Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.Cl[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].C(N(CC)CC)C>C(#N)C.[Pd]>[N+:16]([C:6]1[CH:7]=[C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:9]=[CH:10][CH:5]=1)([O-:18])=[O:17]
Reactant: CC(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C(=O)O)c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Yield: 92.1 %

Procedure:
16.5 ml of formic acid are added over 5 minutes to a round-bottomed flask, under inert atmosphere, containing 67.7 g of (RS)-2-(4-chloro-3-nitrophenyl) propionic acid, 87 ml of triethylamine and 6.1 g of 5% palladium-on-charcoal in 680 ml of acetonitrile. The reaction medium is heated at reflux for 18 hours and, after cooling to a temperature in the region of 20° C., is then filtered through Celite. The filtrate is evaporated to dryness under reduced pressure and taken up in 500 ml of water and 400 ml of ethyl acetate. The organic phase is separated out after settling has taken place and the aqueous phase is extracted with twice 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. 53 g of 2-(3-nitrophenyl)propionic acid are thus obtained in the form of a brown oil [IR spectrum (CH2 Cl2, cm-1) δOH acid: 3250-2450; γCH Aliph.: 2985-2940; γC=0: 1715; γaNO2 : 1535; γsNO2 : 1355; γPh m-subst.: 690; NMR spectrum (DMSO-d6, 200 MHz): 1.45 (d, J=7 Hz, 3H); 3.9 (q, J=7 Hz, 1H); 7.6 (t, J=7 Hz, 1H); 7.8 (d, J=7 Hz, 1H); 8.1 (d, J=7 Hz, 1H); 8.15 (s, 1H); 12.5 (broad s, acidic OH)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:14]=2)=[CH:4][CH:3]=1.[CH2:34]=O.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: C[C@H](Nc1cc(-c2sc(C3CCNCC3)nc2-c2ccc(F)cc2)ccn1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](Nc1cc(-c2sc(C3CCN(C)CC3)nc2-c2ccc(F)cc2)ccn1)c1ccccc1
Yield: 106.8 %

Procedure:
4-(4-Fluorophenyl)-2-(4-piperidinyl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole (500 mg 1.09 mmol) is dissolved in MeOH (11 ml) and treated with an aqueous 36%-solution of formaldehyde (0.17 ml 2.18 mmol) and NaBH4 (83 mg 2.18 mmol), which is added as a solid in 3 portions. After 30 min at room temperature the reaction mixture is poured on water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 95/4.5/0.5) to yield the title compound (550 mg 86%) as pale yellow foam.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([N:12]2[C:17]3[N:18]=[C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][C:24]=4[O:42][CH3:43])[N:20]=[CH:21][C:16]=3[C:15]([CH3:44])=[CH:14][C:13]2=[O:45])[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH:2]=[CH2:3].C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.CC#N>C(O)(C(F)(F)F)=O.O>[CH3:43][O:42][C:24]1[CH:25]=[C:26]([N:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)[CH:27]=[CH:28][C:23]=1[NH:22][C:19]1[N:20]=[CH:21][C:16]2[C:15]([CH3:44])=[CH:14][C:13](=[O:45])[N:12]([C:8]3[CH:7]=[C:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH:11]=[CH:10][CH:9]=3)[C:17]=2[N:18]=1
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4OC)nc32)c1
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCNCC5)cc4OC)nc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude tert-butyl 4-(4-((8-(3-acrylamidophenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (18b) from the previous step was treated with DCM (5 mL) and TFA (5.0 mL, 64.9 mmol) and allowed to stir at RT for 30 min. The reaction mixture was concentrated and purified on the on an ISCO Combiflash RF (24 g Redisep Gold column, using a gradient of 5-20% 2 M NH3/MeOH in DCM) affording enriched product. It was repurifed on a Gilson (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water), concentrated in the genevac overnight and then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 20% MeOH/DCM to remove any residual salt then dried under vacuum affording N-(3-(2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (18) (20.6 mg, 0.040 mmol) as a bright yellow amorphous solid. m/z (ESI, +ve ion) 512.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1H, s), 8.80 (1H, s), 8.08 (1H, s), 7.87 (1H, d, J=8.2 Hz), 7.57 (1H, s), 7.50 (1H, t, J=8.0 Hz), 7.27 (1H, d, J=8.8 Hz), 6.97 (1H, d, J=8.6 Hz), 6.50 (1H, d, J=2.3 Hz), 6.38-6.48 (1H, m), 6.20-6.35 (2H, m), 5.99 (1H, br. s.), 5.76 (1H, dd, J=10.1, 1.9 Hz), 3.77 (3H, s), 2.87-2.99 (4H, m), 2.74-2.85 (4H, m), 2.46 (3H, s).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([CH:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:23])[N:14]=[C:13]4[NH:24][CH:25]=[CH:26][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl(O)(=O)(=O)=O>C(OC(C)=O)(C)(C)C>[C:5]([O:22][CH:17]([C:16]1[C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[O:1][CH2:2][CH2:3][CH2:4]3)=[C:12]2[CH:26]=[CH:25][NH:24][C:13]2=[N:14][C:15]=1[CH3:23])[C:18]([O:20][CH3:21])=[O:19])([CH3:10])([CH3:6])[CH3:4]
Reactant: COC(=O)C(O)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of crude methyl 2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate in t-BuOAc (22 mL) was treated with perchloric acid (0.131 mL, 2.176 mmol) and stirred at ambient temperature for 30-60 minutes until LCMS indicates reaction was nearly complete (70-90% conversion to desired product). The mixture was then cooled in an ice bath, quenched with saturated sodium bicarbonate and then extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-50% hex/EtOAc) to afford the desired product (75 mg, 0.184 mmol, 33.8%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.10 (d, 1 H), 7.29-7.16 (m, 3 H), 6.92 (d, J=8.4 Hz, 1 H), 6.24 (d, J=9.4 Hz, 1 H), 5.46 (s, 1 H), 4.36-4.23 (m, 2 H), 3.81-3.73 (m, 3 H), 2.96-2.79 (m, 2 H), 2.78-2.72 (m, 3 H), 2.17-2.00 (m, 2 H), 0.95 (s, 9 H); LC/MS (m/z) ES+=409.37 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:29]#[N:30]>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:29]#[N:30]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COc1ccc2cc3ncc(C#N)c(Cl)c3cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc3ncc(C#N)c(Nc4ccc(Cl)cc4Cl)c3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
According to the procedure of Example 14, a reaction mixture of 657.8 mg (4.06 mmol) of 2,4-dichloroaniline and 162.4 mg (4.06 mmol) of sodium hydride in 18 mL of anhydrous DMF is stirred at room temperature for 0.5 hour. To the mixture is added 494.0 mg (1.84 mmol) of 4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile. The resulting mixture is heated at 55° C. for 1 hour. After work up, 624.6 mg (86.2%) of 4-(2,4-dichloroanilino)-7-methoxybenzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp 215–217° C.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].CN(CCN1CCOCC1)C(=O)C1C=CC=[C:50]([C:51]([NH:53][C:54]2C=CC(N3CCCCC3)=C[C:55]=2[C:66]2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=[CH:68][N:67]=2)=[O:52])C=1.CC#N.N1CC[C@@H](NC(=O)C)C1>CN(C=O)C>[C:51]([NH:53][C@H:54]1[CH2:55][CH2:66][N:67]([C:34]([C:33]2[CH:32]=[C:31]([CH:39]=[CH:38][CH:37]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:44])[F:43])[CH:4]=2)=[O:9])=[O:30])=[O:35])[CH2:68]1)(=[O:52])[CH3:50]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CC(=O)N[C@@H]1CCNC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)N[C@H]1CCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e using the procedure described for the preparation of N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)-pyridin-2-yl)phenyl)isophthalamide 4.8, except that CH3CN was substituted for DMF as the reaction solvent and (R)—N-(pyrrolidin-3-yl)acetamide was used as the amine component. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.99 (d, J=6.0 Hz, 1H), 8.70 (d, J=9.6 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J=6.0 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.01 (s, 1H), 7.88˜7.78 (m, 2H), 7.72˜7.54 (m, 6H), 4.72 (s, 1H), 4.51˜4.28 (m, 1H), 3.91˜3.52 (m, 8H), 2.30˜1.79 (m, 11H). MS (ES, m/z): 713 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.P(Br)(Br)[Br:15].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:15][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11]
Reactant: OCc1ccc(I)cc1C(F)(F)F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1cc(I)ccc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of [4-iodo-2-(trifluoromethyl)phenyl]methanol (2.1 g, 6.95 mmol) in DCM (15 ml) in an ice-water bath was added dropwise a solution of phosphorous tribromide (0.66 ml, 7.00 mmol, Aldrich) in DCM (15 ml). The resulting solution was allowed to warm to ambient temperature and stirred under nitrogen for 2 h. The reaction mixture was poured onto a mixture of ice-water (50 ml) and saturated sodium hydrogen carbonate (50 ml). The biphasic mixture was diluted with DCM (50 ml). The phases were separated and the aqeuous phase washed with DCM (50 ml). The combined organic phases were washed with water (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave 1-(bromomethyl)-4-iodo-2-(trifluoromethyl)benzene as a brown oil (1.24 g).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][S:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)(=[O:14])=[O:13])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.[NH4+].[OH-].O>C(Cl)(Cl)Cl>[NH:33]1[CH2:34][CH2:35][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15][S:12]([NH:11][CH2:10][CH2:9][P:4]([OH:8])(=[O:3])[OH:5])(=[O:14])=[O:13])[CH2:31][CH2:32]1
Reactant: CCOP(=O)(CCNS(=O)(=O)CCCCc1ccccc1OCCCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC
Agent: C[Si](C)(C)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=P(O)(O)CCNS(=O)(=O)CCCCc1ccccc1OCCCCC1CCNCC1

Procedure:
A solution of 6-9 (0.63 g, 0.142 mmol) in CHCl3 (5 ml) at rt was treated with TMSBr (0.85 mmol) for 16 hrs. The solvent was removed and the residue was dissolved in 10% aqueous acetone and this stripped to dryness. The residue was mixed with toluene and the resulting gum was purified by flash chromatography on silica gel eluting with 4:1:1 EtOH/H2O/NH4OH to provide pure 6-11. Rf 0.38 (silica gel, 4:1:1EtOH/NH4OH/H2O. ##STR65##
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[C:6]1([S:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[C:6]1([S:12]([C:15]2[CH:20]=[CH:2][C:3]([OH:4])=[C:17]([C:18](=[O:21])[CH3:19])[CH:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: O=S(=O)(c1ccccc1)c1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1O
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
Chloroacetyl chloride (2.35 g; 0.030 mol) was added at 0° C. to a solution of 4-benzenesulfonyl-phenol (2.34 g; 0.010 mol) in carbon disulfide (50 mL). After 10 minutes at ambient temperature, aluminum trichloride was added in small portions. The reaction was heated at 130° C. under reflux, and the carbon disulfide was distilled, after which the reaction was heated at 180° C. for 45 minutes. After cooling to ambient temperature, the mixture was treated with 10% aqueous HCl (25 mL), extracted with ethyl acetate (100 mL×2), dried (Na2SO4) and concentrated in vacuo. The solid residue was purified by column chromatography on silica gel (hexane-ethyl acetate; 7:3) to give 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone as a white solid (1.924 g; 70%). A sample was recrystallized from ethyl acetate-hexane: MS; (M)+ 276, m. p. 155.5-157.3° C.
Reaction SMILES: C([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH:9]2[CH:18]([OH:19])[C:17]3[C:12](=[C:13]([CH3:24])[C:14]([O:20]C(=O)C)=[CH:15][CH:16]=3)[O:11][CH2:10]2)=[CH:7][CH:6]=1)(=O)C.N1C=CN=C1>C(O)C>[OH:4][C:5]1[CH:26]=[CH:25][C:8]([CH:9]2[CH:18]([OH:19])[C:17]3[C:12](=[C:13]([CH3:24])[C:14]([OH:20])=[CH:15][CH:16]=3)[O:11][CH2:10]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C2COc3c(ccc(OC(C)=O)c3C)C2O)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: Cc1c(O)ccc2c1OCC(c1ccc(O)cc1)C2O

Procedure:
4′,7-Dihydroxy-8-methylisoflavan-4-ol was prepared from 4′,7-diacetoxy-8-methylisoflavan-4-ol (0.4 g, 1.1 mmol) and imidazole (1.0 g) in ethanol (7.0 ml) as described for cis- and trans-tetrahydrodaidzein.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:19]2([CH3:20])[C:6]([C:7](=[CH2:24])[C@@H:8]([CH3:23])[C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][C@@H:12]([F:22])[C:13]2=[O:21])=[CH:5][C:4](=[O:25])[CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:1][C:2]1[C@@:19]2([CH3:20])[C:6]([C:7](=[CH2:24])[C@@H:8]([CH3:23])[C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][C@@H:12]([F:22])[C:13]2=[O:21])=[CH:5][C:4](=[O:25])[CH:3]=1
Reactant: C=C1C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: C=C1C2=CC(=O)C=C(C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C
Yield: 75.4 %

Procedure:
0.560 g of 1β,7α-dimethyl-16α-fluoro-6-methylenandrost-4-ene-3,17-dione and 0.59 g of dichlorodicyanobenzoquinone is refluxed in 20 ml of anhydrous dioxane for about 15 hrs. The the reaction mixture is filtered, the solvent removed in vacuo, the residue dissolved in ethyl acetate, the organic layer washed with water, dried over sodium sulfate and the solvent evaporated under vacuum. The crude product is chromatographed on silica gel using hexane/ethyl acetate 40% as eluant to yield 0.42 g of pure 1,7α-dimethyl-16α-fluoro-6-methylenandrosta-1,4-diene-3,17-dione.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][N:12]([CH3:17])[CH:13]=[CH:14][C:15]#[N:16].[OH-].[Na+]>ClCCCl>[C:15]([C:14](=[CH:13][N:12]([CH3:17])[CH3:11])[CH:3]=[O:4])#[N:16]
Reactant: CN(C)C=CC#N
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CN(C)C=C(C#N)C=O
Temperature: 25 °C

Procedure:
36 ml. (0.465 mole) Of N,N-dimethylformamide were stirred at 0° and 36 ml. (0.392 mole) of phosphorus oxychloride were added dropwise (a salt/ice bath was used in order to keep the reaction mixture at 0°). To the stirring semi-solid, faintly colored reaction mixture was added 300 ml. of 1,2-dichloroethane. Upon warming to room temperature by means of a water bath (25°), a clear solution resulted which was cooled to -7° with an ice/salt bath. A solution of 30 ml. (0.293 mole) of β-dimethylaminoacrylonitrile in 90 ml. of 1,2-dichloroethane was added dropwise keeping the temperature between -4° to -7°. The addition required about 1 hour. The cooling bath was removed and the clear amber reaction mixture allowed to come to room temperature. The reaction mixture was transferred to a 2 liter, round bottomed flask and the solvent removed in vacuo leaving a semi-solid orange colored residue. A 100 g. of ice was added to the residue which gradually dissolved with evolution of heat. The solution was transferred to a beaker and the pH adjusted to 8.4 by adding carefully 2N sodium hydroxide (815 ml. were required) to the stirred solution at 15°-20°. The resulting solution was extracted with ethyl acetate in a liquid-liquid extractor overnight. The ethyl acetate extract was cooled, the crystals which had separated were filtered off, washed with cold ethyl acetate and dried in vacuo, affording crude 2-cyano-3-dimethylaminoacrolein, as deep yellow prisms, m.p. 143°-144°. This material was dissolved in 500 ml. of hot water, treated with 2 g. of norite, the solvent removed in vacuo and the residue crystallized from absolute ethanol, producing the pure product in the form of light yellow prisms, m.p. 143°-144°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[S:28](=[O:32])(=[O:31])([OH:30])[OH:29]>CO.C(OCC)(=O)C>[S:28]([O:30][S:28]([OH:31])(=[O:30])=[O:29])([OH:29])(=[O:32])=[O:31].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1
Reactant: O=S(=O)(O)O
Agent: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=S(=O)(O)OS(=O)(=O)O
Temperature: 0 °C

Procedure:
3-(3-(4-(Pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-yl amine (150 mg) was dissolved in methanol (2 mL) and ethyl acetate (2 mL), and concentrated sulfuric acid (0.026 mL) was added thereto. The solvent was concentrated under a reduced pressure, to the residue was added ethanol (10 mL), and dissolved by heating. Then, the solution was cooled to 0° C, concentrated sulfuric acid (0.026 mL) was added to be solidified. The solids were filtered to obtain the title compound (47 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=[CH:15][C:8]=3[C:7](=[O:19])[C:6]=2[CH:20]=1.[CH3:21][N:22](C)C=O.C(Cl)(Cl)Cl.[C-]#N.[Na+]>O>[CH:16]([C:13]1[CH:14]=[CH:15][C:8]2[C:7](=[O:19])[C:6]3[CH:20]=[C:2]([C:21]#[N:22])[CH:3]=[CH:4][C:5]=3[CH2:11][O:10][C:9]=2[CH:12]=1)([CH3:18])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(C)c1ccc2c(c1)OCc1ccc(Br)cc1C2=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(c1)OCc1ccc(C#N)cc1C2=O

Procedure:
Reflux a mixture of 8.39 gm. (0.0253 mole) of 9-bromo-6,11-dihydro-3-isopropyl-11-oxodibenz[b,e]oxepin, 4.83 gm. (0.0539 mole) of cuprous cyanide and 30 ml. of dimethylformamide for 8 hours with vigorous stirring. Cool the reaction mixture and shake with a mixture of 36 ml. of chloroform, 25 ml. of saturated sodium cyanide solution and 25 ml. of water until all solids have dissolved. Separate the organic layer, wash with aqueous sodium cyanide solution and water and dry over anhydrous magnesium sulfate. Remove the solvent under vacuum. Purity the resulting oil (7.01 gm.) by column chromatography on silica gel with benzene as eluant to obtain the title product [yield 2.8 gm., m.p. 101°-108° C., showing a single spot, Rf =0.18 on thin layer chromatography or silica gel with benzene as the solvent system, pmr (CDCl3 1,23(6H, d, (CH3)2CH--), 2.95 (1H,m, (CH3)2CH--), 5.20 (2H,s, CH2O)].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:6]=[C:2]([NH:1][C:20]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:27])[S:3][C:4]=1[CH2:12][N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Nc1nc(-c2ccco2)c(CN2CCOCC2)s1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(CN2CCOCC2)s1)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.2 %

Procedure:
2-Amino-4-(2-furyl)-5-(morpholinomethyl)thiazole (225 mg, 0.85 mmol) obtained in Step 1 was dissolved in DMF (4 mL), and nicotinoyl chloride hydrochloride (302 mg, 1.70 mmol) and triethylamine (0.24 mL, 1.70 mmol) were added thereto, followed by stirring at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate 1:1) to afford the entitled Compound 94 (73.0 mg, 23%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])([O:3]C(C)(C)C)=O.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(OC(=O)[CH2:44][NH:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.CCOC(C)=O>[CH2:46]([N:45]1[CH2:44][C:1](=[O:3])[NH:8][C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:18]1=[O:20])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: Cc1ccccc1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1C[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Reaction time: 16 h
Yield: 139.8 %

Procedure:
A solution of Boc-2-methyl-L-phenylalanine (2.79 g, 10 mmol) in DMF (25 mL) was treated sequentially with HOBt (2.03 g, 15 mmol), diisopropylethylamine (4.35 mL, 25 mmol), N-benzylglycine ethyl ester (2.03 mL, 11 mmol), and HBTU (5.69 g, 15 mmol). The resulting solution was allowed to stir for 16 h after which time the mixture was poured onto a mixture of a 1 N aqueous HCl (50 mL) solution and EtOAc (50 mL). The organic portion was separated and further extracted with a saturated aqueous NaHCO3 solution (50 mL) follow by brine (50 mL). The organic phase was dried over MgSO4, filtered and evaporated to an oil, which was purified by silica gel flash chromatography with 20% then 30% EtOAc/hexanes as eluant to afford titled compound as a solid (4.31 g, 95%). LC/MS (Method A) 7.43 min, [M+1]+ 455.