Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23][CH3:24])=[O:22])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH2:31]([O:33][CH2:34][CH2:35]Br)[CH3:32]>CN(C=O)C>[CH2:31]([O:33][CH2:34][CH2:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23][CH3:24])=[O:22])[CH2:12][CH2:11]2)=[CH:2]1)[CH3:32]
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)OC)CC2)c2ccccc21
Reaction time: 4 h

Procedure:
8.0 g (0.021 mol) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate were dissolved in 125 ml of DMF and, at room temperature, 1.12 g (0.028 mol) of 60% sodium hydride was carefully added. This mixture was stirred for half an hour. 2.9 ml (0.023 mol) of 2-bromoethyl ethyl ether were dropwise added and the stirring was continued for 4 h. The solvent was evaporated under reduced pressure and the residue was worked-up as usual. The crude mixture was purified by flash-chromatography over silica gel affording 4.12 g (54% of yield) of methyl 2-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoate
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@H:9]2[C:15]([O:17]C)=[O:16])=[CH:4][CH:3]=1.[OH-].[Li+].Cl.[Cl-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@H:9]2[C:15]([OH:17])=[O:16])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CC(=O)CC[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC[C@@H](c2ccc(Cl)cc2)[C@H](C(=O)O)C1
Temperature: 25 °C

Procedure:
A stirred mixture of 0.435 g (1.63 mmol) of methyl trans-2-(4-chlorophenyl)-5-oxocyclohexanecarboxylate (described in Step B of Example 1) and 1 N lithium hydroxide (3.26 mL, 3.26 mmol) in tetrahydrofuran (3.3 mL) was heated at reflux for approximately 1 h. After cooling to room temperature, the reaction mixture was poured into 1 N hydrochloric acid/brine (1:1) and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residual crude title compound was used without further purification in the subsequent reaction.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][CH:13]=1)=[O:11])[CH3:8].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>COCCOC.CCOC(C)=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>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:15]1[S:16][C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[CH:13][N:14]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: OB(O)c1ccccc1F
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: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1cnc(-c2ccccc2F)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol), and a degassed solution of 2.0M Na2CO3 (10 mL) are added to a degassed solution of 2-bromo-1,3-thiazole-5-carboxylic ethyl ester (1.18 g, 5.0 mmol) and 2-fluorophenylboronic acid (0.77 g, 5.5 mmol) in DME (10 mL). The resulting suspension is stirred under argon at 80° C. for 4 hours. The reaction mixture is cooled, diluted with EtOAc, and then washed with two portions of 1.0 M NaOH, then one portion of brine. The combined organic phases are concentrated in vacuo, and the resulting oil purified with flash chromatography. Yield 37%. HRMS (FAB) calculated for C12H10FNO2S+H 252.0495, found 252.0496.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]=1[CH3:18]>C1COCC1.O=[Mn]=O>[CH:2]([C:3]1[NH:7][C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]=1[CH3:18])=[O:1]
Reactant: CC(=O)Nc1cccc(-c2nc(C)c(CO)[nH]2)c1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-c2nc(C)c(C=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-[3-(5-hydroxymethyl-4-methyl-1H-imidazol-2-yl)-phenyl]-acetamide (0.064 g, 0.23 mmol, 1.0 equiv) in THF (2 mL) was added activated MnO2 (0.20 g, 2.3 mmol, 10.0 equiv). The reaction mixture was stirred vigorously for 18 h at ambient temperature and then filtered through Hyflo Super Cel. The organic phase was concentrated by evaporation under reduced pressure and the crude reaction product directly used in the following reductive alkylation step without further purification assuming quantitative conversion. MS (ESI): 244.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[CH:16]1[CH2:18][CH2:17]1)/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH:16]1(/[C:7](/[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:19])=[O:2])[CH2:18][CH2:17]1
Reactant: COC(=O)/C=C/C=C(/c1ccc(OC)cc1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C/C=C/C(=O)O)C2CC2)cc1
Yield: 87.1 %

Procedure:
As described in Example 99, (E,E)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester (6.8 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 2.5 hours the cooled reaction was worked up in the usual manner, and the crude acid was crystallized from 2-propanol-hexane to give 5.6 g of (E,E)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid, mp 158°-160° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][CH2:23][CH2:22][C:21]([C:32](O)=[O:33])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:47]([N:50]1[C:54]([CH2:55][S:56]([C:58]2[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=2)=[O:57])=[CH:53][N:52]=[CH:51]1)[CH2:48][CH3:49]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][CH2:23][CH2:22][C:21]([C:32]([NH:62][C:61]4[CH:60]=[CH:59][C:58]([S:56]([CH2:55][C:54]5[N:50]([CH2:47][CH2:48][CH3:49])[CH:51]=[N:52][CH:53]=5)=[O:57])=[CH:64][CH:63]=4)=[O:33])=[CH:20][C:19]=3[CH:35]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3c2ccccc2)cc1
Reactant: CCCn1cncc1CS(=O)c1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3c2ccccc2)cc1
Reaction time: 1 h

Procedure:
(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartarate monohydrate (368 mg) was dissolved in ethyl acetate (5 ml) and 1N hydrochloric acid (1.87 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (1.87 ml) was added, followed by extraction with 2-propanol-ethyl:acetate (1:4). The organic layers were washed with saturated brine, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue was added tetrahydrofuran, after which the solvent was distilled off again under reduced pressure to give (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 8-(4-(2-butoxyethoxy)phenyl)-1-phenyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (200 mg) in tetrahydrofuran (10 ml) was added a drop of DMF, and then oxalyl chloride (0.04 ml) was added, and the mixture was stirred under nitrogen atmosphere for 1 hour. The resulting solution was added dropwise to a solution of (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and triethylamine (1.54 ml) in tetrahydrofuran (10 ml) at 0° C. under nitrogen atmosphere. The mixture was returned to room temperature and stirred for 3 hours, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous acetic acid solution twice, with aqueous saturated sodium bicarbonate solution twice, and with saturated brine once, after which the resultant was dried with magnesium sulfate. After distilling off the solvent under reduced pressure, the resultant was separated and purified with a basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:99) to give 8-[4-(2-butoxyethoxy)phenyl]-1-phenyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (14.6 mg) (Compound 35) as a yellow amorphous material.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=O.C(OP([CH2:54][C:55]#[N:56])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:54][C:55]#[N:56])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc(F)cc2)cc1OC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc(F)cc2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(4′-fluorophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4′-fluorobenzophenone (1.3 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (5.5 mL, 5.5 mmol, 1M) with a reaction time of 22 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 2.38 g (55%) of a mixture of the E and Z isomers as a white solid: mp 100–102° C.; 1H NMR (CDCl3) δ 7.54–6.74 (m, 14H), 5.67 (s, 1H), 5.57 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H); 13 C NMR (CDCl3) δ 166.0, 165.6, 162.0, 161.6, 151.3, 150.7, 148.9, 148.7, 135.4, 135.4, 133.2, 133.1, 131.7, 131.6, 131.3, 130.7, 130.5, 129.2, 123.1, 122.1, 118.1, 118.0, 115.8, 115.8, 115.5, 115.4, 112.6, 111.0, 110.8, 93.4, 93.2, 56.0, 56.0, 55.9; Anal. Calcd for C17H14FNO2. Theoretical: C, 72.07; H, 4.98; N, 4.94. Found: C, 71.91; H, 4.98; N, 4.79.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([O:12][CH3:13])=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc(C)c1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1c(C)cc(Br)cc1CO
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Methyl 5-bromo-2-methoxy-3-methylbenzoate (2.26 g, 8.7 mmol) was dissolved in methylene chloride (30 mL), cooled to −78° C., and treated with diisobutylaluminum hydride (1 M in methylene chloride, 26.1 mL, 26.1 mmol). After stirring at −78° C. for 1 h the reaction was quenched by a few drops of methanol (until no bubbling was observed) followed by addition of excess saturated sodium potassium tartarate (2 mL). The reaction was stirred at room temperature overnight. The layers were separated and the organic layer washed with brine (2×), dried over sodium sulfate, and concentrated to afford 2.0 g (quant). 1H-NMR (CDCl3, 500 MHz) δ 7.30-7.31 (m, 1H), 7.21-7.22 (m, 1H), 4.62 (s, 2H), 3.71 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]([N:11]1[CH2:38][C:19]2([CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]3[CH:35]4[CH2:36][CH:31]5[CH2:32][CH:33]([CH2:37][CH:29]3[CH2:30]5)[CH2:34]4)=[O:26])[CH2:21][CH2:20]2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])=[O:5])C.[Li+].[OH-]>C(#N)C>[CH:29]12[CH2:37][CH:33]3[CH2:32][CH:31]([CH2:36][CH:35]([CH2:34]3)[CH:28]1[O:27][C:25]([N:22]1[CH2:21][CH2:20][C:19]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][N:11]([C:9]([CH:7]4[CH2:8][CH:6]4[C:4]([OH:5])=[O:3])=[O:10])[CH2:38]3)[CH2:24][CH2:23]1)=[O:26])[CH2:30]2
Reactant: CCOC(=O)C1CC1C(=O)N1Cc2ccccc2C2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)C1CC1C(=O)N1Cc2ccccc2C2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
2-Adamantyl 2-((1RS,2RS)-2-(ethoxycarbonyl)cyclopropanecarbonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (9 mg, 0.017 mmol) was mixed with 2N aq LiOH (2004, excess) and acetonitrile (3 mL). The mixture was stirred overnight at rt. LC-MS showed the reaction was complete. The mixture was concentrated, acidified with 5% aq HCl and extracted with EtOAc (3×3 mL). The combined organic layers were concentrated and purified by preparative HPLC to afford (1RS,2RS)-2-(1′-(2-adamantyloxycarbonyl)-2,3-dihydro-1H-spiro[isoquino line-4,4′-piperidine]-2-ylcarbonyl)cyclopropanecarboxylic acid (4.6 mg, 54%). LC-MS Method 1 tR=1.98 min, m/z=493; 1H NMR (CDCl3) δ=7.37 (t, 1H), 7.31-7.19 (m, 2H), 7.13 (d, 1H), 4.89 (m, 3H), 4.16 (m, 3H), 3.15 (m, 2H), 2.50 (m, 1H), 2.29 (m, 1H).
Reaction SMILES: [C:1]([C@@:3]1(O)[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH:15]=[CH:16]1)[CH2:11][CH2:10]3)#[CH:2]>C1C=CC=CC=1>[C:1]([C:3]1[C@:4]2([CH2:21][CH2:20][C@H:19]3[C@@H:9]([CH2:10][CH2:11][C:12]4[C@:17]3([CH3:18])[CH:16]=[CH:15][C:14](=[O:22])[CH:13]=4)[C@@H:6]2[CH2:7][CH:8]=1)[CH3:5])#[CH:2]
Reactant: C#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Solvent: c1ccccc1
Product: C#CC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Benzene and saturated saline were added to the reaction mixture to extract the product into benzene. The separated benzene layer was further washed three times with saturated saline, dried over anhydrous sodium sulfate and concentrated to give crystals. The high-speed liquid chromatographic analysis of the crystals showed that 17β-ethynyl-17α-hydroxyandrosta-1,4-diene-3-one and 17-ethynylandrosta-1,4,16-trien-3-one were formed in yields of 63 mol % and 32 mol %, respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:26])[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:16][CH2:17][OH:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:18][CH2:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:26])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CN(CCCO)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
(S)-6-Benzyloxycarbonylamino-4-(tert-butoxycarbonyl)-4-azaheptan-1-ol (380 g, 1.04 mol) and triethylamine (147 g, 1.45 mol) were dissolved in methylene chloride (5.0 L). The resulting solution was cooled to 0° C., to which a solution of methanesulfonyl chloride (143 g, 1.25 mol) in methylene chloride (0.1 L) was added at an internal temperature of 5° C. or below. Subsequently, the reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting materials by TLC, purified water was added to the reaction mixture for extraction. The resulting organic layer was washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The resulting mixture was filtered and concentrated under reduced pressure to give the target product as a yellow oil (425 g, yield 92.0%). Despite the fact that the compound thus obtained was refrigerated, the degradation reaction proceeded, revealing that this compound was unstable.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]([C:13]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:14]=1[NH:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[C:5]([C:13]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:14]=1[NH:15][C:16](=[O:23])[C:17](=[N:1][OH:3])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 50 g. of sodium nitrite is added dropwise to a solution of 34.6 g. of ethyl 2'-benzoyl-4'-chloro-malonanilate in 250 ml. of glacial acetic acid. After 1 1/2 hours stirring at room temperature, the oxime crystallizes out and is filtered off by suction, washed with water and dried in vacuum. Ethyl 2'-benzoyl-4'-chloro-mesoxalanilate 2-oxime, m.p. 98°-105° is obtained.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]1(/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)/C=C\c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C\c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
1.1 g of methyl (Z)-3-phenylacrylate are dissolved in a mixture of 30 ml of tetrahydrofuran and 10 ml of water, and 340 mg of lithium hydroxide are added. The mixture is stirred at 60° C. After four hours, the reaction mixture is acidified by adding one molar hydrochloric acid solution and extracted five times with 50 ml of ethyl acetate each time. The combined organic phases are dried over MgSO4 and then the solvent is removed in vacuo. 900 mg of (Z)-3-phenylacrylic acid are obtained as an oil.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]1([CH2:43][NH:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[CH2:4][CH2:3]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:34][CH:35]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]1([CH2:43][NH:44][CH2:45][CH2:46][N:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.1 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperidin-1-yl)ethylamino)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (119 mg, 0.167 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 6 h then was concentrated under reduced pressure. The residue was dissolved in dioxane and MeOH and was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure. The residue was dissolved in dioxane and methanol and the mixture was heated with a heat gun to reflux. Water was slowly added until the mixture was slightly cloudy. The mixture was allowed to cool to rt and then was refrigerated overnight. The solids that formed were collected by filtration and were washed with water to afford the title compound as a light-yellow solid (57 mg, 0.087 mmol, 52.1% yield). LCMS: m/e 655.6 (M+H)+, 2.28 min (method 6). 1H NMR (400 MHz, Acetic Acid d4) δ ppm 7.99 (d, J=8.28 Hz, 2H), 7.25 (d, J=8.28 Hz, 2H), 5.32 (d, J=4.52 Hz, 1H), 4.75 (s, 1H), 4.63 (s, 1H), 3.72 (s, 2H), 3.56-3.66 (m, 2H), 3.33 (d, J=12.80 Hz, 1H), 2.98 (d, J=12.80 Hz, 1H), 2.48 (br. s., 1H), 1.71 (s, 3H), 1.14 (s, 3H), 1.09-2.22 (m, 32H), 1.05 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([OH:15])=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])=[N:21][CH:22]=1>>[C:24]([N:23]([CH3:27])[C:20]1[N:21]=[CH:22][C:17]([NH:16][C:13]([C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[Cl:1])=[O:15])=[CH:18][CH:19]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)N(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1Cl
Product: CC(=O)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2Cl)cn1

Procedure:
With a procedure similar to example 16 above, 5-chloro-2-phenyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 5-chloro-2-phenyl-oxazole-4-carboxylic acid and N-(5-amino-pyridin-2-yl)-N-methyl-acetamide. LCMS calcd for C18H15ClN4O3 (m/e) 370, obsd 371 (M+H).
Reaction SMILES: C1(PC2C=CC=CC=2)C=CC=CC=1.CO[CH:16]1[C@@H:21]2[C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[O:24][CH2:25][C@@H:20]2[CH2:19][CH2:18][N:17]1[CH2:30][CH2:31][CH3:32].Cl.C1C[O:37]CC1>CCCCCC>[OH:37][C:29]1[C:22]2[C@@H:21]3[C@H:20]([CH2:25][O:24][C:23]=2[CH:26]=[CH:27][CH:28]=1)[CH2:19][CH2:18][N:17]([CH2:30][CH2:31][CH3:32])[CH2:16]3
Reactant: C1CCOC1
Reactant: CCCN1CC[C@H]2COc3ccccc3[C@H]2C1OC
Agent: Cl
Agent: c1ccc(Pc2ccccc2)cc1
Solvent: CCCCCC
Product: CCCN1CC[C@H]2COc3cccc(O)c3[C@H]2C1
Reaction time: 0.05 h

Procedure:
To a solution of 0.48 g of diphenylphospine in 4 ml THF under nitrogen at 0° is added 1.38 ml n-butylithium (2.24M in hexane). After 3 min., 0.238 g (±)-[4aR*,10bS*]-1,3,4,4a,5,10b-hexahydro-1-methoxy-2-propyl-2 H-[1]benzopyrano[4,3-c]pyridine in 1 ml THF is added. The mixture is refluxed 2.5 hours. After cooling 8 ml 2N HCl is added and the THF evaporated under reduced pressure. The aqueous phase is extracted with two 10 ml portions of ether, basified with solid NaHCO3 and extracted with six 20 ml portions of CH2Cl2. The CH2Cl2 extracts are dried over Na2SO4, filtered, concentrated under reduced pressure and flash chromatographed with CH2Cl2 /ammonia saturated methanol (20:1) to yield the title compound; m.p. of HCl salt 264°-265° dec.