Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH2:28][OH:29])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:30])[CH2:11]1>CO.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH2:28][OH:29])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:30])[CH2:11]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O)CC[C@@]43CO)[C@@H]1CCC2=O

Procedure:
A solution of 3β,19-dihydroxyandrost-5-en-17-one diacetate in methanol is hydrogenated with a 10% Palladium-on-charcoal catalyst at atmospheric pressure for 8 hours. The catalyst is removed by filtration and the filtrate concentrated to a small volume, cooled, and filtered to yield the desired 3β,19-dihydroxy-5α-androstan-17-one diacetate. Recrystallization from hexane results in pure material.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[O:17]C)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[SH:13])([O-:3])=[O:2].Cl>[OH-].[Na+]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[OH:17])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[SH:13])([O-:3])=[O:2]
Reactant: COc1ccc(Cn2ccnc2S)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(Cn2ccnc2S)ccc1O
Yield: 0.1 %

Procedure:
A solution of 1-[3'-nitro-4'-methoxybenzyl]-2mercaptoimidazole (1.59 g, 6.0 moles) in 10% aqueous NaOH (200 ml) was refluxed for two hours, cooled, acidified with concentrated HCl, cooled and filtered. The crystalline product was washed with water. Recrystallization from ethanol provided 1.25 g (80%) of product as yellow prisms: mp 225-227° (dec).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[C:17]1(/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccccc1
Reactant: C=CC(=O)OCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
0.38 g (2.9 mmol) of butyl acrylate and 0.30 g (2.2 mmol) of K2CO3 are added to a solution of 0.32 g (2.0 mmol) of bromobenzene in 20 ml of dimethylformamide. After the mixture has been stirred at room temperature for 5 minutes, 0.08 g (0.05 mmol) of [{Pd[P(C2F5)2O]2H}2(μ-Cl)2], prepared in accordance with Example 13, is added, and the reaction mixture is heated under reflux for 20 hours. After cooling and addition of 100 ml of water, the reaction mixture is extracted with 100 ml of diethyl ether. The organic phase is washed with water and dried using MgSO4. After filtration and removal of the solvent (in vacuo), 0.26 g of butyl (E)-3-(phenyl)acrylate is isolated as a colourless oil. The yield is 64%, based on the bromobenzene employed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:24][CH2:25][C:26]3[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=3[CH3:32])=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(Cl)cc3)nc21
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(Cl)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 6-(4-chlorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.222 mmol), DMSO (2 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone HCl salt (62.7 mg, 0.333 mmol), N-methylmorpholine (0.097 mL, 0.887 mmol), 1-hydroxy-7-azabenzotriazole (60.3 mg, 0.443 mmol) and EDC (85 mg, 0.443 mmol). The final product was collected as 77 mg (78%). LCMS E-S (M+H)=450.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.6 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 4.41 (d, J=4.6 Hz, 2H), 5.34 (quin, J=6.7 Hz, 1H), 5.91 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 8.19 (s, 1H), 8.31 (d, J=8.6 Hz, 2H), 8.39 (s, 1H), 8.97 (t, J=4.7 Hz, 1H), 11.58 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:28]3[C:14](=[CH:15][C:16]4[O:17][CH2:18][CH2:19][CH2:20]S[CH2:22][CH2:23][CH2:24][O:25][C:26]=4[CH:27]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].O[O:30][S:31]([O-:33])=O.[K+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:28]3[C:14](=[CH:15][C:16]4[O:17][CH2:18][CH2:19][CH2:20][S:31](=[O:33])(=[O:30])[CH2:22][CH2:23][CH2:24][O:25][C:26]=4[CH:27]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3cc4c(cc23)OCCCSCCCO4)cc1Cl
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=S1(=O)CCCOc2cc3ncnc(Nc4ccc(F)c(Cl)c4)c3cc2OCCC1
Reaction time: 4 h

Procedure:
(3-Chloro-4-fluoro-phenyl)-(2,10-dioxa-6-thia-14,16-diaza-tricyclo[9.8.0.013,18]nonadeca-1-(11),12,14,16,18-pentaen-17-yl)-amine (16, 140 mg, 0.33 mmol) was suspended in MeOH, to which was added a cloudy aqueous solution of oxone (monopersulfate compound) (820 mg, 1.33 mmol) at room temperature. The suspension was stirred and monitored by TLC which indicated that the reaction was completed in 4 h. The reaction mixture was poured into H2O (10 mL), and extracted with EtOAc (3×15 mL). The organic layers were collected, dried and concentrated to give a pale yellow residue which was flash chromatographed to give the product as a white solid: 140 mg (93%). 1H NMR (CDCl3) δ 8.75 (s, 1H), 8.00 (d, 1H), 7.24 (s, 1H), 7.26 (s, 1H), 7.42 (s, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 4.40 (t, 4H), 4.75 (t, 2H), 3.40 (t, 2H), 2.55 (m, 2H), 2.23 (m, 2H); ES-MS m/z: 452 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][C:12]([O:15]C(OC(OC(C)(C)C)=O)=O)(C)C.CCN(CC)CC>CC#N.CN(C1C=CN=CC=1)C.O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:12](=[O:15])[CH3:11])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Ic1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5-iodo-1H-indazole (1.00 g, 4.10 mmol) in CH3CN (20 ml) were added Boc2O (984 mg, 4.51 mmol), DMAP (125 mg, 1.02 mmol) and Et3N (0.64 ml, 4.6 mmol). The reaction mixture was stirred at room temperature for 5 hours, diluted with H2O and extracted with AcOEt. The organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound. This compound (>1.5 g) was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 1.72 (9H, s), 7.79 (1H, d, J=8.8 Hz), 7.98 (1H, d, J=8.8 Hz), 8.10 (2H, s). MS (ESI) m/z 345 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f4) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: S1CCCS[CH:2]1[C:7]1[CH2:12][CH2:11][CH2:10][CH:9]([NH:13][C:14]([NH:16][CH2:17][CH2:18][F:19])=[O:15])[C:8]=1[CH3:20].ClN1C(=[O:27])CCC1=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CC#N.O.[N+]([O-])([O-])=O.[Ag+]>[F:19][CH2:18][CH2:17][NH:16][C:14]([NH:13][CH:9]1[CH2:10][CH2:11][CH2:12][C:7]([CH:2]=[O:27])=[C:8]1[CH3:20])=[O:15]
Reactant: CC1=C(C2SCCCS2)CCCC1NC(=O)NCCF
Reactant: O=C1CCC(=O)N1Cl
Agent: [Ag+]
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Solvent: O
Product: CC1=C(C=O)CCCC1NC(=O)NCCF
Reaction time: 0.5 h

Procedure:
1-(3-[1,3]Dithian-2-yl-2-methyl-cyclohex-2-enyl)-3-(2-fluoro-ethyl)-urea (630 mg, 2.00 mmol) dissolved in 3 mL CH3CN was added to a solution of N-chlorosuccinimide (845 mg, 6.30 mmol) and AgNO3 (1.24 g, 7.30 mmol) in 14 mL of 80% aqueous CH3CN at 0° C. The reaction mixture was stirred for 30 minutes, and then 3.60 g of Na2S2O3 in 7.0 mL of H2O was added, followed by 4.20 g of Na2CO3 in 7.0 mL of H2O. The resulting mixture was stirred for 5 minutes and filtered through a pad of celite. The celite was washed with EtOAc and the combined organic phases were washed with brine (1×15 mL), dried over MgSO4 and concentrated. Purification by column chromatography using hexane:EtOAc (4:1) as the eluant gave the desired title urea. Spectroscopic data: 1H NMR (500 MHz, DMSO-d6) δ 1.49-1.58 (m, 3H), 1.60-1.67 (m, 1H), 1.92-2.00 (m, 1H), 2.08-2.14 (m, 4H), 3.29 (q, J=4.88 Hz, 1H), 3.35 (q, J=5.86, 4.88 Hz, 1H), 4.20-4.25 (m, 1H), 4.35 (t, J=4.88 Hz, 1H), 4.45 (t, J=4.88 Hz, 1H), 6.01 (t, J=5.37 Hz, 1H), 6.28 (d, J=8.79 Hz, 1H), 10.1 (s, 1 H). 13C NMR (126 MHz, DMSO-d6) δ 15.62, 18.72, 22.79, 30.23, 40.62 (d, J=20.14 Hz), 50.08, 84.04 (d, J=163.98 Hz), 134.63, 155.68, 158.31, 193.00.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.[F:23]C1C=CC(COC(CC)=C)=CC=1OC1C=CC=CC=1>>[F:23][CH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: C=C(CC)OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(C)(CCl)COCc1ccc(F)c(Oc2ccccc2)c1
Product: CC(C)(CF)COCc1ccc(F)c(Oc2ccccc2)c1

Procedure:
A mixture of 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propy-1-yl p-toluenesulphonate (2.5 g), potassium fluoride (0.8 g) and tetraethylene glycol (7 cm3) was heated at 160° C. (under a drying tube to exclude moisture) for 3 hours. The reaction mixture was allowed to cool and stood at the ambient temperature for 17 hours. The mixture was poured into water and the products extracted into diethyl ether (2×200 cm3). The combined organic extracts were washed with water and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave an orange oil (1.5 g) which was passed through a short silica gel column using petroleum ether (boiling range 40°-60° C.) containing 10% by volume diethyl as eluent. Analysis of the resulting oil indicated 3 major components which were separated and isolated by high pressure liquid chromatography (eluting with hexane containing 1% by volume ethyl acetate). The first and third fractions were identified as 1-chloro-2,2-dimethyl-3-(4 -fluoro-3-phenoxybenzyloxy)propane (0.25 g--thought to have been formed owing to the presence of chloride ion contamination of the starting materials) and 2-(4-fluoro-3-phenoxybenzyloxy)-but-1-ene (an elimination by-product) respectively. The title compound (0.29 g) was obtained as the second eluted fraction; characterising data for this compound are given below:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(=[O:18])[C:11](N1C=CN=C1)=[O:12]>O1CCCC1>[OH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[NH:1][C:10](=[O:18])[C:11](=[O:12])[NH:8]2
Reactant: O=C(C(=O)n1ccnc1)n1ccnc1
Reactant: Nc1cccc(O)c1N
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(O)c2[nH]c1=O

Procedure:
A solution of 2,3-diaminophenol (50 g) and 1,1′-oxalyldiimidazole (92 g) and tetrahydrofurane (1.2 L) is refluxed 30 minutes. The solvent is removed under reduced pressure and the remaining solid taken into ethyl acetate. The organic phase is washed with 1M aqueous hydrochloric solution, dried over sodium sulphate and concentrated under vacuum. The crude solid obtained is recrystallised from dimethylformamide; yield: 14.8 g; MS: 177.1 (M−1); 1H NMR (DMSO-d6, 300 MHz): δ [ppm] 6.61 (m, 2H); 6.91 (ss, 1H), 10.21 (s (1H); 11.05 (s, 1H); 11.85 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH2:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C(OCC)C>O.C(OCC)(=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:19](=[O:20])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][CH2:5]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NC1CCc2cc(Br)ccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a vigorously stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-amine (8.54 g, 40.3 mmol) and potassium carbonate (11.1 g, 80 mmol) in water (100 mL) and ethyl acetate (100 mL) was added benzyl chloroformate (7.56 g, 44.3 mmol). The reaction was stirred at rt overnight before being diluted with water (200 mL) and dichloromethane (200 mL). The organic phase was collected and the aqueous phase was extracted once more with dichloromethane (100 mL). The clear colourless organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a white solid. The material was co-evaporated once with diethyl ether and the residue was triturated with diethyl ether. The white solid was collected by filtration and dried on air to afford the title compound as a white solid (11.5 g, 82%). MS (ESI): m/z [M+H]+ 347.0
Reaction SMILES: [Mg].BrCCBr.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1.[O:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C1COCC1.O>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][C:16]2([OH:15])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1ccc(CCl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium (1.2 g) and 1,2-dibromoethane (0.11 mL) in THF (30 mL) was added a solution of 4-fluorobenzyl chloride (6.3 mL) in THF (10 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hr at the same temperature. The reaction mixture was cooled to −78° C., a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g) in THF (10 mL) was added thereto, and the mixture was allowed to warm to room temperature, and stirred for 2 days. To the reaction mixture was added water at 0° C., and then saturated aqueous potassium sodium tartrate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (4.8 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]2[OH:17])[CH:3]=1.[I-:18].[Na+]>I>[OH:15][CH2:14][C@H:12]1[CH2:13][C@@H:9]([NH:8][C:4]2[CH:3]=[C:2]([I:18])[N:7]=[CH:6][N:5]=2)[C@H:10]([OH:17])[C@@H:11]1[OH:16]
Reactant: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Reactant: [I-]
Agent: I
Agent: [Na+]
Product: OC[C@H]1C[C@@H](Nc2cc(I)ncn2)[C@H](O)[C@@H]1O
Temperature: 70 °C
Yield: 944.2 %

Procedure:
To a solution of (1R,2S,3R,5R)-3-[(6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diol (1.880 g, 7.239 mmol) in hydroiodic acid (23.9 mL) was added sodium iodide (5.42 g, 36.2 mmol). The mixture heated to 70° C. for 10 min then concentrated and azeotroped using toluene (3×). The residue was dissolved in acetone and NaHCO3 was added. The suspension was filtered and the filtrate was concentrated in vacuo to obtain the title compound (24 g, >99%). LC/MS: Rt=0.76 min ES+ 352 (FA standard).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH2:28][NH2:29])(=[O:20])=[O:19])[CH3:17].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:29]([CH2:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])[CH:10]=1
Reactant: CCS(=O)(=O)c1ccc(F)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 50.9 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.43 g), 1-[2-(ethylsulfonyl)-5-fluorophenyl]methanamine hydrochloride obtained in Step 3 (0.55 g) and potassium carbonate (0.75 g) were stirred in ethanol (15 ml) at 85° C. for 16 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.19 g).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][P:8]([CH3:12])(=[O:11])[O:9][CH3:10].C([O:15][C:16](=O)[C:17]([CH3:24])([CH3:23])[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])C.C(O)(=O)C>CCCCCC.O1CCCC1>[CH3:6][O:7][P:8]([CH2:12][C:16]([C:17]([CH3:24])([CH3:23])[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[O:15])(=[O:11])[O:9][CH3:10]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)C(C)(C)CC=C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)(C)CC=C(C)C)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
Under argon at -60° C., 49.5 ml of a 2.02 N butyllithium solution in hexane was added dropwise to a solution of 13 g of methanephosphonic acid dimethyl ester in 160 ml of absolute tetrahydrofuran. After 15 minutes, a solution of 9.2 g of 2,2,5-trimethyl-4-hexenoic acid ethyl ester in 25 ml of absolute tetrahydrofuran was added dropwise thereto. After 2 hours at -60° C., the reaction mixture was allowed to warm up to room temperature within one hour, combined with 5.72 ml of glacial acetic acid, and then concentrated under vacuum. The residue, a white, gel-like mass, was distributed in a two-phase mixture of 35 ml of water and 165 ml of ether. The organic phase was dried over magnesium sulfate and concentrated on a forced circulation evaporator. After removing the volatile byproducts by distillation under 0.1 torr and at 60° C., the residue was purified by column chromatography on silica gel with hexane/50-100% ethyl acetate as the mobile phase, thus obtaining 8.6 g of the title compound.
Reaction SMILES: O[C:2]1([CH:12]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[C:13]2[N:17]=[CH:16][NH:15][N:14]=2)[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.S(Cl)(Cl)=O>ClCCl>[CH:3]12[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]([CH2:8]3)[C:2]1=[C:12]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[C:13]1[N:17]=[CH:16][NH:15][N:14]=1)[CH2:4]2
Reactant: N#Cc1ccc(C(c2nc[nH]n2)C2(O)C3CC4CC(C3)CC2C4)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=C2C3CC4CC(C3)CC2C4)c2nc[nH]n2)cc1
Reaction time: 2 h
Yield: 62.2 %

Procedure:
9 g of crude 4-[2-hydroxyadamant-2-yl-1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved at 0° in 50 ml of dichloromethane and stirred at 0° with 24 ml of thionyl chloride for 1 hour. Then the mixture is concentrated to dryness in an oil pump vacuum, dissolved in 50 ml of dichloromethane, stirred for 2 hours with 32 ml of triethylamine, diluted with water, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, yielding 5.3 g of 4-[2-adamantylidene-1-(1,2,4triazolyl)methyl]benzonitrile as the free base, mp 130°, which is converted with hydrochloric acid into the hydrochloride, mp 105°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:12]1[C:13]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14][C:15]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:17]=1[CH3:18])(=[O:11])[CH3:10].C(Cl)(Cl)(Cl)Cl>C(O)C>[C:9]([C:12]1[C:13]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14][C:15]([NH:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[C:16]([Br:1])[C:17]=1[CH3:18])(=[O:11])[CH3:10]
Reactant: CC(=O)c1c(C)cc(NC(C)(C)C)nc1NC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CC(=O)c1c(NC(C)(C)C)nc(NC(C)(C)C)c(Br)c1C
Reaction time: 8 h

Procedure:
534 mg. (3 mmol.) of N-bromosuccinimide (recrystallized from water) were added in small portions to a solution of 831 mg. (3 mmol.) of 3-acetyl-2,6-di-t-butylamino-4-methylpyridine (Compound V) in 20 ml. of carbon tetrachloride and 5 ml. of ethanol, and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was evaporated down at reduced pressure, and the residue was partitioned between ether and water. The organic phase was dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain yellow crystals. Recrystallization from methanol/water gave the product (990 mg.), m.p. 99°-100° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([CH2:12][CH2:13][CH2:14][C@H:15]([NH2:37])[C:16]([O:18][C@@H:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:20][C:21]([NH2:23])=[O:22])=[O:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[C:40]([C:48](O)=[O:49])[CH:39]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:2]([O:9][C:10]([CH2:12][CH2:13][CH2:14][C@H:15]([NH:37][C:48]([C:40]1[CH:39]=[N:38][C:47]2[C:42]([CH:41]=1)=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:49])[C:16]([O:18][C@@H:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:20][C:21]([NH2:23])=[O:22])=[O:17])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@@H](N)CCCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-aminopentanoyl]oxyhexadecanamide hydrochloride (1.79 g), 3-quinolinecarboxylic acid (630 mg) and 1-hydroxybenzotriazole (536 mg) in N,N-dimethylformamide (40 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (616 mg) at 0° C., and the mixture was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate (200 ml) and washed with 0.5N hydrochloric acid (200 ml), 10% aqueous citric acid (200 ml), saturated aqueous sodium bicarbonate (200 ml) and brine, successively. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give (3S)-3-[(2S)-5-benzyloxycarbonyl-2-{(3-quinolyl)carbonylamino}pentanoyl]oxyhexadecanamide (2.16 g).