Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:12]#[N:13])[C:5]([Cl:11])=[N:6][C:7]=1[N:8]([CH3:10])[CH3:9].C(=O)([O-])[O-:16].[Na+].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:12]([NH2:13])=[O:16])[C:5]([Cl:11])=[N:6][C:7]=1[N:8]([CH3:9])[CH3:10]
Reactant: Cc1c(Br)c(N(C)C)nc(Cl)c1C#N
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)c(N(C)C)nc(Cl)c1C(N)=O

Procedure:
A solution of 5-bromo-2-chloro-3-cyano-6-(N,N-dimethylamino)-4-methylpyridine (1.3 g) in concentrated sulfuric acid (3 mL) was heated at 120° C. for 10 minutes. The mixture was cooled, diluted with water (50 mL), and neutralized with saturated sodium carbonate. After extraction with methylene chloride, evaporation of the organic phase gave 1.37 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:15][C:16](O)=[O:17])[C:9](=[O:10])[C:8]2=[CH:30][CH:31]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:15][C:16]([NH:45][OH:46])=[O:17])[C:9](=[O:10])[C:8]2=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(NC(C)=O)cc3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(NC(C)=O)cc3C2=O)ccc1OC
Yield: 43.4 %

Procedure:
3-(4-Acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(4-acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.7 mmol), carbonyldiimidazole (836 mg, 5.16 mmol) and hydroxylamine hydrochloride (391 mg, 5.63 mmol) in tetrahydrofuran (8 mL) to afford 3-(4-acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a yellow solid (0.9 g, 43% yield): mp, 138.0-140.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 2.12 (s, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.98 (q, J=6.9 Hz, 2H, CH2), 5.64 (t, J=7.8 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.77-7.86 (m, 2H, Ar), 8.17 (br s, 1H, Ar), 8.80 (br s, 1H, OH), 10.58 (br s, 2H, 2NH); 13C NMR (DMSO-d6) δ14.69, 24.18, 34.27, 50.15, 55.43, 63.69, 111.68, 112.26, 112.46, 119.63, 123.11, 124.37, 124.79, 131.26, 132.76, 114.87, 147.65, 148.48, 165.98, 167.26, 169.22; Anal Calcd for C22H23N3O7: C, 59.86; H, 5.25; N, 9.52. Found: C, 59.49; H, 5.24; N, 9.40.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5](#[N:8])[CH:6]=[CH2:7].Cl>CO>[CH2:1]([O:4][CH2:7][CH2:6][C:5]#[N:8])[CH2:2][O:3][CH2:7][CH2:6][C:5]#[N:8]
Reactant: OCCO
Reactant: C=CC#N
Agent: Cl
Solvent: CO
Product: N#CCCOCCOCCC#N
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.9 %

Procedure:
Small scale: Ethylene glycol (1 g, 16.1 mmol) was mixed with Triton B (40% in MeOH, 0.22 g, 0.53 mmol) and cooled in an ice-bath while acrylonitrile (1.71 g, 32.2 mmol) was added. The mixture was stirred at room temperature for 60 hours after which it was neutralized with 0.1 M HCl (0.6 cm3) and extracted with CH2Cl2 (80 cm3) The extracts were concentrated under reduced pressure and the residue was Kugelrohr-distilled to give 3,3′-(ethane-1,2-diylbis(oxy))dipropanenitrile (1.08 g, 39.9%) as a light colored oil, bp 150-170° C./20 Torr.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.S([O-])([O-])(=O)=O.[Na+].[Na+].C([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])C.Cl.Cl.[NH2:26][OH:27]>O>[CH:23]1[CH:22]=[CH:21][C:19]([NH:20][C:3](/[CH:2]=[N:26]/[OH:27])=[O:5])=[CH:18][CH:17]=1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Reactant: CCc1cccc(N)c1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(/C=N/O)Nc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
A mixture of chloral hydrate (59.3 g, 0.36 mol), water (700 ml), and sodium sulphate (85.8 g, 0.60 mol), was heated to 50° C. When 50° C. was reached, sequentially a mixture of 3-ethylaniline (40.8 g, 0.33 mol), water (700 ml) and conc. hydrochloric acid (33.6 ml) and a mixture of hydroxylamine hydrocloride (74.8 g, 1.04 mol) and water (330 ml) were added. The resulting mixture was heated to 80° C. during 30 minutes and kept for another 10 minutes at this temperature before the reaction mixture was cooled on an ice-bath. The resulting precipitate was filtered off, washed with water and dried in vacuum over P2O5 to give an isonitrosoacetanilide (36.6 g), yield 58%
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)C=O.[C:22](O)(=O)C>C(O)C.[O-2].[Mn+4].[O-2]>[Cl:13][C:14]1[CH:21]=[C:20]([C:7]2[N:6]([CH3:22])[C:4](=[O:5])[C:3]3[C:2](=[CH:11][CH:10]=[C:9]([OH:12])[CH:8]=3)[N:1]=2)[CH:19]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CNC(=O)c1cc(O)ccc1N
Reactant: CC(=O)O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCO
Product: Cn1c(-c2cccc(Cl)c2)nc2ccc(O)cc2c1=O

Procedure:
To a solution of 2-amino-5-hydroxy-N-methylbenzamide (Intermediate 32A) (280 mg, 1.68 mmol) and 3-chlorobenzaldehyde (0.23 mL, 2.02 mmol) in ethanol (10 mL) was added a catalytic amount of acetic acid (0.07 mL) and the mixture heated under reflux for 23 h. The reaction was cooled before manganese (iv) oxide (225 mg, 1.68 mmol) was added and the reaction heated under reflux until complete by Ic/ms. On cooling the reaction was filtered and the filtrate evaporated to dryness to afford 2-(3-chlorophenyl)-6-hydroxy-3-methylquinazolin-4(3H)-one (450 mg, 1.57 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[OH2:18].[CH2:20]([O:19][C:17]([C:16](=[C:30]1[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]1=[O:29])[C:14]1[N:15]=[C:11]([NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:23])[S:12][CH:13]=1)=[O:18])[CH3:21].[CH2:20]([O:19][C:17]([C:16](=[C:30]1[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]1=[O:29])[C:14]1[N:15]=[C:11]([NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:23])[S:12][CH:13]=1)=[O:18])[CH3:21]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2cccc(F)c2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2cccc(F)c2)n1
Product: O

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.7 g of ethyl 2-(3-m-fluorophenylureido)thiazol-4-ylglyoxylate, 0.96 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was an orange powder having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][CH3:22])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:4][CH:3]=1.[O:29]=[C:30]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:31]([OH:33])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([N:21]([CH3:22])[C:31](=[O:33])[C:30](=[O:29])[N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:27][CH:28]=1
Reactant: O=C(O)C(=O)N1CCCC1
Reactant: CNC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(=O)N1CCCC1)C12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
To a stirred solution of N-(4-fluorobenzyl)-3-hydroxy-10-(methylamino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (50 mg, 0.100 mmol) in (DMF (2 mL) was added 2-oxo-2-(pyrrolidin-1-yl)acetic acid (57.2 mg, 0.400 mmol), diisopropyl-ethylamine (0.105 mL, 0.599 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (152 mg, 0.400 mmol) and 4-(dimethylamino)pyridine (DMAP) (1.221 mg, 9.99 μmol) and the resulting mixture was stirred at room temperature for 3 h. The crude was then purified by preparative HPLC and recrystallized from methanol to afford the title compound as a glassy white crystals (20 mg, 40% yield). 1H NMR (500 MHz, CDCl3) δ: 12.1 (1 H, s), 9.6 (1 H, brs), 7.4-7.4 (2 H, m), 7.0-7.0 (2 H, m), 4.8-4.9 (1 H, m), 4.6-4.7 (1 H, m), 4.4-4.5 (1 H, m), 3.6-3.7 (2 H, m), 3.5 (2 H, t, J=6.71 Hz), 3.3-3.4 (2 H, m), 3.0 (3 H, s), 2.5 (1 H, brs), 1.9-2.1 (9 H, m), 1.7-1.8 (2 H, m). LCMS (M+H)=512.24. HPLC purity: >95%.
Reaction SMILES: ICI.[CH3:4][C:5]1([CH3:29])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]2[CH:10]=[C:9]([C:17]([C:19]3[CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:23][CH:24]=3)=[CH2:18])[CH:8]=[CH:7][C:6]1=2.[CH2:30]([Zn]CC)C.CCCCCCC>ClCCl>[CH3:4][C:5]1([CH3:29])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]2[CH:10]=[C:9]([C:17]3([C:19]4[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:25]([O:27][CH3:28])=[O:26])[CH2:30][CH2:18]3)[CH:8]=[CH:7][C:6]1=2
Reactant: C=C(c1cccc(C(=O)OC)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Solvent: CCCCCCC
Product: COC(=O)c1cccc(C2(c3ccc4c(c3)C(C)(C)CCC4(C)C)CC2)c1
Reaction time: 15 h

Procedure:
Diiodomethane (1.1 ml, 13.7 mmol) is added dropwise, at 60° C., to a mixture of methyl 3-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)vinyl]phenylcarboxylate (2.2 g, 6.3 mmol) and a 1M solution of diethylzinc in heptane (13 ml, 13 mmol) in dichloromethane (50 ml). The heating is continued for 15 h. The solution is extracted with ethyl acetate. After separation of the phases by settling, the organic phase is washed with 1N HCl solution and then with water, dried over anhydrous magnesium sulphate and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][C:20](C2C=CC=CC=2)(C2C=CC=CC=2)[C:21]2[CH:26]=CC=CC=2)=[CH:17][CH:18]=1)[C:5]([OH:15])([C:10]#[C:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([F:9])([F:8])[F:7].N1C=CC=CC=1.BrCCC(Br)=[O:49]>CCOCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[NH:19][C:20](=[O:49])[C@H:21]([CH3:26])[O:15][C@:5](/[CH:10]=[CH:11]/[CH:12]3[CH2:14][CH2:13]3)([C:6]([F:9])([F:8])[F:7])[C:4]=2[CH:3]=1
Reactant: OC(C#CC1CC1)(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Reactant: O=C(Br)CCBr
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred ice-cooled solition of 291 mg of trans-6-Amino-3-chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part C.) in 13 mL of dry ether was added 0.180 mL of dry pyridine and 0.120 mL of bromopropionyl bromide. After 1 h, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF and was treated at 0° with 40 mg of 100% sodium hydride. After 15 min the cooliing bath was removed and stirring was continued at ambient temperature for 20 h. The reaction was poured onto aqueous ammonium chloride and extracted with ether. The ether layer was washed with brine, dried and evaporated. The residie was dissolved in a small amount of ethyl acetate, and addition of hexane resulted in the crystallization of 40 mg of the title compound as colorless crystals: mp 171-172°; HRMS: Calcd. for C16H16NO2ClF3 (M+H)+ : 346.082166. Found: 346.080681. A second crop of slightly less pure product weighed 41 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([C@@H:14]([OH:26])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[O:16])[C:9]2=[O:27])=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][O:31][CH2:32][C:33](O)=[O:34].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C@H:14]([OH:26])[C@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]4[CH2:29][CH2:30][O:31][CH2:32][C:33]4=[O:34])=[CH:3][CH:4]=3)[C:9]2=[O:27])=[CH:19][CH:20]=1)#[N:25]
Reactant: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(N)cc3)C2=O)cc1
Reactant: O=C(O)COCCCl
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(N4CCOCC4=O)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a suspension of compound 26-5 (0.1 g) and 2-chloroethoxy acetic acid (45.4 mg) in DMF (2 mL), was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM; 87.7 mg). The reaction mixture was stirred at room temperature overnight. Then, according to the Step 29-1 in synthetic method for EXAMPLE 29, cyclization reaction was pursued to obtain compound 30-1 (90 mg) as a colorless amorphous solid.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[CH:26]=[CH:27][C:28]([N+:42]([O-:44])=[O:43])=[C:29]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH:30]=2)=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CCOC(C)=O>[OH:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[CH:26]=[CH:27][C:28]([N+:42]([O-:44])=[O:43])=[C:29]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH:30]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)s3)ccc2[N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(CO)s3)ccc2[N+](=O)[O-])cc1
Yield: 193.9 %

Procedure:
A solution of compound 189 (0.673 g, 1.08 mmol) in a 1M solution of tetrabutylammonium fluoride in THF (1.5 mL, 1.5 mmol) was stirred for 90 min at room temperature. The reaction mixture was diluted with AcOEt, washed with 5% KHSO4, water, dried over MgSO4, filtered and concentrated to give a solid material which was triturated with DCM, to afford title compound 190 (0.805 g, 75% yield). The supernatant was collected, evaporated and the residue was purified by flash column chromatography (eluent: 50% AcOEt in DCM) to afford additional amount of 190 (0.161 g, 15% yield).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH2:12](Cl)[O:13][CH3:14]>CN(C=O)C>[CH3:12][O:13][CH2:14][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To the suspension of NaH (3.25 g, 0.135 mol) in DMF (150 mL) was added 4-hydroxy-benzaldehyde (15.0 g, 0.123 mol) in DMF (10 mL) at 0° C., 5 min. later the reaction mixture became a cake. The heterogeneous mixture was stirred at 0° C. for 30 min. MOMCl (9.96 g, 0.123 mol) was added slowly and the reaction mixture was allowed to warm up to r.t. After stirring at r.t. for 16 h, the volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water and the water layer was further extracted with ethyl acetate. The combined ethyl acetate extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes; 1:4) to afford 4-methoxymethoxy-benzaldehyde (19.0 g, 93%): 1H NMR (300 MHz, CDCl3): δ 9.94 (s, 1 H), 7.88 (m, 2H), 7.18 (m, 2H), 5.29 (s, 2H), 3.53 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:4); Rf=0.86.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3Cl)[O:7]1)(=[O:3])[CH3:2].[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:12]([O:11][C@H:10]1[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3[NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:7][C@@H:6]1[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:14])[CH3:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1.15 g of [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]methyl acetate (Toronto Research Chemicals) was placed in 20 mL of DMF (dimethylformamide) and stirred. To this solution was added 0.42 mL of cyclopentyl amine and 10 mL of DIPEA (diisopropylethylamine). The resulting mixture was stirred overnight at room temperature. The next morning, the solvent was removed and the residue purified using a dichloromethane/methanol 20:1 column to provide (2R,3R,4R,5R)-4-acetyloxy-2-(acetyloxymethyl)-5-[6-(cyclopentylamino)-2-iodopurin-9-yl]oxolan-3-yl acetate, a compound of formula (10).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[BrH:21].N([O-])=O.[Na+].[Br-]>O>[Br:21][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c(Br)c1

Procedure:
To 11.1 g. (0.044 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylate suspension in 225 ml. of 40% hydrobromic acid and cooled to 0° C is added dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. of water. To this mixture is added a solution of 20 g. of curpous bromide in 350 ml. of 40% hydrobromic acid added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water, extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is then crystallized to obtain 3-bromo-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([O-:33])(=[S:32])[CH3:31].[K+].C(OCC)(=O)C.Cl>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:32][C:30](=[O:33])[CH3:31])[CH2:10][C@H:9]1[CH2:18][N:19]1[C:20](=[O:29])[C:21]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]2[C:23]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)S[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 74.2 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (3 g) in dimethylformamide (30 ml), potassium thioacetate (1.65 g) is added. The mixture is stirred at 60° C. for 3.5 hours. The reaction mixture is poured into a mixture of ethyl acetate and dilute hydrochloric acid. The organic layer is taken, washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give (2S,4S)-1-t-butoxycarbonyl-2-phthalimidomethyl-4-acetylthiopyrrolidine (2.12 g). Yield: 74%. Orange colored syrup.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:5]=1[O:30][CH3:31])(=[O:3])[CH3:2]>[Ni].O1CCCC1>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[NH2:19])=[C:6]([CH2:24][CH2:25][C:26]([F:28])([F:27])[F:29])[C:5]=1[O:30][CH3:31])(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)ccc(OCCCOc2cccc([N+](=O)[O-])c2)c1CCC(F)(F)F
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1c(C(C)=O)ccc(OCCCOc2cccc(N)c2)c1CCC(F)(F)F

Procedure:
2.0 g of Raney nickel are added to a solution of 10 g of 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-nitrobenzene in 100 ml of tetrahydrofuran and the starting substance is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. Evaporation of the filtrate under reduced pressure gives 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-aniline as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(N(CC)CC)C>ClCl.O>[C:13]([NH:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)(=[O:15])[CH3:14]
Reactant: COc1ccc(C2(N)CC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: ClCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(NC(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.1 %

Procedure:
To a stirred suspension of Compound 7 (1.25 g, 7.66 mmol) in CH2 Cl2 (40 ml) was added acetic anhydride (860 mg, 8.42 mmol) and triethylamine (2.32 g, 22.98 mmol) at room temperature. The reaction mixture was stirred at room temperature for 22 h. The mixture was diluted with H2O (50 ml) and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with 10% HCl aq., sat. NaHCO3 aq. and brine, dried (MgSO4) and concentrated in vacuo to give crude product (1.58 g, quant.), which was recrystallized from hexane-ethyl acetate to give Compound 8 (1.26 g, 80%) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1([N:18]([CH3:20])[CH3:19])[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28]([Cl:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH-].[K+]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[ClH:36].[CH2:1]([C:8]1([N:18]([CH3:20])[CH3:19])[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][CH2:16][CH3:17])[C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNC1CCC(Cc2ccccc2)(N(C)C)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(C(=O)c1ccccc1)C1CCC(Cc2ccccc2)(N(C)C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
700 mg of the nonpolar diastereomer of 1-benzyl-N,N-dimethyl-N′-propyl-cyclohexane-1,4-diamine were dissolved in 10 ml methylene chloride, and 370 μl triethylamine and approx. 10 mg DMAP (4-dimethylaminopyridine) were added. 311 μl benzoyl chloride were added dropwise, while cooling in an ice/methanol bath, and the reaction mixture was then stirred overnight, while warming to room temperature. For working up, 10 ml five molar KOH solution and 10 ml water were added, the mixture was stirred for ten minutes and extracted three times with 20 ml methylene chloride each time, the combined extracts were dried over magnesium sulfate and filtered and the filtrate was concentrated. From the crude product obtained (834 mg), 909 mg N-(4-benzyl-4-dimethylamino-cyclohexyl)-N-propyl-benzamide hydrochloride were prepared as described for example 1 with water and chlorotrimethylsilane in 2-butanone.