Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:53]=[CH:54][CH:55]=1)[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][OH:24])=[C:15]([Cl:52])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:53]=[CH:54][CH:55]=1)[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:44][C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])([CH2:25][O:26][Si:27]([C:40]([CH3:42])([CH3:43])[CH3:41])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=[O:24])=[C:15]([Cl:52])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(CO)(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(C=O)(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.7 %

Procedure:
The compound of Example 191 (940 mg) was dissolved in DMF (10 mL). To this solution, pyridinium dichromate (800 mg) was added and the mixture was stirred for 48 hours at room temperature. Following addition of water, the mixture was extracted with ethyl acetate. The extract was then washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was purified on a silica gel chromatography (hexane:ethyl acetate=3:1) to give the desired product as a colorless oil (710 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:9]=[C:8]([C:18](OCC)=[O:19])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:9]=[C:8]([CH2:18][OH:19])[CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc(OCC(C)C)n(-c2ccccc2C)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-n1nc(CO)cc1OCC(C)C
Temperature: 0 °C
Yield: 92.2 %

Procedure:
To a solution (10 mL) of ethyl 5-isobutoxy-1-(2-methylphenyl)-1H-pyrazole-3-carboxylate (1.07 g, 3.54 mmol) in anhydrous tetrahydrofuran was added lithium aluminum hydride (0.13 g, 3.54 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 2 hr. After completion of the reaction, sodium sulfate decahydrate (2.28 g, 7.08 mmol) was added to the reaction system and the mixture was stirred at room temperature for 2 hr. The precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-1/1) to give the title compound (0.85 g, yield 92%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([CH3:10])[N:3]=1.CO[C:13](OC)(OC)[CH2:14][CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>COCCO>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([NH:9][C:13]([CH2:14][CH2:15][CH3:16])=[N:8]2)=[C:4]([CH3:10])[N:3]=1
Reactant: CCCC(OC)(OC)OC
Reactant: Cc1nc(Cl)nc(N)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Temperature: 140 °C
Yield: 47.1 %

Procedure:
A mixture of 2-Chloro-4,5-diamino-6-methylpyrimidine (0.80 g, 5.04 mmol), trimethylorthobutyrate (1.2 ml, 7.6 mmol) and p-TsOH (0.08 g) in 2-methoxy-ethanol (24 ml) was heated in an oil bath at 140° C. for 24 hours. The product was isolated as described in Step 2 of Example 12 and purified by flash chromatography using EtOAc-hexane (1:1) to give the crystalline titled compound (0.5 g, 47%). NMR(CDCl3): δ1.03 (t, J=8 Hz, 3H), 1.9 (q, 2H), 2.82 (s, 3H), 3.0 (t, J=8 Hz, 2H). FAB-MS: m/e 211 and 213 (M+H). Analysis calculated for C9H11N4Cl: C, 51.31; H, 5.26; N, 26.60. Found: C, 51.43; H, 5.50, N, 26.81.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C@@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:10]([S:17](Cl)(=[O:19])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O1CCOCC1.[OH-].[Na+]>[CH2:10]([S:17]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[C@@H:3]([CH2:5][CH3:6])[CH3:4])(=[O:19])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC[C@@H](C)[C@@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a solution of D-isoleucine (3 g, 22.9 mmol) in dioxane (184 ml), 1N aqueous sodium hydroxide (23 ml) and then benzylsulfonyl chloride (6 g, 34.4 mmol) were added and stirred at room temperature. After 3 hours, the reaction mixture was adjusted to pH 2 with 2N aqueous hydrogen chloride and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated under reduced pressure and the residue was applied to flash column chromatography (Merck Silicagel 60; mobile phase: dichloromethane:methanol=10:1, 4:1) to give N-(benzyl-sulfonyl)-D-isoleucine (6.3 g, 22.2 mmol; yield 97%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH2:20][N:19](C(OC(C)(C)C)=O)[CH:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH2:20][NH:19][CH:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of tert-butyl 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (14,700 mg, 1.96 mmol, 1 equiv) in dichloromethane (50 mL) at 23° C., and the resulting mixture was stirred for 30 min, then concentrated to give 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (1-5) as a TFA salt (brown oil). LRMS m/z (M+H) 258.1 found, 258.1 required.
Reaction SMILES: [C:1]1([C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OCC)C.[Pd]>[C:1]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCCCC#Cc1cccc2ccccc12
Agent: [Pd]
Solvent: CCOCC
Product: OCCCCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(1-naphthyl)-4-pentyn-1-ol (500 ng, 2.37 mmol) and 5% palladium on barium sulfate (5 mg) in ethyl ether (30 ml) was stirred at room temperature under a hydrogen atmosphere for two days. Solvent removal, after filtration through celite, gave the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20](O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([O:10][C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C=O)c(O)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
in 40 ml of tetrahydrofuran were dissolved 1.38 g of 2,4-dihydroxybenzaldehyde, 1.87 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.88 g of triphenylphosphone. The thus prepared solution was mixed with 1.91 g of diethyl azodicarboxylate and stirred at room temperature for 1 hour. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography, thereby obtaining 1.2 g of 4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]-2-hydroxybenzaldehyde in a viscous and oily form.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:19][C:20]1[N:29]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:21]=1>>[NH2:29][C:20]1[N:21]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[CH2:6][C:5]=2[N:19]=1
Reactant: CC(=O)C1C(=O)CC(c2cccc(F)c2)CC1=O
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Product: Cc1nc(N)nc2c1C(=O)CC(c1cccc(F)c1)C2

Procedure:
The title compound was prepared from 2-acetyl-5-(3-fluoro-phenyl)-cyclohexane-1,3-dione (100 mg, 0.42 mmol), from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 2/3) except that the title compound was further purified by recrystallisation in methanol.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:16][C@H:11]1[N:9]2[C:10]3[C:2]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=[C:8]2[C:14](=[O:15])[NH:13][CH2:12]1
Reactant: C[C@@H]1CNC(=O)c2cc3cccc(Br)c3n21
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: C[C@@H]1CNC(=O)c2cc3cccc(-c4ccccc4)c3n21
Temperature: 85 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of (R)-6-bromo-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one [CAS No. 396075-75-5] (69.8 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol) in 1,2-dimethoxyethane (1.67 ml) and 2M sodium carbonate solution (416 μl, 832 μmol) was purged with argon in an ultrasonic bath for 5 min. Then triphenylphosphine (13.1 mg, 50.0 μmol) and palladium(II)acetate (5.61 mg, 25.0 μmol) were added at room temperature, and afterwards the reaction mixture was allowed to stir for 2 h at 85° C. The reaction mixture was cooled to room temperature, poured into water (20 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (1×20 ml), dried (MgSO4) and evaporated. The crude material (70 mg) was purified by flash chromatography on silica gel [dichloromethane-dichloromethane/MeOH 9:1 (20-80%)] and subsequent trituration with diethyl ether (0.5 ml) and heptane (10 ml) to yield the title compound as a grey solid (60 mg, 87%), MS (ISN) m/z=277.2 [(M+H)+], mp 239° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]3[CH:12]=[C:13]([CH2:16][NH:17][C:18]4[CH:39]=[CH:38][C:21]([C:22]([NH:24][C@H:25]([C:33]([O:35]CC)=[O:34])[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:23])=[CH:20][CH:19]=4)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]([NH:40]C(=O)C(C)(C)C)[NH:3]1.Cl>CO.[OH-].[Na+]>[NH2:40][C:4]1[NH:3][C:2](=[O:1])[C:11]2[C:10]3[CH:12]=[C:13]([CH2:16][NH:17][C:18]4[CH:19]=[CH:20][C:21]([C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23])=[CH:38][CH:39]=4)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2ccc3ccc4nc(NC(=O)C(C)(C)C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc2ccc3ccc(CNc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cc3c2c(=O)[nH]1
Yield: 91.7 %

Procedure:
A solution of diethyl N-(4-(((1,2-dihydro-1-oxo-3-pivalamidobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate (0.31 g, 0.49 mmol) in methanol (15 ml) and 1 N NaOH (5 ml) was stirred under nitrogen at reflux for 1.5 hours and then allowed to cool. The solution was adjusted to pH 3 with 1 N-HCl under nitrogen and the resulting precipitate was filtered under nitrogen, washed with water, and dried under high vacuum to give N-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamic acid (0.22 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz δ: 1.82-2.12 (m, 2H, gluCH2), 2.31 (t, J=7 Hz, 2H, gluCH2), 4.27-4.38 (m, 1H, gluCH), 4.50 (d, J=6 Hz, 2H, C9—CH 2), 6.55 (br s, 2H, NH2), 6.62 (d, J=9 Hz, 2H, Ar), 6.96 (t, J=6 Hz, 1H, ArNH), 7.26 (d, J=9 Hz, 1H, Ar), 7.44 (dd, J=8, 2 Hz, 1H, Ar), 7.63 (d, J=9 Hz, 2H, Ar), 7.84 (d, J=8 Hz, 1H, Ar), 7.99 (d, J=9 Hz, 1H, Ar), 8.09 (d, J=8 Hz, 1H, gluNH), 9.67 (s, 1H, Ar), 11.14 (br s, 1H, N2H), 12.32 (br s, 2H, CO2H's). Anal. Calculated for C25H23N5O6H2O: C, 59.17; H, 4.97; N, 13.80. Found: C, 59.31; H, 4.90; N, 13.72.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.Cl.[OH:19][CH:20]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[CH:21]([NH2:33])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[OH:19][CH:20]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[CH:21]([NH:33][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=1
Reactant: O=C(O)CCCc1cccs1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCc1cccs1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-(2-thienyl)butyric acid (86 ml, 0.59 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.10 ml, 1.18 mmol) and N,N-dimethylformamide (0.01 ml) and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) was added (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (110. mg, 56%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH2:16][N:17]([CH3:19])[CH3:18])=[C:10]([Cl:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:27]>ClCCl>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:27])[CH:15]=[CH:16][N:17]([CH3:18])[CH3:19])=[C:10]([Cl:20])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CC#Cc1ccc(NC(=O)OC(C)(C)C)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)C=CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice cold solution of [3-chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl ester (4.0 g) in dichloromethane (30 ml) is added in small portions 3-chloroperoxybenzoic acid (2.34 g). After the reaction is stirred at 0° C. for 20 minutes, the mixture is passed over twenty weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and the N-oxide is eluted using a solution of 5% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness under reduced pressure. The residue is treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness under reduced pressure, and the volume of the solution is adjusted to 250 mL by addition of methanol. The methanolic solution of the N-oxide is then heated to reflux for approximately 15 hours, then cooled, and the solvent is evaporated to dryness under reduced pressure. The residue is purified by chromatography over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the desired product as a pale yellow solid.
Reaction SMILES: [CH:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][C:7](=O)[CH3:8])([CH3:3])[CH3:2].C(O)(=O)C.[NH3:28]>C(OCC)(=O)C>[CH:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:5](=[O:10])/[CH:6]=[C:7](\[NH2:28])/[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(=O)CC(=O)N(c1ccc(Nc2ccccc2)cc1)C(C)C
Reactant: N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C/C(N)=C/C(=O)N(c1ccc(Nc2ccccc2)cc1)C(C)C
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 90.9 %

Procedure:
N-Isopropyl-3-oxo-N-[4-(phenylamino)phenyl]-butyramide (30.0 g, 0.0967 mol) and conc. acetic acid (1.4 g, 0.0233 mol) in ethyl acetate (140 g) were introduced into an autoclave. Ammonia (16.0 g, 0.9395 mol) was introduced in the course of 10 minutes and the temp. of the reaction mixture was increased to 35° C. during this period. After the introduction a pressure of 14 bar is present. The temperature of the reaction mixture was heated to 70° C. in the course of 30 min. In the course of this, the pressure rose to 17 bar. After 2.5 h under these conditions, the reaction mixture was cooled to 25° C. and ammonia was released. The reaction mixture was further cooled to 5° C. in order to crystallize the product. The suspension was filtered. The pale grey solid was washed with cold (0° C.) ethyl acetate (20 ml) and dried in vacuo (50 mbar) at 35° C. for 2 days. (Z)-3-Aminobut-2-enoic acid N-isopropyl-N-[4-(phenylamino)phenyl]amide (27.2 g, 91.0%) was obtained.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>CN(C)C=O.O>[CH:47]1([CH2:46][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=34)=[O:20])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=3)=[CH:33][CH:34]=2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: BrCC1CCCCC1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCC2CCCCC2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and (bromomethyl)cyclohexane (401 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (129 mg, 27%).
Reaction SMILES: [CH:1]1([C:7]([F:14])([F:13])[C:8](OCC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:15]>CCO>[CH:1]1([C:7]([F:14])([F:13])[C:8]([NH2:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(F)(F)C1CCCCC1
Reactant: N
Solvent: CCO
Product: NC(=O)C(F)(F)C1CCCCC1
Reaction time: 8 h

Procedure:
A solution of ethyl cyclohexyl(difluoro)acetate (2.63 g, 12.75 mmol) in EtOH (6 mL) was sparged with anhyd ammonia for 15 minutes at ambient temperature. The mixture was sealed in a pressure tube and allowed to stand overnight. Volatiles were removed in vacuo and the solid residue was recrystallized from dichloromethane-hexanes affording the title compound as a waxy solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.13-1.37 (m, 5H) 1.48-1.85 (m, 8H) 1.98-2.08 (m, 1H) 4.30 (q, J=7.08 Hz, 2H)
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].CC1CCCCC1.Cl.C([O:26][N:27]=O)CCCC>>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])/[C:2](=[N:27]/[OH:26])/[CH3:1]
Reactant: CCCCCON=O
Reactant: CCC(=O)c1ccc(F)cc1F
Agent: Cl
Solvent: CC1CCCCC1
Product: C/C(=N\O)C(=O)c1ccc(F)cc1F
Temperature: 0 °C
Yield: 88.4 %

Procedure:
To a solution of 170 g (1.00 mol) of 2,4-difluoropropiophenone in 200 g methylcyclohexane 37 g (1.01 mol) of gaseous hydrochloric acid is dosed over 3 hours at 0° C. Thereafter 120 g (1.04 mol) of pentylnitrite are added over a period 3 to 4 hours to the reaction mixture at +10° C. to +15° C. Following the end of the addition the batch is stirred for an hour at +10° C. to +15° C. during which time a suspension is formed. The reaction mixture is then cooled to 0° C. and stirred for a further hour. The product is isolated by filtration and the filter cake is washed with 75 g of methylcyclohexane at 0° C.: 176 g of (E)-1-(2,4-difluoro-phenyl)-propane-1,2-dione-2-oxime (m.p. 99-101° C.) are obtained in 88.6% yield.
Reaction SMILES: C([C@@:5]1([OH:26])[C@H:9]([O:10]CCCC)[C@@H:8]([C:15](=[SnH2])[OH:16])[O:7][C@H:6]1[N:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20])CCC.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[I-].[Na+]>CN(C=O)C>[CH2:28]([O:26][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:15][OH:16])[O:7][C@H:6]1[N:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCBr
Reactant: CCCCO[C@@H]1[C@@H](C(O)=[SnH2])O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]1(O)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
Utilizing the procedures of Examples 50 and 51, 2′,3′-O-dibutylstannylene uridine (19.1 g) was treated with bromopentane (7 ml, 1.3 eq.) and sodium iodide (4.5 g) in DMF (90 ml). Purification on a silica gel column utilizing NeOH/CH2Cl2 5%→10% yielded the a mixture of 2′ and 3′ isomers; of the product as a dark oil (9.8 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1.N1CC[O:20][CH2:19][CH2:18]1.[S]>>[C:19]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)(=[O:20])[CH3:18]
Reactant: C1COCCN1
Reactant: CCOC(=O)Cc1ccc(CCN)cc1
Agent: Cl
Agent: [S]
Product: CC(=O)NCCc1ccc(CC(=O)O)cc1

Procedure:
The ethyl 4-(2-aminoethyl)-phenylacetate hydrochloride used as starting material is prepared in the following manner: 4-(2-acetamidoethyl)-acetophenone is reacted with morpholine and sulfur to give the thiomorpholide of 4-(2-acetamidoethyl)-phenylacetic acid (m.p. 117°-118° C.). Subsequent alkaline saponification, followed by esterification with ethanolic hydrochloric acid, gives ethyl 4-(2-aminoethyl)-phenylacetate hydrochloride; m.p. 177°-178° C., after recrystallization from ethanol.