Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br.O>CN(C=O)C>[CH3:12][O:13][C:14](=[O:17])[CH2:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2ccccc21
Reaction time: 24 h
Yield: 61.8 %

Procedure:
NaH (0.6 g, 15.0 mmol.) was added, while cooling with ice, to a solution of indole (1.17 g, 10.0 mmol.) and bromoacetic acid methyl ester (1.43 ml, 15 mmol.) in DMF. (20 ml), and stirring was carried out for 24 h at RT. For working up, water (50 ml) was added to the mixture, and extraction was carried out with EE (5×20 ml). The combined extracts were dried, filtered and concentrated. Chromatography with EE/cyclohexane (1:7) yielded 1.17 g of indol-1-yl-acetic acid methyl ester in the form of a colourless oil. These 1.17 g (6.18 mmol.) were dissolved in abs. methanol (100 ml); KOH (382 mg, 6.8 mmol.) was added and the mixture was heated at reflux for 2 h. For working up, the mixture was concentrated, water (20 ml) was added to the residue, the pH was adjusted to 4 with 1M HCl and the resulting solid was filtered off with suction. Indol-1-ylacetic acid was obtained in a yield of 0.96 g (white solid, m.p. 128–130° C.).
Reaction SMILES: C([O:3][C:4](=[O:27])/[CH:5]=[C:6](\[CH3:26])/[CH:7]=[CH:8]/[CH:9]1[CH2:11][CH:10]1[C:12]1[CH:21]=[CH:20][C:19]2[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=2[CH:13]=1)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:26]/[C:6](/[CH:7]=[CH:8]/[CH:9]1[CH2:11][CH:10]1[C:12]1[CH:21]=[CH:20][C:19]2[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=2[CH:13]=1)=[CH:5]\[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C1CC1c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(/C=C/C1CC1c1ccc2c(c1)C(C)(C)CCC2(C)C)=C\C(=O)O

Procedure:
8.84 g of (2E,4E)-3-methyl-5-[(1RS,2RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2,4-dienoic acid ethyl ester (ca. 94% pure according to 1H-NMR) was dissolved in 100 ml of THF/EtOH=1:1 and treated with 40 ml of 3N aq. NaOH. The reaction mixture was kept in the dark at ambient temperature for three days. It was then poured onto crashed ice, extracted with EtOEt, washed with H2O, and dried over Na2SO4. Evaporation of the solvent and twofold crystallisation (hexane/AcOEt=8:2 and 7:3) yielded 4.25 g of (2E,4E)-3-methyl-5-[(1RS,2RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2,4-dienoic acid as white crystals of m.p. 150°-151° C.
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1>O1CCCC1.C(O)C.[Pd]>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])=[O:21])[C:15]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)F
Yield: 80.3 %

Procedure:
To a solution of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (1.9 g) in tetrahydrofuran (50 mL) and ethanol (50 mL) was added 10% (w/w) palladium on carbon (0.29 g) and the resulting solution was placed under a hydrogen atmosphere (0.75 bar) for 12 h. The catalyst was removed by filtration through diatomaceous earth and the solvent was evaporated. The resulting oil was crystallized from ether. The product was collected and washed with ether:hexane (1:1) to provide 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (1.14 g) as a white solid; NMR (DMSO/D2O): 7.38 (m,6), 4.55 (d,1), 4.37 (d,1), 3.98 (m,1), 2.17 (m,1), 0.79 (d,3), 0.72 (d,3).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][C@H:10]([C@H:16]([OH:20])[CH2:17][CH2:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:16]([OH:20])[CH2:17][CH2:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC[C@@H](O)[C@@H](C/C=C/c1ccccc1)C(=O)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)OCC
Reaction time: 6 h
Yield: 95.7 %

Procedure:
A solution of ethyl (2R,3R)-2-[(2E)-3-phenyl-2-propen-1-yl]-3-hydroxyhexanoate (1.76 g, 6.38 mmol) in 30 mL of EtOAc is treated with 200 mg of 10% palladium on carbon. The resulting suspension is repeatedly evacuated and purged with a hydrogen balloon, then stirred under 1 atmosphere pressure of hydrogen gas for 6 h. The catalyst is filtered and the filtrate is concentrated in vacuo to provide ethyl (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxyhexanoate as an oil (1.70 g, 96% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:14][CH2:15][CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:14]([O:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
Formation of compound (c): A mixture of 3,5-dimethyl-4-nitrophenol (b) (2 g, 12 mmol), bromobutane (1.6 mL, 15 mmol), K2CO3 (2.1 g, 15 mmol) in DMF (6 mL) was stirred at 60° C. for 6 hours. The reaction mixture was poured into 50 mL of H2O and extracted with ether (3×50 mL). The combined ether layer was washed with H2O and subsequently with brine, dried over Na2SO4, filtered and concentrated to give compound (c), 4-butoxy-2,6-dimethyl-nitrobenzene (2.6 g, 97% yield) as a dark brown oil. 1H-NMR in CDCl3.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[CH2:17]([O:19][CH2:20][CH2:21]O)[CH3:18]>>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:16][CH2:18][CH2:17][O:19][CH2:20][CH3:21])[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CCOCCO
Reactant: CC(=O)Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Product: CCOCCOc1nc(NC(C)=O)nc2ccc(Cl)nc12
Yield: 48.3 %

Procedure:
4 mmol 2-acetamido-6-chloro-pyrido[3,2-d]pyrimidin-4(3H)-one (0.954 g) was reacted with 6 mmol 2-ethoxyethanol (0.54 g) yielding the pure title compound (0.6 g, yield: 48%) which was characterised as follows:
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:22]([C:24]1[N:25]=[C:26]([CH2:35][CH3:36])[O:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:23])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:21]=[C:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[O:13][CH:14]=[C:10]([NH:9][C:22]([C:24]2[N:25]=[C:26]([CH2:35][CH3:36])[O:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:23])[N:11]=1
Reactant: CCc1nc(C(=O)N(C(=O)OC(C)(C)C)c2coc(CCCCC(C)=O)n2)c(-c2ccccc2)o1
Agent: N#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(=O)Nc2coc(CCCCC(C)=O)n2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-ethyl-5-phenyl-oxazole-4-carbonyl)-[2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (43 mg, 0.09 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.07 mL, 0.90 mmol). After stirring at rt for 4 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a white solid. LC-MS-conditions 01: tR=1.05 min, [M+H]+=382.12.
Reaction SMILES: [CH:1]1([C:4]2[CH:18]=[CH:17][C:7]3[NH:8][C:9]([CH:11]4[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)=[N:10][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.[Cl:19][C:20]1[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:19][C:20]1[C:25]([N:14]2[CH2:13][CH2:12][CH:11]([C:9]3[NH:8][C:7]4[CH:17]=[CH:18][C:4]([CH:1]5[CH2:2][CH2:3]5)=[CH:5][C:6]=4[N:10]=3)[CH2:16][CH2:15]2)=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: Clc1nccnc1Cl
Reactant: c1cc2[nH]c(C3CCNCC3)nc2cc1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1nccnc1N1CCC(c2nc3cc(C4CC4)ccc3[nH]2)CC1
Temperature: 80 °C
Yield: 60.7 %

Procedure:
The mixture of 5-cyclopropyl-2-piperidin-4-yl-1H-benzoimidazole (98 mg, 0.41 mmol), 2,3-dichloro-pyrazine (74 mg, 0.5 mmol) and K2CO3 (115 mg, 0.83 mmol) in CH3CN (15 mL) was heated to 80° C. for 10 h. Then it was concentrated and partitioned between DCM and H2O, the organic layer was dried over Na2SO4, and concentrated to give the desired compound 2-[1-(3-chloro-pyrazin-2-yl)-piperidin-4-yl]-5-cyclopropyl-1H-benzo imidazole (88 mg, 65%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12]C)=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.[Na].[CH3:15][OH:16]>>[CH3:15][O:16][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: CCOC(=O)Cc1cncnc1Cl
Agent: [Na]
Product: COC(=O)Cc1cncnc1OC
Temperature: 120 °C
Yield: 93 %

Procedure:
To a solution of 0.250 g (1.25 mmol) of ethyl (4-chloro-5-pyrimidinyl)acetate (see i-48, Step A) in 10 mL of absolute methanol was dissolved 0.060 g (2.50 mmol) of sodium metal. The resulting solution was heated under microwave conditions at 120° C. for 10 min. All volatiles were removed in vacuo and the residue was diluted with saturated sodium bicarbonate and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to afford the title compound as a clear gum (0.21 g, 93%). 1H-NMR (500 MHz, CD3OD) δ: 8.72 (s, 1H), 8.35 (s, 1H), 3.96 (s, 2H), 4.01 (s, 3H), 3.70 (s, 3H), 3.57 (s, 2H). LC-MS: m/z (E/S) 183 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][CH:17]1[CH2:19][O:18]1>CCO>[CH:7]([N:8]1[CH2:19][CH:17]([OH:18])[CH2:16]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClCC1CO1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCO
Product: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
A solution of diphenylmethanamine (16.2 g, 88.5 mmol) and 2-(chloromethyl)oxirane (8.19 g, 88.5 mmol) in dry EtOH was stirred at RT for 48 hours and then heated at reflux for 48 hour. The reaction mixture was concentrated under reduced pressure and the residue was stirred in acetone (300 mL) for 30 min. The resulting off-white solid precipitate was filtered, washed with cold acetone (100 mL), and dried in vacuo to obtain 1-benzhydrylazetidin-3-ol as white crystalline solid (11.0 g, 51% yield); LC-MS: 240.3 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CO>[C:16]1([CH:22]2[CH2:23][CH2:24][N:25]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH2:26][CH2:27]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)CNS(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reaction time: 21 h

Procedure:
A stirred mixture of (4-fluoro-benzenesulfonyl-amino)-acetic acid (0.0895 g, 0.000384 mol), 4-phenyl-piperidine (0.618 g, 0.000383 mol), and potassium carbonate (0.109 g, 0.000789 mol) in dry dimethyl sulfoxide (0.10 mL) in a tightly capped vial was placed in a hot sand bath (115° C.). After 21 hours, the reaction mixture was cooled and partitioned between ethyl acetate and water. The mixture was acidified with 1M hydrochloric acid (3.2 mL, 0.0032 mol) and the layers were separated. The aqueous layer was washed with additional ethyl acetate. The organics were combined, dried (MgSO4), and rotary evaporated to give a glass. The glass was dissolved in methanol, silica gel was added (4.2 g, 230-400 mesh), and the mixture was rotary evaporated to dryness. The resulting powder was poured onto a column of silica gel (14 g, 230-400 mesh), and eluted with a mixture of hexanes-ethyl acetate-acetic acid (15:15:1, 11×15 mL). Fractions containing product were combined and rotary evaporated. The residue was crystallized from methanol-water (1:1) after a hot filtration to give the title compound as a pale yellow solid; yield 0.070 g (49%), mp=154.5-155.5° C.
Reaction SMILES: [CH3:1][SH:2].[Na].[CH3:4][C:5]1([CH3:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16]Cl)[C:6]1=[O:18]>C(O)C>[CH3:4][C:5]1([CH3:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][S:2][CH3:1])[C:6]1=[O:18]
Reactant: CC1(C)C(=O)N(CCl)C(=O)c2ccccc21
Reactant: CS
Agent: [Na]
Solvent: CCO
Product: CSCN1C(=O)c2ccccc2C(C)(C)C1=O
Temperature: 0 °C

Procedure:
1.92 gm of methylmercaptan were added to an ice-cooled solution of 0.92 gm of sodium in 50 ml of ethanol. A suspension of 8.6 gm of 4,4-dimethyl-2-chloromethyl-2H,4H-isoquinoline-1,3-dione in 100 ml of ethanol was added, and the mixture was refluxed for 45 minutes. Thereafter, the reaction mixture was evaporated, the residue was triturated with water, filtered, the filter cake was recrystallized from isopropanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[N:20]1([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=2)[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: c1nc[nH]n1
Reactant: FC(F)(F)c1cc(Cl)c2cccc(C(F)(F)F)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)c1cc(-n2cncn2)c2cccc(C(F)(F)F)c2n1
Reaction time: 23 h
Yield: 72.7 %

Procedure:
A mixture of 3.0 g of 4-chloro-2,8-bis-trifluoromethyl-quinoline, 1.38 g of 1,2,4-triazole, 1.38 g of potassium carbonate and 30 ml of acetone is heated to boiling for 23 hours whereupon the reaction mixture is poured into 100 ml of water. The precipitated product is filtered, dissolved in 5 ml of ethanol, whereupon 5 ml of water are added. The precipitated product is filtered. Thus 2.42 g of the desired compound are obtained, yield: 73%, mp.: 106°-107° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=C(O)c1cc(NCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 77.4 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (2.00 g, 13.0 mmole) and 4-nitrobenzyl bromide (3.38 g, 15.6 mmole), 2.90 g (79% yield) of 5-(4-nitrobenzyl)aminosalicylic acid was obtained as a pale yellow solid.:mp 211-212° C.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH:8]=1.[CH3:38][NH2:39].C(O)C>O1CCCC1>[CH3:38][NH:39][CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH:8]=1
Reactant: CN
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c1cccc(OCC=CCBr)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CNCC=CCOc1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1-bromo-4-[3-(perfluoro-n-octyl)phenoxy]but-2-ene (12.9 g) in tetrahydrofuran (20 mL) is added to a solution of 40 wt % methyl amine (20 mL), ethanol (20 mL) and tetrahydrofuran (20 mL) at 40° C. The mixture is stirred at ambient temperature for 2 hr. and extracted in the normal fashion. The resulting oil is Kugelrohr distilled to give N-methyl-4-[3-(perfluoro-n-octyl)phenoxy]but-2-enamine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[OH:9])[CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)c1cccc(Br)n1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a chilled (0° C.) solution of (6-bromopyridin-2-yl)-(4-fluorophenyl)-methanol (6.2 g, 22 mmol) in dichloromethane (88 mL) is added pyridinium chlorochromate (PCC) (7.1 g, 33 mmol). The reaction mixture is allowed to warm to room temperature. After 5 hours, the reaction mixture is concentrated and purified by silica gel chromatography eluting with 10% EtOAc in hexanes to afford (6-bromopyridin-2-yl)-(4-fluorophenyl)-methanone.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[CH:4]=1)[CH3:2].[OH-].[Na+].[I:18]I>O>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[C:4]=1[I:18])[CH3:2]
Reactant: CCc1cc(=O)[nH]c(-c2ccccc2)n1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(-c2ccccc2)[nH]c(=O)c1I
Temperature: 50 °C
Yield: 94.5 %

Procedure:
A mixture of 8.18 g (40.9 mmol) of 6-ethyl-2-phenyl-4(3H)-pyrimidinone, 1.68 g (42.0 mmol) of sodium hydroxide, 10.42 g (41.0 mmol) of iodine and 50 mL of water was heated at 50° C. for 4 h. The mixture was cooled and filtered. The white solid collected was dried in a vacuum oven to leave 12.60 g (75%) of 6-ethyl-5-iodo-2-phenyl-4(3H)-pyrimidinone. 1H-NMR (d6-DMSO) δ1.25(3H,t), 2.85(2H,q), 7.50(3H,m), 8.15(2H,m).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[N-:25]=[N+:26]=[N-:27].[Na+].CN(C)C=O>O>[N:25]([C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])=[N+:26]=[N-:27]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N=[N+]=[N-])C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2α,3α-epoxy-5α-pregnane-11,20-dione (1 g) was added to a mixture of sodium azide (1g), boric acid (1g) and dimethylformamide (20 ml) and the mixture refluxed for 5 hours. The mixture was cooled, poured into water and the resulting emulsion extracted into methylene chloride (2 × 150 ml.). The organic extracts were washed with water (2 × 300 ml.) dried over anhydrous sodium sulphate and evaporated to a red oil which was purified by preparative T.L.C. using ethyl acetate/petrol (1/1), the main band giving 2β-azido-3α-hydroxy-5α-pregnane-11,20-dione (580 mg) as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH:12]CC=C)[C@H:9]([OH:16])[C@H:8]([O:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:7]=1)=[O:5])[CH3:2].C(CN)O.S(=O)(=O)(O)O>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH2:12])[C@H:9]([OH:16])[C@H:8]([O:17][CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: C=CCN[C@@H]1CC(C(=O)OCC)=C[C@@H](OC(CC)CC)[C@H]1O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: NCCO
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](O)[C@H](N)C1
Temperature: 78 °C

Procedure:
In a 2.5 l 4-necked round bottom flask equipped with a reflux condenser, a thermometer, a mechanical stirrer and an inert gas supply 312.8 g of (3R,4S,5R)-5-allylamino-3-(1-ethyl-propoxy)-4-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester obtained according to (a) were dissolved at room temperature and stirring under argon in 1560 ml of ethanol. To the clear, dark yellow solution were added 66.2 ml of ethanolamine (d=1.015, 1.10 mol) and 31.3 g of palladium on charcoal 10%. The black suspension was heated to 78° C. in the course of 25 min and refluxed for 3 h. The suspension was cooled below 40° C., filtered through a filter paper and the filter cake was washed with 100 ml of ethanol. The combined orange filtrates were cooled to 0 to 5° C., treated with 59.0 ml of sulfuric acid (d=1.83, 1.10 mol) keeping the temperature below 30° C. The yellow suspension (pH=2.5) was evaporated in a rotary evaporator at 48° C./160 to 50 mbar and the remaining oily, yellow crystals (956 g) were dissolved in 1000 ml of deionized water and the orange solution was extracted with a mixture of 500 ml of tert.-butyl methyl ether and 500 ml of n-hexane. The organic phase was extracted with 260 ml of 0.5M aqueous sulfuric acid and the combined aqueous phases (pH=2.3) were cooled to 10° C. and treated with stirring with about 128 ml of 50% aqueous potassium hydroxide until pH=9.5 was reached keeping the temperature in the range of 5° C. to 20° C. The organic phase was separated and the aqueous phase was extracted first with 1000 ml, then twice with 500 ml, in total with 2000 ml of tert.-butyl methyl ether. The combined organic extracts were dried over 1000 g of sodium sulfate and filtered. The filter cake was washed with about 300 ml of tert.-butyl methyl ether and the combined filtrates were evaporated in a rotary evaporator at 48° C./360 to 20 mbar and dried at 48° C./15 mbar for 2 h to yield crude (3R,4S,5R)-5-amino-3-(1-ethyl-propoxy)-4-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (271.4 g) as a red oil containing about 4% of the 4-amino-5-hydroxy isomer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11]CN(CC)CC.S(Cl)(Cl)(=O)=O>CO>[CH3:11][O:9][C:8]([C:5]1[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=1)=[O:10]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ncc(Br)cn1
Solvent: CO
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-2-pyrimidine carboxylic acid (6 g, 29.6 mmol) in MeOH (300 mL) was added Et3N (5.98 g, 59.2 mmol). The mixture was cooled to 0 degrees Celsius, and sulfonyl chloride (5.3 g, 44.4 mmol) was added dropwise to the solution. After addition, the mixture was stirred at rt for 12 hours. The solvent was removed and the residue was dissolved in ethyl acetate. The organic layer was washed with sodium bicarbonate, brine, and dried with sodium sulfate. The solvent was removed to give the pure product. MS: calc'd 217 (MH+), exp 217 (MH+).