Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[OH:31][C:27]1[C:28]([CH3:30])=[CH:29][C:24]([C:14]2([C:10]3[CH:9]=[C:8]([CH3:40])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:15]2=[O:23])=[CH:25][C:26]=1[CH3:39]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(c3ccccc3)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.6 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.816 g, 1.36 mmol), phenylboronic acid (0.330 g, 2.71 mmol), copper (II) acetate (0.25 g, 1.36 mmol), triethylamine (0.38 mL, 2.71 mmol), 4 angstrom molecular sieves, and dichloromethane (20 mL). Stir at room temperature for 72 h under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound in (0.446 g, 0.655 mmol), Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (1.64 mL). Stir for 1 h. Add 1N aqueous HCl (10 mL), water (40 mL), and ethyl acetate (50 mL). Separate the layers, and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.236 g (39%) of the title compound: mass spectrum (FAB): m/z=450(M+1); 1H NMR(DMSO-d6): δ8.24 (s, 2H), 7.58-7.54 (m, 2H), 7.48-7.41 (m, 3H), 7.32 (dd, 1H), 7.22 (td, 1H), 7.10 (td, 1H), 6.77 (d, 1H), 6.74 (s, 4H), 2.07 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH2:12])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.N1C=CC=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][NH:41][C:42](=O)[OH:43])=[O:37])([CH3:34])([CH3:33])[CH3:32].Cl>O1CCCC1>[C:31]([O:35][C:36](=[O:37])[NH:38][CH2:39][CH2:40][NH:41][C:42]([NH:12][C:10]1[S:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=2[N:11]=1)=[O:43])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)O
Reactant: COc1ncnc2sc(N)nc12
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ncnc2sc(NC(=O)NCCNC(=O)OC(C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
A solution of 7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylamine (233 mg, 1.28 mmol) and pyridine (310 μL, 3.53 mmol) in tetrahydrofuran (6 mL) at 25° C. was treated with a solution of triphosgene (190 mg, 0.64 mmol) in tetrahydrofuran (2 mL) followed by (2-tert-butoxycarbonylamino-ethyl)-carbamic acid (225 mg, 1.40 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was treated with a 1N aqueous hydrochloric acid solution and was stirred at 25° C. for an additional 30 min. At this time, the resulting precipitate was collected by filtration and was washed with a 1N aqueous hydrochloric acid solution and diethyl ether to afford {2-[3-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-ureido]-ethyl}-carbamic acid tert-butyl ester (170 mg, 36.8%) as a pink solid; LRMS for C14H20N6O4S (M+H)+ at m/z=369.
Reaction SMILES: CCC([O:5][CH2:6][C:7]([C@:9]1([O:32]C(CC)=O)[C@@:13]2([CH3:30])[CH2:14][C@H:15]([OH:29])[C@:16]3([Cl:28])[C@:26]4([CH3:27])[C:20](=[CH:21][C:22]([CH:24]=[CH:25]4)=[O:23])[CH2:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][C@@H:10]1[CH3:31])=[O:8])=O>O.C(Cl)(Cl)Cl.CC(C)=O>[CH3:31][C@@H:10]1[C@:9]([OH:32])([C:7]([CH2:6][OH:5])=[O:8])[C@:13]2([CH3:30])[C@H:12]([C@H:17]3[C@:16]([Cl:28])([C@@H:15]([OH:29])[CH2:14]2)[C@:26]2([CH3:27])[C:20](=[CH:21][C:22]([CH:24]=[CH:25]2)=[O:23])[CH2:19][CH2:18]3)[CH2:11]1
Reactant: CCC(=O)OCC(=O)[C@@]1(OC(=O)CC)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@@]21C
Solvent: O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO

Procedure:
Also preferably, the steroidal anti-inflammatory of the present formulations is beclomethasone dipropionate or its monohydrate. Beclomethasone dipropionate has the chemical name 9-chloro-11b,17,21-trih-ydroxy-16b-methylpregna-1,4-diene-3,20-doine17,21-dipropionate. The compound may be a white powder with a molecular weight of 521.25; and is very slightly soluble in water (Physicians' Desk Reference.RTM), very soluble in chloroform, and freely soluble in acetone and in alcohol.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1.C(OCC)C>[C:5]12([CH2:4][CH2:3][NH:2][CH3:1])[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][CH:7]([CH2:13]3)[CH2:6]1)[CH2:14]2
Reactant: CNC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCCC12CC3CC(CC(C3)C1)C2
Yield: 61.8 %

Procedure:
A solution of 1-adamantaneacetic acid N-methylamide (1.54 g, 7.45 mmol) in tetrahydrofuran (15.0 ml) was added dropwise to a solution of lithium aluminum hydride (569 mg, 15.0 mmol) in diethyl ether (34.0 ml) under ice-cooling over five minutes. The mixture was refluxed for six hours and then stirred under ice-cooling again. Ethyl acetate was added to the reaction mixture to treat excess lithium aluminum hydride, and then the whole was extracted with 1 N hydrochloric acid (50 ml) twice. A 4 N aqueous sodium hydroxide solution was added to the extract to basify it, and the whole was extracted with diethyl ether (80 ml). The organic layer was washed with a saturated aqueous sodium chloride solution (60 ml) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 890 mg (66%) of the titled compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:8][C:7]=2[CH:21]=1)=[O:2].Cl([O-])=[O:23].[Na+].S(=O)(=O)(O)N>C1COCC1.C(O)(C)(C)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:8][C:7]=2[CH:21]=1)([OH:23])=[O:2]
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccc2oc(C(=O)OCc3ccccc3)cc2c1
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2oc(C(=O)OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
To a solution of benzyl 5-formylbenzofuran-2-carboxylate (0.380 g, 0.1.36 mmol) in THF (5 mL) and t-butanol (1 mL) was added slowly a solution of sodium chlorite (0.245 g 2.71 mmol) and sulfamic acid (0.277 g, 2.86 mmol) in water (2 mL). After stirring at room temperature for 3 h, the solution was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate, and brine then collected, dried (MgSO4), filtered and concentrated to yield the title compound as an off-white solid (0.272 g, 68%). 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.23 (d, 1H), 7.67 (m, 2H), 7.49 (m, 2H), 7.41 (m, 3H), 5.46 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:9][C:10]1=[O:14]
Reactant: Cc1ncccc1-c1cc[nH]c(=O)n1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1-c1ccn(CCCCCl)c(=O)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a solution of 4-(2-methyl-pyridin-3-yl)-1H-pyrimidin-2-one (199 mg, 1.06 mmol) in dry DMF (20 ml), 60% NaH (55 mg, 1.38 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (160 μl, 1.38 mmol) was added and the mixture was stirred at room temperature for 1 hour and heated at 70° C. for 2 hours. Water was added and the mixture extracted with diethyl ether and with ethyl acetate. The organic layers were mixed together, dried (Na2SO4) and evaporated to afford 161 mg of the title compound that was used in the next step without further purification (54% yield).
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[Na+].[CH2:6]([O:8][C:9](=[O:20])[CH:10]([NH2:19])/[CH:11]=[C:12](\[CH3:18])/[CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH3:7].[BH4-].Cl.[C:23](O)(=O)C>O.CC(C)=O>[CH2:6]([O:8][C:9](=[O:20])[CH:10]([NH:19][CH:1]([CH3:2])[CH3:23])/[CH:11]=[C:12](\[CH3:18])/[CH2:13][P:14]([OH:16])([OH:17])=[O:15])[CH3:7]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(N)/C=C(\C)CP(=O)(O)O
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(/C=C(\C)CP(=O)(O)O)NC(C)C
Reaction time: 0.5 h

Procedure:
6.64 g of sodium acetate (anhydrous) and 18 ml of acetone are added to a solution of 6.40 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester in 54 ml of water and 18 ml of glacial acetic acid. 17.67 g ofsodium borohydride are added in approximately 70 portions within a period of 90 minutes with intensive cooling with ice/sodium chloride, 18 ml of acetone being added after 20 minutes and after 50 minutes. When the addition is complete, the thick white suspension is stirred at 0° for 30 minutes to complete the reaction, and then 1N hydrochloric acid is added dropwise until an acidic reaction to Congo red takes place. The resulting clear solution is concentrated by evaporation in vacuo, and the residue is concentrated by evaporation twice more after the addition of ethanol. The residue is then stirred with 200 ml of ethanol at room temperature, and the undissolved material is filtered off and washed with ethanol. The filtrate is concentrated by evaporation in vacuo, and the residue is recrystallised from isopropanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 70 °C
Reaction time: 19 h

Procedure:
2.28 g of 1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 4 g of toluene and 1.02 g of acetic anhydride were fed, and the mixture was heated to 70° C. A toluene (0.56 g) solution of 61 mg of 4-dimethylaminopyridine, and then 0.59 g of pyridine were slowly added in dropwise, and the mixture was stirred for 19 hours to heat to 80° C. The mixture was cooled to room temperature and separated by adding water, and the solvent was distilled off under reduced pressure. 2.20 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C([NH:27][OH:28])=O)(=O)=O)CC3)=NC=2)=CC=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH:46]3[CH2:51][CH2:50][N:49]([S:52]([CH2:55][C@H:56]([CH:60]([CH3:62])[CH3:61])[C:57](O)=[O:58])(=[O:54])=[O:53])[CH2:48][CH2:47]3)=[N:43][CH:44]=2)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH:46]3[CH2:51][CH2:50][N:49]([S:52]([CH2:55][C@H:56]([CH:60]([CH3:61])[CH3:62])[C:57]([NH:27][OH:28])=[O:58])(=[O:54])=[O:53])[CH2:48][CH2:47]3)=[N:43][CH:44]=2)=[CH:37][CH:38]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Yield: 53 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 2-(R)-{4-[5-(4-fluorophenyl)pyridin-2-yloxy]piperidine-1-sulfonylmethyl}-3-methylbutyric acid (0.19 g), to give the title compound as a white solid (0.10 g, 53%)
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:9]2[CH:21]=[CH:22][CH:23]=[C:8]2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[C:7]([OH:24])[C:8]2=[CH:23][CH:22]=[CH:21][N:9]12
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2Cl)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccccc2Cl)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(2-chloro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 376 (M+H)+.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:15][N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH3:16])[CH2:24][CH2:25]2)=[CH:6][CH:7]=1)[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Cc1ccc(OCC2CO2)cc1
Reactant: Cc1ccccc1N1CCNCC1
Product: CC(=O)Cc1ccc(OCC(O)CN2CCN(c3ccccc3C)CC2)cc1

Procedure:
4-(2,3-Epoxypropoxy)-phenylacetone is reacted with 2-methylphenyl-piperazine analogously to Example 2(a). 1-[4-(propan-2-on-yl)-phenoxy]-3-[4-(2-methylphenyl)-piperazin-1-yl]-propan-2-ol is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1([OH:21])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:2].C[O:23][C:24](=[O:47])[C@H:25]([C@@H:44]([CH3:46])O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1([O:21][C@H:44]([CH3:46])[C@@H:25]([C:24]([OH:47])=[O:23])[NH2:26])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:2]
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: CCc1ccsc1C1(O)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccsc1C1(O[C@H](C)[C@H](N)C(=O)O)c2ccccc2-c2ccccc21

Procedure:
from 9-(3-ethylthien-2-yl)-9H-fluoren-9-ol and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:3][CH:2]=1.[CH2:14]=[O:15]>>[OH:15][CH2:14][C:9]1[C:10](=[O:13])[NH:11][CH:12]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:8]=1
Reactant: O=c1ccc(-c2ccncc2)c[nH]1
Reactant: C=O
Product: O=c1[nH]cc(-c2ccncc2)cc1CO

Procedure:
The process which comprises reacting 5-(4-pyridinyl)-2(1H)-pyridinone with excess formaldehyde at an acidic pH to produce 3-hydroxymethyl-5-(4-pyridinyl)-2(1H)-pyridinone.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][C:7]=1[CH:15]([NH:21][C:22]1[CH:27]=[CH:26][C:25](/[C:28](=[N:31]/[H])/[NH:29]O)=[CH:24][CH:23]=1)[C:16]([O:18][CH2:19]C)=[O:17])(=[O:3])[NH2:2]>CO.C(O)(=O)C.[Ni]>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][CH:15]([C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:1](=[O:3])[NH2:2])[C:16]([O:18][CH3:19])=[O:17])=[CH:27][CH:26]=1)(=[NH:29])[NH2:31]
Reactant: [H]/N=C(\NO)c1ccc(NC(C(=O)OCC)c2cc(OCC)ccc2OCC(N)=O)cc1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1ccc(OCC(N)=O)c(C(Nc2ccc(C(=N)N)cc2)C(=O)OC)c1
Yield: 93.4 %

Procedure:
305 mg of ethyl (Z)-(RS)-(2-carbamoylmethoxy-5-ethoxy-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate were treated in 8 ml of methanol-acetic acid (1:1) with Raney-nickel and stirred under hydrogen. The reaction mixture was filtered, evaporated in a vacuum and, for purification, the residue was triturated in acetonitrile. There were obtained 265 mg of methyl (RS)-(4-carbamimidoyl-phenylamino)-(2-carbamoylmethoxy-5-ethoxy-phenyl)-acetate; m.p. 200° C. (dec.), MS: 401 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Br[CH2:14][CH2:15][OH:16]>C(Cl)Cl>[OH:16][CH2:15][CH2:14][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1]
Reactant: OCCBr
Reactant: Nc1ccccc1OC(F)(F)F
Solvent: ClCCl
Product: OCCNc1ccccc1OC(F)(F)F
Temperature: 115 °C
Yield: 46.5 %

Procedure:
A stirred mixture of 5.64 g of 97% 2-trifluoromethoxyaniline and 3.4 mL of 97% 2-bromoethanol was heated at 115° C. for 8 h. After cooling to r.t., 50 ml, of CH2Cl2 was added and the solution was washed with 20% aq. sodium carbonate and H2O (3×20 mL), dried (anhydrous Na2SO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (CHCl3-2 N methanolic NH3 100:0.5) affording 3.18 g (46.5%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)=[N:1]2
Reactant: O=Cc1cccnc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccnc3)nc2c1
Yield: 48 %

Procedure:
5,7-Dimethoxy-2-(pyridin-3-quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3-pyridine carboxaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (105 mg, 48%) was isolated as a white solid. Selected data: MS (m/z): 284.0; MP 257-259° C. (hydrochloride).
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[K+:5].[K+].O.[S:8]([O-:12])([OH:11])(=[O:10])=[O:9].[K+].O=O>>[Si:2]([OH:9])([OH:4])([OH:1])[OH:3].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[K+:5].[K+:5]
Reactant: O=S(=O)([O-])O
Reactant: O=[Si]([O-])[O-]
Agent: O=O
Agent: [K+]
Solvent: O
Product: O=S(=O)([O-])[O-]
Product: O[Si](O)(O)O
Reaction time: 0.03 h

Procedure:
About 1 part by weight of dry granular potassium metasilicate, containing less than 6 mols of water per mol of potassium metasilicate, and 12 mols of potassium hydrogen sulfate are mixed. The mixture is agitated at ambient pressure and chemical reaction causes oxygen to evolve in 1 to 3 minutes; considerable heat is produced, the chemical reaction is complete in 1 to 2 hours, thereby producing white granules of a silicic acid compound and potassium sulfate. The mixture is washed with water and filtered to remove the salt. The silicic acid compound is air dired at 25° to 75° C.
Reaction SMILES: CON(C)[C:4](=[O:47])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[C:49]([Mg]Br)([CH3:51])=[CH2:50]>>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=3)(=[O:39])=[O:38])[C@@H:6]([CH2:5][C:4](=[O:47])[C:49]([CH3:51])=[CH2:50])[CH2:11]2)=[CH:17][CH:16]=1
Reactant: C=C(C)[Mg]Br
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Product: C=C(C)C(=O)C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
Similar to example 29b, 0.20 g of N-methoxy-2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-N-methyl-acetamide (from example 29c) are reacted with isopropenyl magnesium bromide (0.5M in tetrahydrofuran) to afford the crude title compound as a yellow-brown oil which is used in the next step without any further purification. Rf=0.22 (EtOAc-heptane 1:1); Rt=5.49.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:10]([CH:12]1[NH:18][C:17](=O)[CH:16]=[CH:15][CH2:14][CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>C1COCC1.C(OCC)C>[NH:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C@@H:10]([OH:11])[C@@H:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C=CCCC([C@@H](O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)N1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O[C@H](C1CCCCCN1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Yield: 18.1 %

Procedure:
Dissolve 7-((1R,2S)-2-dibenzylamino-1-hydroxy-3-phenylpropyl)-1,5,6,7-tetrahydroazepin-2-one (Isomer 1) (40 mg, 0.09 mmol) in THF (5 mL) and add BH3SMe2 (2 M in diethyl ether, 0.14 mL, 0.27 mmol). Stir the reaction at 50° C. for 3 hour. Add saturated aqueous citric acid (10 mL). Extract aqueous twice with ethyl acetate, combine organics and wash with saturated sodium chloride, dry (magnesium sulfate) and concentrate under reduced pressure. Add 20% palladium hydroxide on carbon (90 mg) and methanol (10 mL) and stir under 1 atmosphere of hydrogen overnight. Filter and evaporate to give a foam. Purify the product using a SCX column to give a thick residue (0.007 g, 40%).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].[C:15]([OH:19])(=[O:18])[CH:16]=[CH2:17].C=CC1C=CC=CC=1.C=CC(O)=O.[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1.Cl.N1C=CC=CC=1>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].[C:15]([O:19][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][O:33]1)(=[O:18])[CH:16]=[CH2:17]
Reactant: C1=COCCC1
Reactant: C=CC(=O)O
Agent: Cl
Solvent: C=CC(=O)OC
Solvent: c1ccncc1
Solvent: C=Cc1ccccc1
Product: C=CC(=O)OC1CCCCO1

Procedure:
Using the procedure of Example 6, reaction of 10 g of poly(styrene [55 wt %], methyl acrylate [20 wt %], acrylic acid [25 wt %]) (Joncryl 67), 125 mL of 3,4-dihydro-2H-pyran, and 0.1 g of pyridine hydrochloride gave 10 g of poly(styrene, methyl acrylate, tetrahydropyranyl acrylate) after precipitation from dichloromethane in methanol at -70° C. 1H NMR (360 MHz, THF-d8): 5.9 (OCHO of tetrahydropyranyl ester). Mole ratio of styrene to tetrahydropyranyl ester=1.8:1. GPC: Mn=6260, Mw=15,900, Mw/Mn=2.54. DSC: Tg=52° C., decomposition endotherm peak at 180.77° C. (125.4 J/g). TGA: 20.69% weight loss at about 180° C. Titration of the product with 0.1N sodium hydroxide shows the presence of 0.2 meq/g of residual carboxylic acid groups. Titration of the starting material shows 3.4 meq/g of carboxylic acid.