Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]1(=[O:13])[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH2:6][O:5]1.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.C(OCC)(=O)CC>CO>[NH:14]1[CH:19]=[CH:18][C:17](=[C:20]2[C:6](=[O:5])[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:4]2=[O:13])[CH:16]=[CH:15]1
Reactant: O=Cc1ccncc1
Reactant: O=C1OCC2=C1CCCC2
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CO
Product: O=C1C2=C(CCCC2)C(=O)C1=C1C=CNC=C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Four portions each of 0.99 ml 5,4 M methanolic sodium methylate solution (21.4 mmol) are stirred into a solution of 2.957 g (21.4 mmol) 4,5,6,7-tetrahydro-1(3H)-isobenzofuranone (for preparation see J. Am. Chem. Soc. 118, 1-12 [1996]), 2.02 ml (21.4 mmol) pyridine-4-carbaldehyde, and 10.7 ml (93.2 mmol) ethyl propionate in 17.4 ml methanol at intervals of 5 min respectively and at 0° C. The reaction mixture is stirred for 20 min at RT, heated for 2 h under reflux, and then evaporated under vacuum. Stirring of the residue in 5 ml water, filtration, washing of the filter residue with water, and drying under HV (8 h, 100 ° C.) yields the title compound; m.p. 258-261° C.; ESI-MS: (M+H)+=228. A further, slightly impure batch of title compound may be obtained by extracting the aqueous filtrate with diethylether, adjusting the aqueous phase to pH 7 with glacial acetic acid, filtering, and washing the filter residue with water.
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:45][CH2:44][C:42]1[CH:41]=[CH:40][N:39]=[C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:47])([F:30])[F:46])=[CH:33][CH:34]=2)[CH:43]=1)=[O:7])[CH3:2]
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1cccc(F)c1
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
Acid 4F (330 mg, 1.2 mmol) was dissolved in 15 ml of THF and at rt DEPC (1.3 equiv, 0.23 mL) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 mol equiv., 335 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 mL) and washed with water (1×20 mL) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (EtOAc 1/petroleum ether 1) afforded 100 mg of a white solid. Yield=20% 1HNMR (DMSO, 200 MHz) δ 1.09 (3H, t, J=7.2 Hz), 3.44 (2H, q, J=6.8 Hz), 4.50 (2H, d, J=6 Hz), 5.21 (1H, s), 6.14 (1H, s), 7.34 (1H, dd, J=4.8), 7.65 (m, 4H), 7.81 (d, 2H, J=7.9), 8.01 (s, 1H), 8.31 (d, 2H, J=7.8), 8.65 (d, 1H, J=5.8), 8.92 (t, 1H). [M+1] 507.62 (C24H21F4N3O3S requires 507.50).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:19]([CH3:36])[C:20]([C:34]#[N:35])=[C:21]2[C:25]=1[O:24][C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[C:28](=[O:33])[CH2:27]1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:19]([CH3:36])[C:20]([C:34]#[N:35])=[C:21]3[C:25]=2[O:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[C:28](=[O:33])[CH2:27]2)=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CCN(C)C(=O)C3)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCN(C)C(=O)C3)nc2c1C#N
Temperature: 130 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (67.9 μl, 0.535 mmol) and triethylamine (86.1 μl, 0.618 mmol) were added to a dimethyl sulfoxide (5 ml) solution of 7-fluoro-5-methyl-2-(4-methyl-3-oxopiperazin-1-yl)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-188) (150 mg, 0.412 mmol), followed by stirring in an oil bath at 130° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (50 ml), washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1) to obtain the entitled compound (109 mg, 54.5%) as a colorless foamy substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[O:23])/[C:20](=[CH:24]/[C:25](Cl)=[O:26])/[O:19]1>>[CH3:17][C:18]1([CH3:28])[O:19][C:20](=[CH:24][C:25]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[O:26])[C:21](=[O:23])[O:22]1
Reactant: Cc1ccc(CNc2ccc(F)cc2)cc1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)Cl)O1
Product: Cc1ccc(CN(C(=O)C=C2OC(C)(C)OC2=O)c2ccc(F)cc2)cc1

Procedure:
Acylation of (4-fluorophenyl)-(4-methylbenzyl)-amine (Pombrik, S. I. et al., Izv. Akad. Nauk. SSSR Ser. Khim., 10, 1981, 2406-2408) with (Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one as described in the preparation of Intermediate 71A gave the title amide as a syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.72 (6H, s, CH3), 2.31 (3H, s, CH3) 4.87 (2H, s, NCH2), 5.63 (1H, s, CH), 6.93-7.11 (8H, m, aromatics). HRMS (MAB N2) calculated for C21H20FNO4 [M−]: 369.137637: found: 369.137900.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])=[CH:5][CH:4]=1.[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])#[N:19]>>[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=1)=[O:24])#[N:19]
Reactant: COc1ccc(OCc2ccccc2N)cc1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: COc1ccc(OCc2ccccc2NC(=O)c2cccc(C#N)c2)cc1

Procedure:
Using a procedure similar to Example 1B except starting from 2-[(4-methoxyphenoxy)methyl]aniline and 3-cyanobenzoyl chloride, the title compound was obtained as a solid (0.50 g, 36%); MS(FD): 359.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11](OS(C(F)(F)F)(=O)=O)=[C:10]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)[CH3:35].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:39]2[CH:40]=[CH:41][C:36]([CH2:34][CH3:35])=[CH:37][CH:38]=2)=[C:10]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Reactant: CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2c(-c3cc(C)no3)c(=O)n(Cc3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 1-benzyl-6-chloro-3-(3-methyl-isoxazol-5-yl)-2-oxo-1,2-dihydro-quinolin-4-yl ester (40 mg, 0.080 mmol), 4-ethylbenzeneboronic acid (14.4 mg, 0.096 mmol), Pd(PPh3)4 (9.2 mg, 0.0080 mmol) and Na2CO3 (80 ul, 0.16 mmol, 2.0 M)in 1 ml of 1,4-dioxane was stirred at 100° C. for 1 h, then cooled to rt. Treated with 40 ml of EtOAc, the mixture was washed with H2O (2×10 ml), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (25% EtOAc/hexane) gave 29.5 mg (81%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) δ7.41 (dd, 1H, J=9.0, 2.2 Hz), 7.24-7.38 (m, 8H), 7.15 (d, 2H, J=8.0 Hz), 6.48 (s, 1H), 5.64 (s, 2H), 3.71 (s, 1H), 2.74 (q, 2H, J=7.6 Hz), 2.23 (s, 3H), 1.31 (t, 2H, J=7.6 Hz),. Mass spectrum (ESI, m/z): Calcd. for C28H23ClN2O2, 455.1 (M+H), found 455.1.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:22]([O:24][P:25]([C:30]1[C:31](=[O:45])[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([S:40]([NH2:43])(=[O:42])=[O:41])=[C:35]([Cl:44])[CH:34]=2)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:27]([O:26][P:25]([C:30]1[C:31](=[O:45])[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([S:40]([NH:43][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:41])=[O:42])=[C:35]([Cl:44])[CH:34]=2)(=[O:29])[O:24][CH2:22][CH3:23])[CH3:28]
Reactant: CCOP(=O)(OCC)c1cc2cc(S(N)(=O)=O)c(Cl)cc2[nH]c1=O
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOP(=O)(OCC)c1cc2cc(S(=O)(=O)NC(=O)c3ccccc3)c(Cl)cc2[nH]c1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of benzoic acid (111 mg, 0.912 mmol) in 3 ml of anhydrous THF containing 173 mg (1.06 mmol) of carbonyldiimidazole is stirred for 45 minutes at reflux. In parallel, there is prepared a suspension of 300 mg (0.760 mmol) of the compound obtained in Step A in 3 ml of THF, to which there is added 0.125 ml (0.836 mmol) of DBU. Stirring is carried out for 15 minutes at room temperature, and then the benzoic acid solution prepared above is added thereto. The mixture is heated for 3 hours at 60° C. The reaction mixture is cooled in an ice bath and rendered acidic by the addition of 1N HCl. Extraction is carried out with ethyl acetate. The organic phases are combined and washed with a saturated NaCl solution and then dried over MgSO4. After evaporation, the residue is chromatographed over a silica column whilst eluting with a gradient (95/5-90/10) of CH2Cl2/MeOH. The title product is obtained in the form of a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34]>ClCCl.O>[C:33]([O:36][CH2:37][C:38]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[CH:16]=[C:11]([C:9](=[O:10])[NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)[N:12]=[C:13]([CH3:28])[N:14]=3)[CH2:21]2)[CH2:27][CH2:26]1)=[O:39])(=[O:35])[CH3:34]
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)COC(C)=O)CC4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (1.8 g, 3.87 mmol, Preparation #K.1) in dichloromethane (20 mL) were added TEA (3.3 mL, 23.2 mmol) and acetoxyacetyl chloride (0.5 mL, 4.65 mmol). The reaction mixture was slowly warmed to RT and stirred for about 10 min. The reaction mixture was diluted with water (10 mL) and the product was extracted with DCM (2×20 mL). The combined organic layers were washed with water (1×25 mL) followed by brine (1×50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 2-(4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)piperidin-1-yl)-2-oxoethyl acetate as a brown solid 1.8 g (90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:24])=[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:38]([CH2:40][CH2:41][CH2:42]Cl)[CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.CCOCC>[CH3:1][O:2][C:3]1[N:4]([CH2:42][CH2:41][CH2:40][N:38]([CH3:39])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:5]([CH3:24])[C:6]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Reactant: CN(CCCCl)Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC1=NC(c2cccc([N+](=O)[O-])c2)=C(C(=O)OC(C)C)C(C)N1CCCN(C)Cc1ccccc1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methyethyl ester (2.0 g, 6.0 mmol) in dimethylformamide (7.0 ml) was treated with finely ground potassium carbonate (1.7 g, 12.0 mmoles), N-benzyl-3-chloro-N-methylpropylamine (2.37 g, 12.0 mmol) and a catalytic amount of 18-crown-6. The reaction was heated at 70°-75° C. under argon overnight. The reaction was allowed to cool down to room temperature and was diluted with ether. It was filtered, and the filtrate was washed with water, brine and was dried over anhydrous magnesium sulfate. Evaporation of solvent provided a brown oil which was purified by flash chromatography (20% acetone in hexanes) to yield the title compound (1.51 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]2[C:45](=[O:56])[C:46]3[C:51]([C:52]=2[CH:53]=1)=[CH:50][C:49]([O:54][CH3:55])=[CH:48][CH:47]=3>>[CH3:55][O:54][C:49]1[CH:48]=[CH:47][C:46]2[C:45]([C:35]3[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=3)[C@@H:8]3[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]3[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])([OH:56])[C:44]3[C:52]([C:51]=2[CH:50]=1)=[CH:53][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3
Reactant: COc1ccc2c(c1)-c1cc(OC)ccc1C2=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: COc1ccc2c(c1)-c1cc(OC)ccc1C2(O)c1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O

Procedure:
5-(3,6-Dimethoxy-9-hydroxyfluoren-9-yl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 3,6-dimethoxyfluoren-9-one (J. Org. Chem. (1993) 58 (16), 4398-4404) instead of benzophenone) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1>>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:11][CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccncc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: C(=NC1CCN(Cc2ccccc2)CC1)c1ccncc1

Procedure:
Pyridine-4-carboxaldehyde was reacted with 4-amino-N-benzylpiperidine by the procedure of example 1(c) to afford the title compound as a yellow oil.
Reaction SMILES: COC(C1OC(C2[Se]C=CC=2[C:15]([C:17]2[CH:21]=[CH:20][Se:19][C:18]=2[C:22]2[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:26]=2)=O)=CC=1)=O.[C:31]1([NH:37][NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1>C(O)(=O)C>[CH3:30][O:29][C:27]([C:24]1[O:23][C:22]([C:18]2[C:17]3[CH:21]=[CH:20][Se:19][C:15]=3[N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:38]=2)=[CH:26][CH:25]=1)=[O:28]
Reactant: COC(=O)c1ccc(-c2[se]ccc2C(=O)c2cc[se]c2-c2ccc(C(=O)OC)o2)o1
Reactant: NNc1ccccc1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nn(-c3ccccc3)c3[se]ccc23)o1

Procedure:
Compound 73 (3.8 g, 0.013 mole), phenylhydrazine 8 (5.0 g, 0.046 mole) and glacial acetic acid (1.5 ml) were allowed to react as in the preparation of compound 55 to afford compound 78. Yield: 0.62 g (12.8%); white needle crystals; mp 167-169° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.C(Cl)Cl>[C:34]1([CH:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)=[O:32])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3)) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 512.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.[H-].[Na+].Cl[CH2:26][O:27][CH3:28]>CN(C=O)C>[F:21][C:19]1[CH:18]=[C:15]([CH:14]=[C:13]([C:11]2[CH:10]=[CH:9][C:4]3[N:5]([CH2:26][O:27][CH3:28])[C:6](=[O:8])[O:7][C:2]([CH3:22])([CH3:1])[C:3]=3[CH:12]=2)[CH:20]=1)[C:16]#[N:17]
Reactant: COCCl
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)OC(C)(C)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile (0.150 g, 0.51 mmol) in DMF (5 mL) was treated at rt with sodium hydride (0.061 g, 1.53 mmol). The mixture was stirred for 30 minutes and treated with chloromethyl methylether (0.062 g, 7.7 mmol). Upon completion of the reaction, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3×30 mL), dried over MgSO4, and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 3-fluoro-5-(1-methoxymethyl4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile as a white solid (0.11 g, 65%): mp 169-171° C.; 1H-NMR (DMSO-d6) δ8.17 (bs, 1H), 8.03 (dt, 1H, J=10.4, 2.13 Hz), 7.85-7.77 (m, 3H), 7.31 (d, 1H, J=8.49 Hz), 5.33 (s, 2H), 3.35 (s, 3H), 1.7 (s, 6H); MS (APCI) m/z 341 ([M+H]+, 50%); Anal. Calc. For C19H17FN2O3: C, 65.32, H, 5.19, N, 8.02. Found: C, 64.92, H, 4.96, N, 7.73.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[O:11][C:12]([CH2:15][CH3:16])=[N:13][N:14]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:15]([C:12]1[O:11][C:10]([CH2:9][CH2:8][NH2:7])=[N:14][N:13]=1)[CH3:16]
Reactant: CCc1nnc(CCNC(=O)OC(C)(C)C)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnc(CCN)o1

Procedure:
2.95 g (12.23 mmol) tert-butyl[2-(5-ethyl-[1,3,4]oxadiazol-2-yl)-ethyl]-carbamate and 10 ml trifluoroacetic acid are stirred in 100 ml dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is made basic and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC)(OC)OC.[CH3:21][C:22]([CH3:27])([CH2:25]O)[CH2:23][OH:24]>>[CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]32[O:24][CH2:23][C:22]([CH3:27])([CH3:25])[CH2:21][O:13]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCCC1C1CCCCC1
Reactant: CC(C)(CO)CO
Solvent: COC(OC)OC
Product: CC1(C)COC2(CCCCC2C2CCCCC2)OC1

Procedure:
1.170 g (6.5 mols) of 2-cyclohexyl-cyclohexanone are reacted with 757.9 g (7.15 mols) of trimethyl orthoformate and 743.6 g (7.15 mols) of anhydrous 2,2-dimethyl-1,3-propanediol in a manner analogous to that in Example 1:
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[S:22][CH2:23][CH3:24].C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:25][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[S:22]([CH2:23][CH3:24])=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SCC)c1CC(C)C
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)CC)c1CC(C)C

Procedure:
Prepared from product of Example 6 (7.0 g, 18.1 mmol) and MCPBA (3.7 g of an 85% mixture with MCBA, 18.1 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (6.23 g).