Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.C(O)C.Cl.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:17]N)[CH:14]=[CH:15][CH:16]=1.O=[C:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:22][CH2:21]1>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:14]([C:21]3[CH2:22][CH:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])[CH2:24][CH2:25][C:20]=3[NH:17]2)=[CH:15][CH:16]=1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Reactant: COc1cccc(NN)c1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2c3c([nH]c2c1)CCC(NC(=O)C(C)C)C3
Yield: 31.1 %

Procedure:
Follow the procedures essentially as described in Preparation 6, above, using acetyl chloride (26 mL, 360 mmol) and absolute ethanol (90 mL) with 3-methoxyphenylhydrazine hydrochloride (5.24 g, 30 mmol) and N-(4-oxo-cyclohexyl)-isobutyramide (5.50 g, 30 mmol). When complete, dilute the reaction with ethyl acetate (200 mL) and wash with 0.5N NaOH and sodium bicarbonate solution. Filter the solids in the organic phase, triturate in dichloromethane and filter to give 2.67 g (31%) gray solid. MS (ES): m/z 287 (M+1), 285 (M−1); 1H NMR(DMSO-d6): δ 10.52 (s, 1H), 7.83 (d, 1H, J=7.5 Hz), 7.21 (d, 1H, J=8.4 Hz), 6.78 (s, 1H), 6.60 (d, 1H, J=8.4 Hz), 4.00 (m, 1H), 3.75 (s, 3H), 2.87 (dd, 1H, J=14.8, 5.1 Hz), 2.76 (m, 2H), 2.48-2.36 (m, 2H), 2.48-2.36 (m, 2H), 1.76 (m, 1H), 1.03 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCCNC(=O)c2ccc(Cl)cc2)cc1
Yield: 87.7 %

Procedure:
Ten grams of methyl 4-[2-(4-chlorobenzamido)ethoxy]benzoate was dissolved in 100 ml of hot ethanol. A solution of 2.4 g of sodium hydroxide in 20 ml of water was added to the above ethanolic solution and the mixture was heated to reflux for 2 hours. The reaction solution was concentrated in vacuo, 100 ml of water was added to the residue, the mixture was neutralized with 10% hydrochloric acid, crystals separated out were collected by filtration, washed with water, dried and recrystallised from ethanol to give 8.4 g (yield: 87%) of crystalline product. M.p. 219°-220° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)(=O)CCCCCCCCC=C.[OH-].[K+]>C(O)C>[CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CCCCCCCCCCC
Agent: C=CCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C#CCCCCCCCCCC
Temperature: 0 °C

Procedure:
The procedure for the bromination of 1-dodecene was essentially identical to that for 10-undecenoic acid (Step A), and was carried out on a 0.54 mol scale. Dehydrohalogenation was likewise carried out as in Step A using 250 g of 85% KOH (3.78 mol) and heating under reflux for 22 hours in 1.4 L ethanol. The product was isolated by pouring the cooled reaction mixture into 3L of ice-water slush and extracting with ether. The ether layers were washed and dried as before, evaporated, and the residue distilled. The fraction bp 103-113/25 Torr contained the product (36 g, 40%), which was characterized by spectral data: nmr (CDCl3) 0.9 τ(m, 3 H, CH3), 1.3(m, 16 H, CH2), 1.91(t, J=2.5 Hz, 1H, ≡CH), 2.18 (m, 2H, ≡CCH2); IR (film) 3350 (ν≡CH), 2150(νC≡C).
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Br:26]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:26][CH:10]([C:9](=[O:16])[C:8]([N:5]1[C:4](=[O:19])[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:2]([CH3:1])[O:7][CH2:6]1)([CH3:17])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C(Br)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Yield: 65.1 %

Procedure:
A mixture of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (500 mg), N-bromosuccinimide(258 mg) and benzoyl peroxide (10 mg) was refluxed under a lamp whilst stirring in benzene for 10 minutes. After cooling, the solid was filtered, the filtrate evaporated and the residue purified by column chromatography (hexane/ethyl acetate 4:1) to give ethyl 2-bromo-4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (Compound 190, 400 mg ) as a yellow gum, NMR 1.21(t,3H), 1.55(d,6H), 1.94(s,3H), 4.15(q,2H), 5.23(s,1H), 5.26(d--d,2H) and 7.21-7.37(m,5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([CH:12]([CH2:15][CH3:16])[CH:13]=O)[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:13]/[CH:12]([CH2:15][CH3:16])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCC(C=O)CC
Solvent: ClCCl
Product: CCC(/C=N/CC(=O)OC(C)(C)C)CC
Yield: 93.8 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with 2-ethylbutyraldehyde (Aldrich) (0.55 g, 5 mmol) in CH2Cl2 at room temperature for 18 h to give [2-ethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1 g, 94%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[CH2:9][O:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)(O)[O-].[Na+].[O-]CC.[Na+].Cl.[S:28]1C=CC=C1CC(O)=O>C(O)C.C(OCC)(=O)C>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:7]([OH:8])([CH2:9][SH:28])[CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: O=C(O)Cc1cccs1
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC(CS)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
2-(1H-1,2,4-Triazol-1-ylmethyl)-2-(2,4-dichlorophenyl)oxirane 5 g (0.185M) was heated under mild reflux in thiolacetic acid (CH3COSH) (5 ml) for three hours. The mixture was then cooled and added to a mixture of ice-cooled saturated sodium bicarbonate solution (200 ml) and ethyl acetate (200 ml) and the aqueous layer was separated. The organic layer was washed a further four times with ice cooled saturated sodium bicarbonate solution (200 ml in total), dried (MgSO4) and evaporated to give a red gum which was dissolved in ethanol (20 ml). This solution was added dropwise over 15 minutes to a stirred and ice-cooled solution of sodium ethoxide (3.78 g, 0.0556M) in ethanol (100 ml). After one hour the mixture was poured into 1N hydrochloric acid (100 ml) and this solution was then neutralized by addition of solid sodium bicarbonate. Extraction with methylene chloride (6×50 ml), drying (MgSO4), and evaporation of the combined extracts gave a gum which was chromatographed on silica, eluting with ethyl acetate, to give after one recrystallization from ethyl acetate/hexane the title compound, yield 2.3 g, m.p. 139°-142.5° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:18][OH:19])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:19][CH2:18][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCC(F)=CC1(c2ccc(F)cc2)CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC1(c2ccc(F)cc2)CC1
Yield: 96 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.46 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(4-fluorophenyl)cyclopropane (Example 12) (0.2 g), benzene (12 ml) and pyridine to yield the title compound (0.23 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:23]=O.C[O-].[Na+].[BH4-].[Na+]>CO.CC(C)=O>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:23])=[CH:3][CH:4]=2)[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: C=O
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 1,1-dimethylethyl (2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D22) (4.14 g, 13.56 mmol) in dry MeOH (80 mL) at 50° C. under an argon atmosphere was added paraformaldehyde (1.22 g, 40.67 mmol) and sodium methoxide (3.65 g, 67.78 mmol). The mixture was stirred for ˜24 h then sodium borohydride (1.54 g, 40.67 mmol) was added portion-wise and the reaction stirred at 50° C. overnight. After cooling to room temperature, acetone (10 mL) was added and the solvent removed in vacuo. The residue was partitioned between DCM and water and the organic phase was washed with brine, then dried and concentrated. Column chromatography gave the title compound as a colourless, crystalline solid (3.73 g). δH (CDCl3, 400 MHz) 7.13 (2H, d), 6.57 (2H, d), 4.16 (1H, br.s), 3.78 (1H, d), 3.67 (1H, br.s), 3.42 (1H, d), 3.30 (1H, d), 3.08 (1H, td), 2.83 (3H, s), 2.75 (1H, m), 2.59 (1H, m), 2.06 (1H, dd), 1.94 (1H, m), 1.45 (9H, s), 1.21 (3H, d).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[O:24][C:20]=2[N:21]=[CH:22][N:23]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:18]2[C:19]3[C:26]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[C:25]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])[O:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCCN(Cc2ccccc2)C1
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(Cl)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCN(Cc5ccccc5)C4)c23)cc1
Reaction time: 0.17 h

Procedure:
Dissolve 1037 mg (5.37 mmol) of (3R)-1-benzylpiperidin-3-ol [H. Tomori, Bull. Chem. Soc. Jpn. 69, 1, 207-216 (1996)] in 10 ml of THF and add 268 mg (6.71 mmol) of sodium hydride (60% in mineral oil). After 10 minutes, add a solution of 2000 mg (5.64 mmol) of 4-chloro-6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidine in 10 ml of THF and 99 mg (0.27 mmol) of tetra-n-butylammonium iodide. Heat the reaction mixture under reflux for 16 hours. Then add 100 ml of water and 100 ml of ethyl acetate. Remove the organic phase and wash with 50 ml of 1N hydrochloric acid and 100 ml of satd. sodium chloride solution. Re-extract the aqueous phase with 50 ml of ethyl acetate, dry the combined organic extracts over sodium sulphate, filter and concentrate under reduced pressure. 2645 mg (89% of theory, 92% purity) of the desired product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](F)([F:12])[C:7](F)([F:14])[CH:6]=[CH:5]2.O.O.O.O.O.O.[OH-].C[N+](C)(C)C>[Zn].C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([F:14])[CH:6]=[CH:5]2
Reactant: FC1(F)C=Cc2cc(Br)ccc2C1(F)F
Agent: C[N+](C)(C)C
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2cc(Br)ccc2c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Zinc (0.89 g, 14 mmol) was added to a stirred mixture of 2.4 g (8.7 mmol) of 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene, 4 ml of water, 6 ml of THF, and 7.6 g of tetramethylammonium hydroxide pentahydrate that was cooled in an ice bath. The mixture was allowed to warm to room temperature. After 2 hours, the zinc was filtered, and the phases were separated. The aqueous layer was extracted three times with hexanes. The combined organic phase was washed three times with brine, stirred over MgSO4 and activated carbon for 3 hours, and then stored for 15 hours. The MgSO4 and carbon were filtered off, and the solvent was removed under vacuum. A colorless solid (1.9 g, 7.7 mmol, 89%) remained.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH:7]2[O:12][C:10](=[O:11])[C:9]([OH:13])=[C:8]2[OH:14])[CH2:4][O:3]1.COCOCOC>>[O:11]=[C:10]1[O:12][C@H:7]([C@H:5]([CH2:4][OH:3])[OH:6])[C:8]([OH:14])=[C:9]1[OH:13]
Reactant: CC1(C)OCC(C2OC(=O)C(O)=C2O)O1
Agent: COCOCOC
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Yield: 32 %

Procedure:
5,6-O-Isopropylidene-L-ascorbic acid was protected in the form of methoxymethyl ether according to the procedure of Kulkami et al. (M. G. Kulkami and S. R. Thopate, Tetrahedron, 1996, 52, 1293). A Mitsunobu reaction (C. Cena et al. Bioorg. Med. Chem. 2008, 16, 5199) with 1,1′,2-trisnorsqualenol followed by hydrolysis gives 2-squalenyl ascorbic acid (2-SQ Vit C) at an overall yield of 32%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:14]N1C(=O)CCC1=O.C(N(C(C)C)CC)(C)C.P([O-])(OCC)OCC>C(#N)C.N(C(C)(C)C#N)=NC(C)(C)C#N.O>[Br:14][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]=[CH:12][O:11][N:10]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ncon2)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCOP([O-])OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: Fc1cc(-c2ncon2)ccc1CBr
Temperature: 70 °C
Yield: 92.1 %

Procedure:
3-(3-Fluoro-4-methylphenyl)-1,2,4-oxadiazole (101.8 g, 0.57 mol) and N-bromosuccinimide (206 g, 1.16 mol) were dissolved in acetonitrile (˜1 L) and azobisisobutyronitrile (4.2 g, 26 mmol) was added at room temperature. The mixture was heated to 70° C. for 2 hours at which point HPLC showed complete conversion of the starting material to a mixture of the monobromide and dibromide. The mixture was cooled to 0° C. and diisopropyl ethyl amine (73 mL, 54.2 g, 0.42 mol) was added while maintaining the reaction temperature below 5 C. Diethyl phosphite (54.7 mL, 58.6 g, 0.42 mol) was added slowly and the reaction mixture was warned to room temperature. After 2 hours HPLC showed complete conversion of the dibromide to the monobromide. Water (1.2 L) was added and the resulting precipitate was filtered. Washing with water (2×200 mL) and drying provided 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (135 g, 92% yield).
Reaction SMILES: NC1C=CC(C(C)C(OC2(C)CCCCC2)=O)=CC=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([CH3:43])[C:30]([O:32][C:33]23[CH2:42][CH:37]4[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]4)[CH2:34]2)[CH2:40]3)=[O:31])=[CH:25][CH:24]=1)([O-])=O>>[NH2:20][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:43])[C:30]([O:32][C:33]23[CH2:42][CH:37]4[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]4)[CH2:34]2)[CH2:40]3)=[O:31])=[CH:27][CH:28]=1
Reactant: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc([N+](=O)[O-])cc1
Agent: CC(C(=O)OC1(C)CCCCC1)c1ccc(N)cc1
Product: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc(N)cc1
Yield: 99.8 %

Procedure:
Using a method similar to that used in the preparation of 1-methylcyclohexyl 2-(p-aminophenyl)-propionate, 21.4 g of 1-adamantyl 2-(p-nitrophenyl)propionate were reacted to obtain 19.42 g (100% yield) of 1-adamantyl 2-(p-aminophenyl)propionate of a light yellow viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:14]=[C:13]([O:28][CH3:29])[N:12]=2)=[CH:7][C:3]=1[CH:4]=[N:5]O.[ClH:30]>C(O)(=O)C.CCOC(C)=O.[Zn]>[ClH:30].[NH2:5][CH2:4][C:3]1[CH:7]=[C:8]([C:11]2[N:12]=[C:13]([O:28][CH3:29])[N:14]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:16]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(C=NO)c3)nc(OC)n2)cc1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CCNc2cc(-c3ccc(F)c(CN)c3)nc(OC)n2)cc1
Reaction time: 1 h

Procedure:
A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde oxime [860 mg, Example 26(a)] in acetic acid (10 mL) is treated with zinc powder (0.6 g, 9.2 mmol). After 1 hour at 20° C., the reaction mixture is filtered through Celite, concentrated, diluted with 1 M sodium hydroxide solution, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered, and subjected to chromatography on silica gel eluting with 10% MeOH in DCM to provide the free base, which is treated with saturated HCl in EtOAc afford [6-(3-aminomethyl-4-fluoro-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine hydrochloride [720 mg, Example 27]. LCMS: RT=1.88 minutes, MS: 383 (M+H). IC50=41 nM
Reaction SMILES: C(O[C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)C1C=CC=CC=1.CC[OH:26]>[Pd]>[N:14]1([CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][CH:9]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: c1ccc(COc2ccccc2OCCN2CCOCC2)cc1
Reactant: CCO
Agent: [Pd]
Product: Oc1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 4-[2-(Benzyloxy-phenoxy)-ethyl]-morpholine (4.77 g, 15.2 mmol) in EtOH (35 mL) was added to palladium on carbon (250 mg) in EtOH (15 mL) under an atmosphere of Hydrogen. The mixture was stirred for 17 h at r.t. The mixture was filtered through celite and the solvent was removed under reduced pressure to give the title compound.
Reaction SMILES: BrC[CH2:3][CH2:4][N:5]1[C:9](=O)[C:8]2=CC=[CH:13][CH:14]=[C:7]2[C:6]1=O.C(#[N:18])C>>[CH2:6]([N:5]1[CH2:9][CH2:8][NH:18][CH2:3][CH2:4]1)[CH2:7][CH2:14][CH3:13]
Reactant: CC#N
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Product: CCCCN1CCNCC1
Yield: 80 %

Procedure:
N-(3-Bromopropyl)phthalimide (15.1 g) was dissolved in acetonitrile (100 ml), and 1-n-butylpiperazine (5.33 g) obtained in Preparation Example 1 and 50% potassium fluoride-Celite (21.8 g) were added at room temperature. After stirring overnight, the reaction solution was filtered off with Celite, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (methylene chloride:methanol=95:5) to give the title compound (9.83 g) as a yellow oily substance. Yield=80%.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:23][C:24]1[N:25]=[C:26]2[N:31]=[C:30]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)[C:29]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:28]([NH:46][CH3:47])[N:27]2[CH:48]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1>[CH3:47][NH:46][C:28]1[N:27]2[CH:48]=[C:24]([CH3:23])[N:25]=[C:26]2[N:31]=[C:30]([C:32]2[CH:39]=[CH:38][C:35]([CH2:36][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:34][CH:33]=2)[C:29]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: CNc1c(-c2ccccc2)c(-c2ccc(C=O)cc2)nc2nc(C)cn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CNc1c(-c2ccccc2)c(-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)nc2nc(C)cn12
Reaction time: 1 h

Procedure:
237.8 mg (0.87 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 6.8 mL NMP. 0.24 mL (1.74 mmol) triethylamine are added and the reaction mixture is stirred for one hour. 270 mg (0.79 mmol) 4-(2-Methyl-5-methylamino-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde and 0.11 mL (1.89 mmol) acetic acid are added. The reaction mixture is stirred for two days at room temperature. 401.1 mg (1.89 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 9 days. After the usual work-up and purification by HPLC 29.6 mg (7.1%) of the desired title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][O:33][CH3:34])[CH2:29][CH2:28][O:27][CH3:26])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCNCCOC
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: COCCN(CCOC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 211.5 %

Procedure:
1.88 g (5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature for 4 hours with 2 g (2.2 mmol) of bis(2-methoxyethyl)-amine and 15 ml of N,N-dimethylformamide. After evaporating the solvent the reaction mixture was taken up in 4N sodium hydroxide solution, whereupon the mixture was extracted three times with methylene chloride. By drying the organic phase over magnesium sulfate and evaporating the solvent there were obtained 2.2 g (93%) of (S)-8-chloro-1-[5-di(2-methoxyethyl)aminomethyl-1,2,4-oxadiazol-3-yl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 188°-190°.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:13])([F:12])[S-:11].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[F:9][C:10]([S:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([F:13])[F:12]
Reactant: FC(F)(F)[S-]
Reactant: BrCc1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: O
Solvent: CC#N
Product: FC(F)(F)SCc1ccccc1
Yield: 82 %

Procedure:
Benzyl bromide, 16.2 g (0.095 mol), was added dropwise at 25° to 0.11 mol of tris(dimethylamino)sulfonium trifluoromethanethiolate (prepared as in Example 11) in 75 mL of acetonitrile. The reaction mixture was stirred one h and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and distilled to give 15.1 g (82%) of benzyl trifluoromethyl sulfide as a colorless liquid: bp 55° (12 mm); 1H NMR (CDCl3) δ4.08 ppm (s, 2H), 7.33 ppm (s, 5H); 19F NMR (CDCl3) δ-42.5 ppm (s).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22](OC)=[O:23])[CH:18]=3)[CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:29][OH:30].[OH-].[K+].C(O)=O>CO.CS(C)=O>[OH:30][NH:29][C:22]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:27])[F:26])[CH:4]=1)=[O:11])[CH2:21][CH2:20]2)=[O:23]
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)Nc1cccc(C(F)(F)F)c1)C2
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Solvent: O=CO
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)Nc1cccc(C(F)(F)F)c1)C2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(3-(trifluoromethyl)phenylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (obtained in step 1) in methanol (1 mL) was added hydroxylamine hydrochloride (40 mg, 0.5 mmol) and potassium hydroxide (100 mg, 2 mmol). The reactions were left to stir for 2 hours at 80° C. Upon cooling to room temperature, the reaction was quenched with the addition of formic acid (75 μL, 2 mmol) and the solvents were evaporated to dryness. The residue obtained was dissolved in DMSO (1 mL), the residual solids removed by filtration and the solution purified via Gilson prep-HPLC to afford a white solid (4.2 mg, 11% over 2 steps). LCMS (FA) ES+380.