydroxide was added to the mixture and the resultant was stirred for 5 minutes at room temperature. Then the reaction mixture was poured into a mixture of 10 ml of concentrated hydrochloric acid and 200 ml of ice water and a precipitate was filtered, which was recrystallized to give a desired compound.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][O:35][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][OH:35])[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cl)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCO)c2)C1=O
Yield: 42.4 %

Procedure:
A solution of 1.2 g (1.7 mmol) of 7-anilino-1-[3-(2-(tert-butyldiphenyl-silyloxy)ethyl)phenyl]-3-(2-chloro-6-methylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 30 ml of tetrahydrofuran was treated with 2.25 ml (2.25 mmol) of tetrabutylammonium fluoride (1M in tetrahydrofuran). The mixture was heated at reflux for 5 hours, cooled and evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of 2M aqueous hydrochloric acid. The organic phase was washed with 40 ml of water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a gradient elution from dichloromethane/methanol 100:1 to dichloromethane/methanol 100:5. Product-containing fractions were evaporated to give 350 mg (42%) of 7-anilino-3-(2-chloro-6-methylphenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a gum. [Mass spectrum (ESI) MH+ =486].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:26])[CH2:7][C:8]1[CH:16]=[C:15]([CH3:17])[C:14]2[C:10](=[CH:11][N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:13]=2)[CH:9]=1.[O:27]=[C:28]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41]([C:44](OC3C=CC([N+]([O-])=O)=CC=3)=[O:45])[CH2:40][CH2:39]2)[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29]1.[H-].[Na+].C(Cl)Cl>O1CCCC1>[O:27]=[C:28]1[N:37]([CH:38]2[CH2:39][CH2:40][N:41]([C:44]([O:26][CH:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH2:7][C:8]3[CH:16]=[C:15]([CH3:17])[C:14]4[C:10](=[CH:11][N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[N:13]=4)[CH:9]=3)=[O:45])[CH2:42][CH2:43]2)[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: Cc1cc(CC(O)c2ccco2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ccco2)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 8 h

Procedure:
To a solution of 1-(furan-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethanol (0.11 mmol) and 4-nitrophenyl 4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (0.13 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (95%, 0.33 mmol) at room temperature under nitrogen. The reaction was stirred overnight. Methylene chloride (15 mL) was added and the mixture washed with water (4×5 mL). The organic layer was dried, filtered and concentrated to give the crude product, which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1.[CH3:11][NH:12][CH3:13]>C(O)C>[CH3:11][N:12]([CH3:13])[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: CNC
Reactant: Clc1ccc2ncnn2n1
Solvent: CCO
Product: CN(C)c1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Chloro[1,2,4]triazolo[1,5-b]pyridazine (0.9 g) is dissolved in 10 ml of ethanol, to which 10 ml of a 7.2% solution of dimethylamine in ethanol is added. The mixture is stirred at room temperature for 24 hours. After the solvent is evaporated off under reduced pressure, the residue is dissolved in methylene chloride, washed with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent is evaporated off under reduced pressure to give 0.82 g of the titled compound as a white crystal.
Reaction SMILES: [ClH:1].[CH3:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]1[NH:12]C(=O)COC>C(O)C.O>[ClH:1].[NH2:12][C@H:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][C@@H:3]1[CH3:2]
Reactant: COCC(=O)N[C@H]1c2ccccc2C[C@@H]1C
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[C@H]1Cc2ccccc2[C@@H]1N

Procedure:
Concentrated hydrochloric acid (8 ml) was added to a solution of N-[(1R,2S)-2-methyl-1-indanyl]-2-methoxyacetamide (5.9 g, 0.0269 mol) in ethanol and water, and the mixture heated for 12 hours at reflux. The solvent was evaporated and a small amount of ethyl acetate added. The undissolved solid was filtered off to give (1R,2S)-1-amino-2-methylindane hydrochloride (1.0 g) as a solid, chemical purity>95%.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][NH2:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].OC(COC1C2C(=CC=CC=2)C=CC=1)CN[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2>>[C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][NH:12][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCC(O)CN)cc1
Reactant: OC(CNc1ncnc2[nH]cnc12)COc1cccc2ccccc12
Product: CC(=O)c1ccc(OCC(O)CNc2ncnc3[nH]cnc23)cc1

Procedure:
By substituting 3-(4-acetylphenoxy)-2-hydroxypropylamine (3.65 g, 0.0174 moles) for the starting material of Example 2 and following the method of Example 2, the desired compound is obtained.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][NH:42][CH:43]([CH3:45])[CH3:44])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=2[CH2:21]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)NC(=O)CCl
Product: CCN(Cc1ccc(OCCNC(C)C)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 11.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-isopropylacetamide (13 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (2.7 mg) was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.C[Si]([N:32]=[C:33]=[O:34])(C)C>C(O)(C)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)[CH:22]1[CH2:27][CH2:26][N:25]([C:33]([NH2:32])=[O:34])[CH2:24][CH2:23]1
Reactant: C[Si](C)(C)N=C=O
Reactant: c1cnc2c(c1)CCCC2N(Cc1nc2ccccc2[nH]1)C1CCNCC1
Solvent: CC(C)O
Product: NC(=O)N1CCC(N(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)CC1
Reaction time: 20 h

Procedure:
A solution of (1H-benzimidazol-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (0.16 g, 0.43 mmol) in isopropanol (3 mL) was treated with trimethylsilylisocyanate (81 μL, 0.60 mmol) at room temperature. The reaction was stirred 20 hours and concentrated under reduced pressure. This afforded, after column chromatography with silica gel (5:0.5:94.5 MeOH:NH4OH:CH2Cl2), 4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-piperidine-1-carboxylic acid amide (112 mg, 66%). 1H NMR (CDCl3) δ 1.42 (m, 1H), 1.60-1.95 (m, 5H), 2.02 (br, 1H), 2.24 (br, 1H), 2.60-2.80 (m, 4H), 2.89 (m, 1H), 3.70 (br, 1H), 4.03 (br, 1H), 4.15 (m, 3H), 4.39 (br, 2H, NH2), 7.18 (m, 3H), 7.45 (d, 1H, J=7.5 Hz), 7.66 (br, 2H), 8.59 (d, 1H, J=4.0 Hz).
Reaction SMILES: [CH3:1][C@@H:2]1O[C@H:3]1[CH2:5]O.CC1C=CC(S([O-])(=O)=O)=CC=1.[Li]CCCC.[O:23]([C:30]([NH:32][O:33][C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(O)(=O)C>[O:23]([C:30]([N:32]([C@@H:3]([C:2]#[CH:1])[CH3:5])[O:33][C:34]([O:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:35])=[O:31])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Reactant: C[C@@H]1O[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#C[C@@H](C)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (2S-trans)-3-methyloxiranemethanol 4-methylbenzenesulfonate (484 mg; 2 mmol), prepared as in step 1, in dry THF (20 ml) was treated at -70° C. to -60° C. with n-BuLi (1.6M in hexane, 7.5 ml, 12 mmol) under an atmosphere of nitrogen. Glacial acetic acid (1 ml) was added after consumption of all the rosylate (monitored by TLC). After 15 min, sodium bicarbonate (600 mg) was added and the reaction mixture was allowed to warm to room temperature. After filtration through Celite, N,O-diphenoxycarbonylhydroxylamine (550 mg, 2.00 mmol) and triphenylphosphine (786 mg, 3.00 mmol) were added to the filtrate. The resulting mixture was treated with DEAD (0.5 ml, 3.0 mmol), taking care that the reaction temperature did not rise above ambient temperature. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purifed by chromatography on silica-gel (10% ethyl acetate/hexane) to give (R)-N,O-bis(phenoxycarbonyl)-N-(3-butyn-2-yl)hydroxylamine(contaminated with phenol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([O:7][CH3:8])=[O:6].[CH3:18][Sn](C)(C)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(CN2CCCC2)c(Br)c1
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CN2CCCC2)c(C)c1
Temperature: 137.5 °C

Procedure:
A solution of methyl 3-bromo-4-[(1-pyrrolidinyl)methyl]benzoate (16 g, 53.7 mmol) in 110 mL of toluene was treated with Pd(PPh3)4 (3.1 g, 2.68 mmol) and tetramethyltin (22.3 mL, 161.1 mmol). The resulting mixture was heated at 135-140° C. for 36 hr in a sealed tube. After cooling to ambient temperature, the reaction mixture was filtered through diatomaceous earth and concentrated in vacuo. The crude brown residue was purified by PrepLC (SiO2; 97:2:1 hexanes-THF-TEA) to afford 11.4 g (48.9 mmol; 91%) of the title compound as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[C:18]([C:24]([O:26]C)=[O:25])[CH2:19][C:20]([O:22]C)=[O:21].C[N+]1([O-])CC[O:32]CC1.O.OS([O-])=O.[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O.CC(C)=O>[C:24]([C@:18]1([OH:32])[C@H:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[O:21][C:20](=[O:22])[CH2:19]1)([OH:26])=[O:25]
Reactant: COC(=O)CC(=CCCCCCCCCc1ccc(Cl)cc1Cl)C(=O)OC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1C[C@](O)(C(=O)O)[C@H](CCCCCCCCc2ccc(Cl)cc2Cl)O1
Temperature: 25 °C
Reaction time: 64 h
Yield: 91.4 %

Procedure:
A mixture of (E) methyl 12-(2,4-dichlorophenyl)-3-methoxycarbonyl-3-dodecenoate (1.50 g, 3.61 mmol), osmium tetroxide (0.229 ml of a 2% solution in t-butanol, 0.018 mmol), N-methylmorpholine-N-oxide (634 mg, 5.42 mmol), water (2 ml), and acetone (2 ml) was stirred at room temperature for 64 h. Aqueous NaHSO3 (1.1M, 6 ml) was added, and the mixture filtered, after 20 min, through a plug of silica gel. The silica gel plug was washed with ether, then the filtrate washed with aqueous HCl, water, and saturated aqueous NaCl. After drying (MgSO4), the solvent was removed under vacuum, and the residue purified by chromatography on silica gel (50-100% ether/petroleum ether 40°-60° C.) to give the title compound (1.33 g), contaminated with the 5-ring lactone.
Reaction SMILES: [CH3:1][C:2]1([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[O:6][CH:5]([CH3:7])[CH2:4][O:3]1.[CH2:16]([Li])CCC.CCCCCC.S(OC)(OC)(=O)=O>O1CCCC1.O>[CH3:1][C:2]1([N:8]([CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[O:6][CH:5]([CH3:7])[CH2:4][O:3]1
Reactant: [Li]CCCC
Reactant: Cc1ccccc1NC1(C)OCC(C)O1
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1N(C)C1(C)OCC(C)O1
Temperature: -60 °C
Reaction time: 15 h

Procedure:
10.0 g (0.048 mole) of 2,4-dimethyl-2-(2-methylanilino)dioxolane was dissolved in about 150 ml of tetrahydrofuran and then cooled to -60° C. 30.15 ml of 1.6 molar n-butyl lithium in hexane (0.048 mole of n-butyl lithium) was added and the temperature of the mixture allowed to raise to 0° C. 4.6 ml (0.048 mole) of dimethyl sulfate was added dropwise at about 0°-10° C. The temperature of the mixture was allowed to raise to 25° C., then refluxed for 3 hours and then stirred overnight (about 15 hours) at room temperature. The mixture was then mixed with about 500 ml of water and extracted with ethyl ether. The ethyl ether extracts were combined, dried over magnesium sulfate and evaporated to dryness affording the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[C:5]2=[N:6][CH:7]=1.[O:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[OH-].[Na+].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>[O:18]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([C:11]4[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=4)[C:5]3=[N:6][CH:7]=2)=[CH:19]1
Reactant: Oc1cccc(-n2cnc3cc(Br)cnc32)c1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1cccc(-n2cnc3cc(-c4ccoc4)cnc32)c1
Temperature: 80 °C
Yield: 99.2 %

Procedure:
A mixture of 3-(6-bromoimidazo[4,5-b]pyridin-3-yl)phenol (2.32 g, 8 mmol), 3-furanboronic acid (1.43 g, 12.8 mmol), potassium phosphate (3.4 g, 16 mmol) and tetrakis(triphenylphosphine)palladium(0) (370 mg) in degassed N,N-dimethylformamide (12 ml) was heated at 80° C. for 20 hours. After cooling to ambient temperature the mixture was dissolved in 3N sodium hydroxide and extracted with dichloromethane, then with ether. The aqueous phase was adjusted to pH 7 with concentrated hydrochloric acid and the resulting solid collected by filtration, washed with water and dried under high vacuum to afford 3-[6-(furan-3-yl)imidazo[4,5-b]pyridin-3-yl]phenol as a cream-coloured solid (2.2 g, 99%); δH (400 MHz, d6-DMSO) 6.86 (1H, ddd, J 8, 2 and 1), 7.15 (1H, s), 7.33-7.45 (3H, m), 7.81 (1H, s), 8.35 (1H, s), 8.46 (1H, d, J 2), 8.54 (1H, d, J 2), 8.91 (1H, s), 9.94 (1H, br s); m/z (ES+) 278 (M++H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:11][CH:10]2C(OCC)=O)=[C:5]([CH3:17])[CH:4]=1)#[N:2].CC[O-].[Na+].O>C(O)C>[CH3:17][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[CH2:9][CH:10]=[O:11])[C:1]#[N:2]
Reactant: CCOC(=O)C1OC1c1ccc(C#N)cc1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C#N)ccc1CC=O
Reaction time: 0.17 h
Yield: 20.4 %

Procedure:
A solution of ethyl 3-(4-cyano-2-methylphenyl)oxirane-2-carboxylate (927 mg, 4.0 mmol) in 10 mL of dry ethanol was cooled to 0° C. Freshly prepared EtONa (12.4 mmol) in 8 mL of ethanol was added and stirred at 0 for 10 min. Then dropwise addition of 0.1 g of water, stirred at 0° C. for 2 hours, and the sodium salt of the epoxy compound was filtered. The sodium salt of the epoxy compound was then dissolved in 5 mL of water and added 5 mL of 1 N of HCl and 20 mL of toluene. The mixture was heated to reflux for 2 hours. The organic phase was separated, washed by saturated sodium chloride, dried over Na2SO4 and distilled off solvent to afford 130 mg of crude 3-methyl-4-(2-oxoethyl)benzonitrile. MS m/z: 160 (M+1)+.