Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13](OC)(=[O:18])[C:14]([O:16][CH3:17])=[O:15].[H-].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COC(=O)C(=O)OC
Reactant: COc1cc(Cl)ccc1C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)CC(=O)c1ccc(Cl)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To dimethylformamide (13 ml), 1-(4-chloro-2-methoxyphenyl)ethanone (3.13 g) and dimethyl oxalate (2.4 g) were added, and 60% sodium hydride suspension in oil (811 mg) was added thereto at 0° C. The mixture was stirred at a room temperature for one hour, and then heated to 50° C. and stirred for 19 hours. The mixture was allowed to cool to a room temperature, 3-N hydrochloric acid was added to the mixture. The resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated saline solution in order, then dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure. In the process of the concentration, the precipitated crystal was separated by filtration to give the title compound (2.47 g, 54%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:17](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:41])[C:25]4[CH:30]=[CH:29][C:28]([N:31]5[C:39]6[CH:38]=[CH:37][N:36]=[CH:35][C:34]=6[N:33]=[C:32]5[CH3:40])=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:42])[CH2:9][C:8]=2[CH:43]=1>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:17](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:41])[C:25]4[CH:26]=[CH:27][C:28]([N:31]5[C:39]6[CH:38]=[CH:37][N:36]=[CH:35][C:34]=6[N:33]=[C:32]5[CH3:40])=[CH:29][CH:30]=4)[CH2:20][CH2:19]3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]([OH:42])[CH2:9][C:8]=2[CH:43]=1
Reactant: Cc1nc2cnccc2n1-c1ccc(C(=O)N2CCC(=C3c4ccc(Cl)cc4CC(=O)c4cccnc43)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1nc2cnccc2n1-c1ccc(C(=O)N2CCC(=C3c4ccc(Cl)cc4CC(O)c4cccnc43)CC2)cc1

Procedure:
This was prepared as described in Example 10 by sodium borohydride reduction of 4-(8-chloro-5,6-dihydro-5-oxo-11H-benzo[5,6]cyclohepta[1,2-b]pyrid-11-ylidene)-1-[4-(2-methyimidazo[4,5-c]pyrid-1-yl)benzoyl]piperidine (from Example 18; 40 mg). The title compound was obtained as a yellow foam (35 mg, 87%) which was characterised as a hydrate containing 0.33 equivalents of ethyl acetate. Found: C,67.7; H,5.2; N,11.4. C33H28ClN5O2. H2O. 0.33 C4H8O2 requires C,67.7; H,5.1; N,11.5%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)ccc1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(Br)c(CBr)c1
Yield: 14.3 %

Procedure:
To a stirred solution of 4-bromo-3-methyl benzonitrile (5 g, 25.5 mmol) in CCl4 (200 mL), was added N-bromosuccinimide (4.99 g, 28.05 mmol) and 2,2-Azobisisobutyronitrile (335 mg, 2.04 mmol). The mixture was heated to reflux overnight then cooled, diluted with CH2Cl2 and quenched with 10% NaHSO3. The layers were separated and the CH2Cl2 layer was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated under vacuum. Column chromatography on silica gel (5-10% ethyl acetate/hexanes) afforded 4.31 g (3.65 mmol, 61%) of a mixture of mono- and di-bromo intermediates. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.55 (s, 2H) 7.42 (dd, J=8.31, 2.01 Hz, 1H) 7.67-7.78 (m, 2H). Mass spec.: 275.94 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([CH3:10])[O:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH2:27])[N:20]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)[N:19]=2)=[CH:14][C:13]=1[O:41][CH3:42]>N1C=CC=CC=1>[NH2:27][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:20]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[CH2:30][CH2:29]3)[N:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:10])=[O:8])=[C:13]([O:41][CH3:42])[CH:14]=3)[C:26]=12
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1c(C)noc1C
Reaction time: 5 h

Procedure:
3,5-Dimethyl-4-isoxazolecarbonyl chloride (22 mg, 0.137 mmol) was added to a solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.067 mmol) in pyridine (0.5 mL). After 5 hours, the solvent was evaporated and the residue was re-crystallized from DMSO to give cis-N4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3,5-dimethyl-4-isoxazolecarboxamide (33 mg, 87%). 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.24 (m, 2H), 2.36 (m, 2H), 2.41 (s, 3H), 2.63 (s, 3H), 2.77 (m, 3H), 3.17 (s, 3H), 3.37 (bm, 8H), 3.95 (s, 3H), 4.95 (m, 1H), 7.37 (m, 2H), 8.17 (d, J=8.17, 1H), 8.30 (s, 1H), 9.26 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.), MH+ =560.2, Rt=2.44 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)CC>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]3)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: COc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
In an 100 mL three-necked RB flask equipped with a magnetic bar, a condenser, and a nitrogen gas inlet, 6-bromo-2-naphthoic acid (2.62 g, 96%, 10 mmol), 4-methoxy-benzeneboronic acid (1.52 g, 10 mmol) and 1-propanol (20 mL) were mixed and stirred at room temperature for about 30 min. Palladium acetate (0.007 g, 0.003 equiv., 0.03 mmol), triphenylphosphine (0.024 g, 0.009 equiv., 0.9 mmol), Na2CO3 solution (2 M, 8 mL, 1.20 equiv., 12 mmol) and water (4 mL) were added and the mixture was refluxed for 2 h. When the mixture was still hot, 20 mL of water was added and the mixture was stirred and cooled to room temperature. The resultant crystals were filtered, washed with water and refluxed with 50 mL of acetic acid for 3-4 h. A white solid was obtained (2.55 g) and recrystallization from acetone gave the title compound as white crystals (2.24 g, 81%): mp 267-269° C.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:8]=[C:9]([C:16]([CH3:29])([CH3:28])[C:17]([N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:16]([CH3:29])([CH3:28])[C:17]([N:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:18])=[CH:8][C:7]=1[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:30])[CH3:1]
Reactant: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(NCCCN(C)C)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc(N)c(NCCCN(C)C)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
2-(3-{[3-(dimethylamino)propyl]amino}-4-nitrophenyl)-N,N-diisobutyl-2-methylpropanamide (44 mg) in solution in a mixture of ethyl acetate/ethanol 2:1 (3 ml), and 10% palladium on carbon (5 mg) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (39 mg; 95% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36]>ClCCl>[Cl:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([N:8]([C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[CH2:13][CH2:14]1)[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=1)=[O:36]
Reactant: COc1ccc(CN[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(C(=O)C(C)(C)CCl)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 2 h

Procedure:
A stirred solution of 15A (200 mg, 0.598 mmol) in dichloromethane (5 mL) was treated with triethylamine (0.208 mL, 1.495 mmol), followed by slow addition of 3-chloro-2,2-dimethyl propanoyl chloride (0.155 mL, 1.196 mmol) at room temperature. After stirring for 2 h, reaction was judged complete by LCMS. It was washed with water, and the organics were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by Isco silica column (24 g) eluted with ethyl acetate:hexane, 0%-100%. Concentration of the appropriate fractions yielded 15B (226 mg, 83% yield) as a white foam. MS (ES): m/z=453.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, 2H, J=8.5 Hz); 6.75 (d, 2H, J=8.5 Hz); 4.41 (s, 2H); 4.22-4.30 (m, 1H); 3.88-3.98 (m, 1H); 3.72 (s, 3H); 3.69 (s, 2H); 3.19-3.30 (m, 1H); 1.92-2.02 (m, 2H); 1.01-1.69 (m, 23H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>C(#N)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ccc(Br)cn1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 105 °C
Yield: 83.2 %

Procedure:
2.15 g (corresponding to 10.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 1.74 g (corresponding to 10.0 mmol) of 2-amino-5-bromopyridine were dissolved in 50 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 105° C. for 6 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile, and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 20 mL of water and 20 mL of methanol, and then supplemented with about 25 mL of a saturated sodium hydrogencarbonate solution and sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 2.41 g (corresponding to 8.32 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 7, Step 2).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[C:9](SC)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[C:3]1=[O:26].OOS([O-])=O.[K+].[NH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH3:1][N:2]1[C:7]2[N:8]=[C:9]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[C:3]1=[O:26]
Reactant: NC1CCOCC1
Reactant: CSc1ncc2cc(-c3cc(-c4nnc[nH]4)ccc3C)c(=O)n(C)c2n1
Agent: O=S([O-])OO
Agent: [K+]
Product: Cc1ccc(-c2nnc[nH]2)cc1-c1cc2cnc(NC3CCOCC3)nc2n(C)c1=O

Procedure:
8-Methyl-2-methylsulfanyl-6-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-8H-pyrido[2,3-d]pyrimidin-7-one was treated with OXONE™ following the procedure of step 3 of Example 1, and the resulting sulfonyl compound was treated with 4-amino-tetrahydropyran using the procedure of step 4 of Example 1, to give 8-methyl-6-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one: MS (M+H)=418, MP=214.9-216.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([CH:13]1[NH:12][C:10](=[O:11])[N:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:21]1=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C=Nc1cc(F)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NC(Cc2ccccc2)C(=O)N1c1cc(F)ccc1F
Reaction time: 8 h
Yield: 82.7 %

Procedure:
2,5-Difluorophenylisocyanate (1.55 g, 10.0 mmol) in methylene chloride (25 mL) was added dropwise to a suspension of phenylalanine (1.65 g, 10.0 mmol) in methylene chloride (50 mL) containing triethylamine (1.4 mL, 1.01 g, 10.0 mmol). The solution was allowed to stir overnight, and was then concentrated. The residue was taken up into 6N HCl and heated to reflux for 3 hours. The cooled solution was extracted with ethyl acetate (3×), and the combined extracts were washed with water (2×), dried (over MgSO4), filtered and concentrated to give 2.7 grams. Purification by column chromatography gave 2.5 grams of 5-benzyl-3-(2.5-difluorophenyl)imidazolidine-2,4-dione.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3([CH2:23][NH:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[ClH:33].O1CCOCC1>O1CCOCC1>[ClH:33].[ClH:33].[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3([CH2:23][NH:24][C:25](=[O:32])[C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccncc2)(N2CCN(C3CC3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of tert-butyl 4-(4-cyclopropylpiperazin-1-yl)-4-(isonicotinamidomethyl)piperidine-1-carboxylate (0.541 mmol) in dioxane (1 ml/mmol) was added saturated dioxane-HCl solution (3.3 ml) and the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and the residue was azeotroped with dioxane (3×). The crude product was used in the next step.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:29])[C@:7]1([OH:28])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[C@@H:13]([CH3:27])[CH2:12]3)[CH2:9][CH2:8]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C>[OH:28][C@:7]1([C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[C@@H:13]([CH3:27])[CH2:12]3)[CH2:9][CH2:8]1)[C:6](=[O:29])[CH2:5][OH:4]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@@H]2C(=CC[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12

Procedure:
A 13.58 g sample of 21-acetoxy-17α-hydroxy-6α-methylpregna-1,4,9-(11)-triene-3,20-dione in methanol (850 ml) was hydrolyzed with 10% potassium carbonate (34 ml). The reaction mixture was acidified, diluted with water and concentrated to give a gummy precipitate which was dissolved in ethyl acetate. The extract was washed with water and brine, then dried over sodium sulfate and evaporated. Crystallization of the residue from acetone-hexane give the title compound, m.p. 204°-206° C.; one spot by TLC (10% CH3OH--CHCl3).
Reaction SMILES: O.[C:2]1(C(C)C)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][CH2:12][C:13](=[O:15])[CH3:14]>CC(C)=O>[C:2]1([OH:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][CH2:12][C:13](=[O:15])[CH3:14]
Reactant: CC(C)c1ccccc1
Agent: CC(=O)CO
Solvent: O
Solvent: CC(C)=O
Product: Oc1ccccc1

Procedure:
In U.S. Pat. No. 4,251,325 (assigned to BP Chemicals), the work-up of a fraction which has been substantially freed of low boilers, water, and acetone has been optimized by operating the cumene column in such a way that a mixture comprising cumene, AMS and hydroxy acetone is taken off at the top, with this mixture being separated virtually completely from the crude phenol remaining in the bottoms and thus not having to be removed in a costly fashion during the work-up of the phenol. This process gives phenol containing less than 30 ppm of hydroxy acetone. A disadvantage of this process is the fact that the input mixture has to be substantially freed of water, which is why an acetone fraction comprising low boilers and also the major part of the water present in the cleavage product mixture has to be separated from the cleavage product mixture in the preceding separation step. The work-up of such an acetone fraction by methods of the prior art is relatively uneconomical, since a high expenditure for apparatus is required.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([O:20]CC4C=CC=CC=4)=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:7]=1)=[O:5])[CH3:2].C1CC=CCC=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([OH:20])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(OCc3ccccc3)cccc21
Agent: [Pd]
Solvent: C1=CCC=CC1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(O)cccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A mixture of 7-benzyloxy-3-(4-fluorobenzoyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (82 mg, 0.17 mmol) and 10% Pd/C (82 mg) and 1,4-cyclohexadiene (0.15 mL, 1.58 mmol) was stirred at 50° C. for 2 hours. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane-EtOAc (85:15) to give the title compound as a yellow solid (42 mg, 62%); 1H-NMR (CDCl3): δ 10.56 (1H, s), 8.0 (1H, s), 7.64-7.59 (2H, m), 7.20-7.11(3H, m), 6.97-6.93 (1H, m), 6.61-6.55 (1H, m), 5.33 (1H, brs), 4.27-4.20 (4H, m), 3.26-3.23 (2H, m), 1.25 (3H, t); MS (ES): 395 (MH+).
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CCCCCCC.[CH2:18]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].S(Cl)(Cl)=O.[CH3:39][CH:40]([CH2:58][CH3:59])[CH2:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][C:54](O)=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)=[O:44]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:39][CH:40]([CH2:58][CH3:59])[CH2:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][C:54]([O:31][C:30](=[O:32])[C:29]3[CH:28]=[CH:27][C:26]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:34][CH:33]=3)=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)=[O:44]
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CCCCCCCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(C(=O)Oc2ccc(-c3ccc(C(=O)OCC(C)CC)cc3)cc2)cc1

Procedure:
p-n-Octylbenzoic acid chloride prepared from 7 g of p-n-octylbenzoic acid and excess thionyl chloride was dissolved in toluene, and the solution was admixed with a pyridine solution of 8.3 g of said 4-hydroxy-4'-biphenylcarboxylic acid 2-methylbutyl ester for reaction at 80° C. for 3 hours. The crude product was obtained in the same manner as described in Example 1 and recrystallized twice from ethyl acetate to obtain p-n-octylbenzoic acid 4'-(2-methylbutoxycarbonyl)-4-biphenylyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[N:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:50]5[CH:49]=[CH:48][CH:47]=[C:46]([CH:44]=[O:45])[CH:51]=5)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=4)=[O:13])[N:15]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)n1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)n1
Temperature: 100 °C
Yield: 49 %

Procedure:
A mixture of N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (900 mg, 1.383 mmol), (3-formylphenyl)boronic acid (207 mg, 1.383 mmol), Na2CO3 (440 mg, 4.15 mmol) and PdCl2(dppf) (101 mg, 0.138 mmol) was diluted in a mixture of 1,4-dioxane (9 mL) and water (3 mL) in a 20 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 min and it was then heated in a Biotage microwave at normal absorption for 10 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and then washed with ethyl acetate. The combined organic layers were washed with brine. The organic layer was concentrated under vacuum to give a crude residue. It was then purified with flash chromatography eluting with 0 to 100% ethyl acetate in dichloromethane (product came out at 85% ethyl acetate in DCM). The product fractions were combined and concentrated under vacuum to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-2,6-pyridinedicarboxamide as an yellowish oil (458 mg, 49%). LC-MS m/z 676.5 (M+H)+, 0.91 min (ret time).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.COC(=O)CCC1C=C(SC#N)C(OC)=CC=1O>[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(=O)oc2c1
Agent: [Pd]
Agent: COC(=O)CCc1cc(SC#N)c(OC)cc1O
Product: COc1ccc2c(c1)OC(=O)CC2
Yield: 96 %

Procedure:
Compound 14A was prepared by hydrogenation of 7-methoxy-chromen-2-one catalyzed by 10% Pd/C in 96% yield. MS: 179 (M+1)+. Preparation of 3-(2-Hydroxy-4-methoxy-5-thiocyanato-phenyl)-propionic acid methyl ester (Compound 14B)
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Agent: Br
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Yield: 50.6 %

Procedure:
A mixture of ethyl 7-methoxy-3-quinolinecarboxylate (12.0 g) and 47% HBr (200 ml) was refluxed for 24 h. The precipitated crystals (12.63 g) were collected and added to a mixture of ethanol (400 ml) and conc.H2SO4 (2 ml). After refluxing for 20 h, the reaction mixture was concentrated, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated to give ethyl 7-hydroxy-3-quinoline-carboxylate (5.70 g, 51%). Recrystallization from ethyl acetate-hexane gave colorless prisms, 179-180° C.