Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]1[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1)[CH3:4].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>O1CCOCC1>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:10]2[CH:6]([O:5][CH2:3][CH3:4])[CH2:7][CH2:8][C:9]2=[O:11])=[O:19])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC1CCC(=O)N1C(=O)c1ccc(OC)cc1
Yield: 44.5 %

Procedure:
2.6 g of sodium hydride (dispersed at 55-60% in oil) is added to a solution of 7 g of 5-ethoxy pyrrolidin-2-one in 150 cm3 of dioxane, with agitation for 1 hour. A solution of 9.25 g of 4-methoxy benzoyl chloride in 60 cm3 of dioxane is added with agitation for 4 hours. After filtering, the dioxane is evaporated under reduced pressure. The residue is chromatographed on 500 g of silica gel (eluent: acetone-n-hexane 1-2) and 6.35 g of expected product is obtained. b.p. =210° C. under 0.09 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)[C:5]([OH:7])=O.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH:12]1([O:11][C:9]2[CH:8]=[C:4]([CH:3]=[C:2]([F:1])[CH:10]=2)[C:5]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([O:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:21][CH:20]=2)=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)c1cc(F)cc(OC2CCCCC2)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(F)cc(OC2CCCCC2)c1
Yield: 26.9 %

Procedure:
3-Fluoro-5-cyclohexyloxybenzoic acid (100 mg, 420 μmol), 4-amino-1-(2-morpholinoethoxy)naphthalene (103 mg, 378 μmol), HBTU (238 mg, 630 μmol), DIPEA (220 μl, 1.26 mmol), and DMF (1.5 ml) are stirred for 12 hours at room temperature. CH2Cl2 (2 ml) is added to the mixture, and it is then washed with H2O, NaHCO3 solution, and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by column chromatography on silica gel eluting with ethyl acetate to provide 3-(cyclohexyloxy)-5-fluoro-N-[4-(2-morpholin-4-ylethoxy)-1-naphthyl]benzamide as a brown solid (50 mg). Mp: 116-118° C.; 1H NMR(DMSO-d6) δ 10.29 (s, 1H), 8.21 (m, 1H), 7.87 (m, 1H), 7.57 (m, 2H), 7.52 (s, 1H), 7.42 (m, 2H), 7.07 (m, 2H), 4.51 (m, 1H), 4.31 (t, 2H), 3.61 (t, 4H), 2.89 (m, 2H), 2.62 (t, 4H), 1.93 (m, 2H), 1.72 (m, 2H), 1.46 (m, 6H); MS 493.32 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:35])([CH3:34])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:28][C:29](OCC)=[O:30])[CH2:22][C:23](OCC)=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[AlH4-].[Li+]>C1COCC1>[CH3:35][Si:2]([CH3:1])([CH3:34])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:22][CH2:23][OH:24])[CH2:28][CH2:29][OH:30])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: CCOC(=O)CC(CC(=O)OCC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)CCO)c3)ncnc21
Reaction time: 1 h
Yield: 76 %

Procedure:
Diethyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate, prepared substantially as described in Example 407 (0.80 g, 0.0016 mol), was dissolved in THF (40 mL, 0.49 mol) and cooled in an ice bath under a nitrogen atmosphere. To this mixture, 1.0 M lithium tetrahydroaluminate in THF (3.2 mL) was added slowly. The reaction was stirred for 1 h, quenched with ice and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give an amber oil. The product was purified by FCC on silica gel eluting with an ethyl acetate: methanol gradient to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol as a clear viscous oil (0.51 gm, 76%), LC/MS (M+H): 418, 1H NMR (DMSO-d6) δ, 8.85 (s, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 7.45 (d, 1H), 6.83 (d, 1H), 5.73 (s, 2H), 4.91 (m, 1H), 3.75 (m, 2H), 3.59 (m, 2H), 3.45 (m, 2H), 2.18 (m, 4H), 0.95 (m, 2H), 0.1 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:32]([N:34]2[CH:38]=N[CH:36]=[CH:35]2)=[O:33])C=1.Cl.[F:40][C:41]1C=[CH:48][CH:47]=[C:46]2[C:42]=1CNC2.Cl>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@H:9]([C:14](=[O:26])[NH:15][C@:16]2([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]2[CH:19]=[CH2:20])[CH2:10][C@@H:11]([O:13][C:32]([N:34]2[CH2:35][C:36]3[C:48](=[CH:47][CH:46]=[CH:42][C:41]=3[F:40])[CH2:38]2)=[O:33])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc2c1CNC2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(F)c3C2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.5 %

Procedure:
To a solution of 8.19 g of crude (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and 60 mL of toluene was added 4.25 g CDI (26.2 mmol) Sin portions at a temperature of 22-25° C. The reaction mixture was stirred for 1.5 h at RT. Then 3.66 g (21.0 mmol) of 4-fluoroisoindoline hydrochloride was added in portions followed by 3.1 mL of TEA. The resulting suspension was heated to 52° C. bath temperature. After stirring for 3 h at this temperature the reaction mixture was cooled with an ice bath and 70 mL of aqueous HCl (1M) were added. The mixture was extracted with 50 mL of toluene. The separated aqueous layer was extracted twice with 50 mL toluene. The combined toluene extracts were washed with 30 mL of water and 30 mL of an aqueous solution of Na2CO3 (5 wt %). The toluene extract was dried (Na2SO4), filtered, and the solvent was completely removed. 9.21 g of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-tert-butoxycarbonyl-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester was obtained as a grey solid, which was used in the next step without further purification.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH:9]([S:12][C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][N:14]=1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C)C=O.C(OCC)(=O)C>[CH:9]([S:12][C:13]1[C:18]([O:19][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[O:8])=[CH:17][CH:16]=[CH:15][N:14]=1)([CH3:11])[CH3:10]
Reactant: O=C1CCCCC1Cl
Reactant: CC(C)Sc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Sc1ncccc1OC1CCCCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
7.29 g of 2-chlorocyclohexanone are added at room temperature to a mixture of 8.4 g of 2-isopropylthio-3-hydroxypyridine and 7.6 g of potassium carbonate in 120 ml of dimethylformamide, and the mixture is stirred for one hour at 45°-50° C. After the addition of 1.46 g of 2-chlorocyclohexanone and 1.52 g of potassium carbonate and after 2 hours of a further analogous addition of 0.73 g of 2-chlorocyclohexanone and 0.76 g of potassium carbonate, the suspension is stirred for a further 3.5 hours at 45°-50° C. The resulting reaction solution is poured onto a mixture consisting of 200 ml of ice-water, 50 ml of 2N acetic acid and 100 ml of ethyl acetate, washed three times with 300 ml of ethyl acetate and 100 ml of saturated sodium chloride solution each time, dried over sodium sulfate and concentrated by evaporation. The residue is triturated with petroleum ether and filtered. 9.57 g of the desired ketone having a melting point of 106°-110° C. are obtained.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12](OC)=[O:13])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][NH2:20]>CO>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:19][NH2:20])=[O:13])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Temperature: 65 °C
Yield: 71.1 %

Procedure:
Methyl 3-(pyrrolidin-1-ylsulfonyl)benzoate (150 mg, 0.557 mmol) was added to the hydrazine (35.7 mg, 1.114 mmol) in methanol and refluxed for 12 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography to yield 3-(pyrrolidin-1-ylsulfonyl)benzohydrazide (110 mg, 0.396 mmol, 71.1% yield). 1H NMR (CDCl3, 400 MHz): δ 8.18 (m, 1H), 8.03 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=8.0 Hz), 7.78 (bs, 1H), 7.63 (t, 1H, J=7.6 Hz), 4.17 (bs, 2H), 3.25 (m, 4H), 1.77 (m, 4H). Mass [M+H]+: 270.1
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2].[F:12][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([F:12])=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1cc(F)c[nH]1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(F)[nH]1
Temperature: 25 °C

Procedure:
4-Fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g, 10.0 mmol) is dissolved in acetonitrile (10 ml), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™, 3.54 g, 10.0 mmol) is added and the mixture is irradiated in a Biotage Initiator microwave synthesizer for 5 minutes at 70° C. The reaction mixture is allowed to cool to room temperature and partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 4,5-difluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 1.78 (C), [M+H] 176; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 12.93 (s, 1H), 6.67 (d, J=4.5 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([NH2:11])=[O:10].C(Cl)(=O)[C:13](Cl)=[O:14].[CH3:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[C:28]([O:30][C:31]3[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=3)[CH:27]=[CH:26][N:25]=2)[CH:21]=[N:20]1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([NH:11][C:13](=[O:14])[NH:37][C:34]1[CH:33]=[CH:32][C:31]([O:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:29]=2)=[CH:36][N:35]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: NC(=O)CC1CC2CCC1C2
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)CC4CC5CCC4C5)nc3)ccn2)cn1
Temperature: 80 °C
Reaction time: 72 h
Yield: 82.6 %

Procedure:
A suspension of 2-(bicyclo[2.2.1]heptan-2-yl)acetamide (0.069 g, 0.449 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.039 mL, 0.449 mmol) and heated at 80° C. for 3 h. The mixture was cooled to RT, added drop wise to a solution of Example A2 (0.10 g, 0.374 mmol) and pyridine (0.151 mL, 1.871 mmol) in THF (3 mL) and stirred at RT for 3 days. The mixture was concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM). The material was treated with MeCN, the solid collected via filtration and dried to afford 2-(bicyclo[2.2.1]heptan-2-yl)-N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)acetamide (138 mg, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 10.82 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.26-8.25 (m, 2H), 8.08 (d, J=9.0 Hz, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 3.83 (s, 3H), 2.36 (dd, J=14.7, 7.8 Hz, 1H), 2.23 (dd, J=14.7, 7.8 Hz, 1H), 2.21 (m, 1H), 1.94 (m, 1H), 1.85 (m, 1H), 1.45-1.38 (m, 3H), 1.31 (m, 1H), 1.11-1.07 (m, 4H); MS (ESI) m/z: 447.3 (M+H+).
Reaction SMILES: CN1CCCC1=[O:7].O[C:9]([CH3:14])([CH3:13])[C:10](N)=[O:11].[C:15]([NH2:20])(=O)[C:16]([CH3:18])=[CH2:17]>CC(C)=O>[C:10]([OH:7])(=[O:11])[C:9]([CH3:14])=[CH2:13].[C:15](#[N:20])[C:16]([CH3:18])=[CH2:17]
Reactant: CN1CCCC1=O
Reactant: C=C(C)C(N)=O
Reactant: CC(C)(O)C(N)=O
Solvent: CC(C)=O
Product: C=C(C)C#N
Product: C=C(C)C(=O)O
Yield: 8 %
Yield: 32 %

Procedure:
At the step (III) of Example 1, the reaction was carried out in the same manner as in Example 1 except that an aqueous solution was used in place of the N-methylpyrrolidone solution. As a result, the conversion of the α-hydroxyisobutyric acid amide as starting material was 98.6%, and the yield of methacrylic acid amide based on the converted starting material was 41.8 ol %. In addition, 32% of methacrylic acid, 10% of acetone, and 8% of methacrylonitrile were formed.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[CH3:34][O:35][NH2:36].CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=1)([CH3:14])[CH2:6]/[C:5]/2=[N:36]\[O:35][CH3:34]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CO/N=C1\CC(C)(COc2ccc(CC3SC(=O)NC3=O)cc2)Oc2c(C)c(C)c(O)c(C)c21
Reaction time: 240 h

Procedure:
A mixture of 1 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 22 of copending U.S. Ser. No. 644,996), 0.6 g of methoxyamine hydrochloride and 5 g of methanol was allowed to stand for 10 days at room temperature. At the end of this time, ethyl acetate and an aqueous solution of potassium carbonate were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to give the title compound softening at 72°-76° C.
Reaction SMILES: [N:1]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]=[O:3].[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH2:13]>C(OCC)C>[CH2:7]([O:6][C:4](=[O:5])[NH:1][C:2]([NH:13][CH2:12][CH2:11][N:10]([CH3:14])[CH3:9])=[O:3])[CH3:8]
Reactant: CN(C)CCN
Reactant: CCOC(=O)N=C=O
Solvent: CCOCC
Product: CCOC(=O)NC(=O)NCCN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl isocyanatoformate (500 mg, 4.2 mmol) in absolute diethyl ether (15 mL) was added dropwise to a solution of N1.N1-dimethylethane-1,2-diamine (440 mg, 550 μL, 5 mmol) in diethyl ether (25 mL) and stirred for 2 h at room temperature. The precipitate was filtered off and the filtrate was concentrated under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[CH:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC>C(O)C.[Cl-].[NH4+]>[CH2:18]([O:17][CH:10]([O:14][CH2:15][CH3:16])[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1])[CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of 2-bromobenzaldehyde (33.2 g), triethyl orthoformate (29 g) and powdered ammonium chloride (0.379 g) in ethanol (30 ml) was stirred for eight hours at room temperature. The resulting suspension was filtered and the filtrate evaporated. The resulting yellow oil was distilled at reduced pressure to give the title compound (31 g). b.p. 63° C. 0.3 mm Hg. T.l.c. (Petrol/diethyl ether, 6:1) Rf=0.6.
Reaction SMILES: C([O:9][C@H:10]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:29]([CH3:37])([CH2:30][CH2:31][C:32]=32)[C@@H:19]([C@H:20]([CH3:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH:17]=4)[C:11]1([CH3:39])[CH3:38])(=O)C1C=CC=CC=1.CO.O>O1CCCC1>[CH3:39][C:11]1([CH3:38])[C@@H:10]([OH:9])[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@H:12]1[CH2:13][CH2:14][C:15]1[C:16]3[C@:29]([CH3:37])([CH2:30][CH2:31][C:32]=12)[C@@H:19]([C@H:20]([CH3:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][CH:17]=3
Reactant: C[C@H](Cc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H](Cc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Yield: 43.1 %

Procedure:
—Potassium hydroxide (0.45 g) was added to a solution of compound 13 (0.84 g) in a mixture of tetrahydrofuran (8.4 ml), methanol (8.4 ml) and water (0.45 ml). The mixture was heated under reflux overnight. After cooling, water was added and the resulting precipitate collected by filtration. The residue was washed with water and dried. Column chromatography and crystallization from dichloromethane/acetone afforded (3β,5α,20R)-4,4,20-trimethyl-21-phenylpregna-8,14-dien-3-ol (1) (0.29 g). M.p. 179-186° C. The product contained 30% (w/w) of (3β,5α,20R)-4,4,20-trimethyl-21-phenylpregna-6,8(14)-dien-3-ol.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([CH3:33])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:34])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:35][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([CH3:33])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:34])([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C)ccc1OC(C)(C)C(=O)O
Reaction time: 4 h

Procedure:
0.243 g (0.483 mmol) of the above prepared 2-methyl-2-{2-methyl-4-[2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was dissolved in 2.9 ml of THF/EtOH=1/1, treated with 1.45 ml (3 eq.) of 1N NaOH and kept at room temperature for 4 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane produced finally 0.221 g of the title compound as white solid of mp. 149–151° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].F[C:24](F)(F)C(O)=O.C1(OC2NC(N)=C3C(N=2)=NC(OC)=N3)CCCC1.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:22][CH2:24][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: COc1nc2nc(OC3CCCC3)[nH]c(N)c-2n1
Agent: ClCCCCBr
Product: COc1nc2c(N)nc(OC3CCCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclopentyloxy)-8-(methyloxy) -1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: Cl.N[C:3]1([Si:11]([CH3:19])([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH:5]([CH2:8]O)[C:4]1=[CH2:10].[NH2:20][C:21]1[NH:22][C:23](=[O:31])[C:24]([N+:28]([O-:30])=[O:29])=[C:25]([NH2:27])[N:26]=1.C([OH:36])CCC.C(N(CC)CC)C>O>[NH2:20][C:21]1[NH:22][C:23](=[O:31])[C:24]([N+:28]([O-:30])=[O:29])=[C:25]([NH:27][CH:6]2[CH2:7][CH:3]([Si:11]([CH3:19])([CH3:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]([CH2:10][OH:36])[C:5]2=[CH2:8])[N:26]=1
Reactant: Nc1nc(N)c([N+](=O)[O-])c(=O)[nH]1
Reactant: CCCCO
Reactant: C=C1C(CO)CCC1(N)[Si](C)(C)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=C1C(Nc2nc(N)[nH]c(=O)c2[N+](=O)[O-])CC([Si](C)(C)c2ccccc2)C1CO
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A 3-necked 500 mL round bottomed flask equipped with stirrer, temperature probe and reflux condenser was charged with the amine 69 (1.49 g, 5 mmol), 2,4-diamino-5-nitropyrimidin-6-one (1.56 g, 5.35 mmol) and n-butanol (20 mL). The resultant thin slurry was subjected to heating at 40–45° C. over 15 minutes. Triethylamine (0.71 mL, 5.1 mmol) was added slowly over a period of 2 minutes. The reaction mixture was stirred at about 70° C. for 1 h. HPLC data showed that the reaction was almost complete. At this point, five washes of 25 mL of water was given to the reaction mixture at 70° C. The last wash was almost colorless. The crude product, 70, in n-butanol was used without further purification in the next reaction.
Reaction SMILES: Cl.N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[Cl:23][C:24]1[C:25]([CH3:31])=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].CN(C)C=[O:35]>>[OH2:35].[ClH:23].[Cl:23][C:24]1[C:25]([CH3:31])=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH:27][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: Cc1c(N)cccc1Cl
Agent: Cl
Product: Cc1cc(Nc2cccc(Cl)c2C)c2c(ccc3nc[nH]c32)n1
Product: O

Procedure:
A stirred reaction mixture of the compound of Example I, C. (22 g., 0.1 mole) and 3-chloro-2-methylaniline (14 g., 0.1 mole) in 200 ml. of dimethylformamide was refluxed for 6 hours. The reaction mixture was stripped in vacuo to yield a tar. Upon standing the tar solidified to give a yellow semisolid. The yellow product was recrystallized twice from methanol/ether to yield 14 g. (37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:25]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 7 was prepared from 2-(4-chloro phenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propan amide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.50 (s, 1H), 7.34–7.19 (m, 6H), 6.96 (d, 1H, J=7.8 Hz), 6.72–6.67 (m, 1H), 3.42 (q, 2H, J=7.1 Hz), 3.31 (q, 3H, J=5.4 Hz), 2.49–2.35 (m, 5H), 2.08–1.95 (m, 2H), 1.82–1.74 (m, 2H), 1.71–1.62 (m, 3H), 1.56 (s, 6H), 1.24 (t, 3H, J=7.8 Hz); ESMS m/e: 470.3 (M+H)+.