Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].O1CCOCC1.[CH3:26][NH:27][CH3:28]>CO>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:27]([CH3:28])[CH3:26])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CNC
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)c1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.4 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-chloro-s-triazolo [4,3-b]pyridazine was suspended in 14 ml. of a mixture of dioxan and methanol (1:1), 6.7 ml. 30percent methanolic dimethylamine solution were added thereto, the reaction mixture was stirred for 1 hour at 60° C., then cooled in an ice bath, the product was filtered off with suction, washed with a mixture of dioxan and methanol (1:1) and then with ether and the product thus obtained (0.66 g.) recrystallized from 15 ml. dioxan-dimethylformamide (9:1), with the addition of charcoal, 0.35 g. of intense yellow crystals of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-dimethylamino-s-triazolo [4,3-b]pyridazine thereby being obtained. It has a melting point of 233° -236° C.
Reaction SMILES: C(N(CC)CC)C.CN(C=O)C.[C:13]1([S:19]([N:22]2[CH:26]=[C:25](I)[C:24]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[N:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:34]#[C:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:13]1([S:19]([N:22]2[CH:26]=[C:25]([C:34]#[C:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:24]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[N:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#CCCCC
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c(-c2cccnc2)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC#Cc1cn(S(=O)(=O)c2ccccc2)nc1-c1cccnc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To triethyl amine (10 ml) and DMF (4 ml) containing 36B (0.97 g, 2.36 mmol), was added 3 eq of hex-1-yne (0.81 ml). The resulting mixture was stirred for another 2 hours under N2. Successively were added 10 mol % of CuI (45 mg), 5 mol % of PdCl2(PPH3)2 (83 mg) and 18 mol % of PPH3 (111 mg). After the addition, the resulting solution was warmed at 70° C. for 18 hours under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE (1/1)) to afford 3-(1-phenylsulfonyl-4-hex-1-ynyl-1H-pyrazol-3-yl)-pyridine (43A) as an oil (0.66 g, 77%). 1H-NMR (400 MHz, CDCl3): δ 9.5-9.2 (bs, 1H), 8.8-8.4 (bs, 1H), 8.34 (bd, J=8 Hz, 1H), 8.21 (s, 1H), 8.08-8.04 (m, 2H), 7.67 (bt, J=7 Hz, 1H), 7.57 (bt, J=7 Hz, 2H), 7.41-7.32 (bs, 1H), 2.42 (t, J=7 Hz, 2H), 1.62-1.53 (m, 2H), 1.49-1.39 (m, 2H), 0.93 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:14]1COCC1>CN(C)C=O>[C:7]1([S:13][CH2:14][CH2:1][C:2]([OH:4])([CH3:5])[CH3:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)CCSc1ccccc1

Procedure:
To a solution of 4-bromo-2-methyl-2-trimethylsilyloxybutane (9) (12 g) in methanol (55 ml) at room temperature was added ethanolic hydrogen chloride (ca. 1M, 0.2 ml). After 10 minutes the solution was concentrated in vacuo (at room temperature) to constant weight. The residue was taken up in chloroform and reconcentrated to constant weight to give 4-bromo-2-methyl-2-butanol (H, y=1, R1 =R2 =Me) as a chromatographically homogenous oil. The product was dissolved in THF (10 ml) and added to a premixed, stirred solution of potassium tert-butoxide (3.7 g) and thiophenol (3.6 ml) in N,N-dimethylformamide (50 ml) at room temperature. After a few minutes a precipitate started forming, and after 30 minutes the mixture was partitioned between ethyl acetate (300 ml) and water (200 ml). The organic layer was washed consecutively with 2N sodium hydroxide solution, water and brine. Drying and concentration in vacuo gave 3-hydroxy-3-methylbutyl phenyl sulphide as a chromatographically homogenous oil. This was dissolved in methanol (60 ml), and to the stirred solution was added sodium hydrogen carbonate (4.7 g), aqueous sodium tungstate solution (2%, 5 ml) and hydrogen peroxide (100 vol, 11.8 ml). The initial exothermic reaction which ensued was checked by momentary ice-cooling. The reaction mixture was then-stirred at 50° C. for 1 hour. After cooling the mixture was partitioned between dichloromethane (200 ml) and water. The aqueous layer was extracted with more dichloromethane, and the combined dichloromethane layers were washed with water, brine, and dried. Concentration in vacuo gave a crude product which was purified by chromatography (150 g silica gel; ether as eluant) to give the sulphone (21) as a viscous oil, 6 (300 MHz) 1.22 (6H, s), 1.64 (1H, bs), 1.88 (2H, m), 3.25 (2H, m), 7.55-7.70 (3H, m), 7.93 (2H, m).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7](=[O:31])[CH2:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]#[N:29])[CH:22]=2)(=[O:20])=[O:19])[C:10]=1[CH3:30].O>C(Cl)Cl>[C:28]([C:23]1[CH:22]=[C:21]([S:18]([N:11]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:17]3[C:9]([CH2:8][C:7]([OH:31])=[O:6])=[C:10]2[CH3:30])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27])#[N:29]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(C#N)c2)c2ncccc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(F)c(C#N)c1
Reaction time: 0.33 h

Procedure:
1M BBr3 in CH2Cl2 (7.66 mL, 7.66 mmol) is added to a solution of [1-(3-cyano-4-fluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.495 g, 1.27 mmol) in CH2Cl2 (2 mL). The reaction mixture is exposed to microwave irradiation at 60° C. for 45 minutes. Water is added to the reaction mixture which is stirred for further 20 minutes. The organic layer is isolated using the Isolute™ phase separator cartridge and evaporated. The residue is loaded on a pre-packed Isolute™ silica column and eluted using a gradient eluent from 100% CH2Cl2 to 5% methanol in CH2Cl2 to afford the title compound; MH+=374.
Reaction SMILES: [OH:1][C@@:2]1([CH3:22])[CH:7]=[CH:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.C=O.F[C:26](F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[OH:1][C@@:2]1([CH3:22])[CH:7]=[CH:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[C:10](=[CH2:26])[CH2:9]3
Reactant: O=C([O-])C(F)(F)F
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=C[C@]2(C)O
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2C=C[C@]3(C)O)[C@@]2(C)CCC(=O)C=C12
Reaction time: 3.5 h
Yield: 43.5 %

Procedure:
500 mg of 17β-hydroxy-17α-methylandrosta-4,15-diene-3-one in 8.3 ml of tetrahydrofuran is stirred at 60° C. under argon with 348 mg of paraformaldehyde and 2.2 g of N-methylanilinium trifluoroacetate. After 3.5 hours, the mixture is diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated under vacuum. After the crude product has been chromatographed on silica gel with a pentane-diethyl ether gradient, 226 mg of 17β-hydroxy-17α-methyl-6-methyleneandrosta-4,15-diene-3-one is obtained, mp 162° C. (from isopropyl ether).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:21]1([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>C(Cl)Cl.CN(C)C=O>[C:34]1([CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)[CH:13]=[CH:12][CH:11]=3)=[O:16])[CH2:32][CH2:33]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1ccc(-c2cccc(C(=O)O)c2)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(C(=O)N3CCN(C(c4ccccc4)c4ccccc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a suspension of 4'-methylbiphenyl-3-carboxylic acid (2.2 g) in a mixture of methylene chloride (20 ml) and dimethylformamide (0.5 ml) was added thionyl chloride (1.48 g). The mixture was refluxed until the suspension dissolved, after which the temperature was allowed to cool to room temperature. To this solution was added 1-(diphenylmethyl)piperazine (3.94 g) in methylene chloride dropwise, and the reaction mixture allowed to stand overnight. Sodium hydroxide (30 ml of 1N) and 50 ml of methylene chloride was added, the organic layer separated, washed with brine, dried over sodium sulfate, and solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 25% ethyl acetate in heptane, to yield 3.8 g of 1-diphenylmethyl-4-(4'-methylbiphenyl-3-carbonyl)piperazine. The dihydrochloride salt was prepared and recrystallized from ethanol, m.p. 226° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[S:3][CH2:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:4]3[S:3][CH2:2][S:1][CH:5]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)C1=CSCS1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)C1=CSCS1
Yield: 38.7 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 1,3-dithiole-4-carboxylic acid (4.6 g), N,N'-carbonyldiimidazole (7.5 g) and 2-amino-7-chloro-1,8-naphthyridine (4.2 g). The product obtained by precipitation in water (4.8 g) is taken up with boiling acetonitrile (300 cc), the insoluble material is removed by filtration, and the filtrate is poured into water (500 cc). The precipitate obtained is purified by recrystallization in an acetonitrile/water (5:2 by volume) mixture (650 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)- 1,3-dithiole-4-carboxamide (2.8 g), m.p. 235° C., is thereby obtained.
Reaction SMILES: ClC1C=CC(C(CCC(O)=O)=O)=CC=1C(F)(F)F.N1CCC[C@H]1C(O)=O.[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([C:32]([CH2:34][CH2:35][C:36]([N:38]2[CH2:45][CH2:44][CH2:43][C@H:39]2[C:40]([OH:42])=[O:41])=[O:37])=[O:33])=[CH:30][C:29]=1[C:48]([F:51])([F:50])[F:49].[C:52]([O-:55])(=[S:54])[CH3:53].[K+]>C(O)C.O>[C:52]([S:54][CH:34]([C:32](=[O:33])[C:31]1[CH:46]=[CH:47][C:28]([Cl:27])=[C:29]([C:48]([F:51])([F:49])[F:50])[CH:30]=1)[CH2:35][C:36]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41])=[O:37])(=[O:55])[CH3:53]
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC([O-])=S
Agent: O=C(O)CCC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The preceding compound is converted to 3-(4-chloro-3-trifluoromethylbenzoyl)propionic acid, hydroxysuccinimide ester and coupled to L-proline as in Example 16. The 1-([3-(4-chloro-3-trifluoromethylbenzoyl)propionyl]-L-proline is brominated as in Example 20 and the product reacted with potassium thioacetate in ethanol-water (1:1) as in Example 21 to give the product of the Example as a glass.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccn1
Reactant: Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2ccccn2)cc1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
A mixture of 29.34 g (0.264 mol) of 4-fluoroaniline (1) and 29.98 g (0.264 mol) of 2-chloropyridine (2) was heated at 150° C. for 2 h. After having been cooled down to RT, it was distributed between 500 ml of 1N NaOH and 500 ml of ethyl acetate. The aqueous phase was extracted twice with in each case 300 ml of ethyl acetate and the combined organic phases were dried with magnesium sulfate. After the solvent had been evaporated, the residue was taken up in 500 ml of ethyl acetate and approx. 40 g of active charcoal were added. The mixture was stirred at RT for 10 minutes and filtered through kieselguhr. The active charcoal was rewashed 4 times with in each case 1 l of ethyl acetate. The solvent was removed in vacuo (i.v.) and the residue was precipitated from 120 ml of ethyl acetate. The solid was filtered off with suction and dried at 50° C. i.v. 41 g of 2-(p-fluoroanilino)pyridine (3) were obtained;
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:12])[CH3:11])[CH2:4][CH2:3]1.[CH3:25][I:26]>C(O)C>[I-:26].[CH2:16]([O:15][C:14]([NH:13][C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][N+:5]1([CH3:25])[CH2:6][CH2:7][C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4]1)=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CI
Reactant: CC1(C)CCN(CCC(C)(C)NC(=O)OCc2ccccc2)CC1
Solvent: CCO
Product: CC1(C)CC[N+](C)(CCC(C)(C)NC(=O)OCc2ccccc2)CC1
Product: [I-]
Temperature: 50 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Benzyl 4-(4,4-dimethylpiperidin-1-yl)-2-methylbutan-2-ylcarbamate (2.25 g, 6.76 mmol) was placed into a 15 mL pressure tube. Absolute ethanol (2 mL) and Methyl iodide (5.0 mL, 11.8 equiv, 80.1 mmol) was added in one portion. A stir bar was added and the pressure tube sealed. The reaction was left to stir at 50° C. for 16 h. The solution was concentrated to a pale yellow solid. The crude solid was dissolved into isopropanol (5 mL) and ethyl acetate (25 mL) and the solution cooled in an ice bath to give a gel. The product was filtered, washed with fresh ethyl acetate and dried under high vacuum to give a white solid (2.06 g, 64.0%). 1H NMR (D2O, 400 MHz): δ 0.98 (s, 3H), 1.03 (s, 3H), 1.30 (s, 6H), 1.50-1.70 (m, 4 H), 2.10-2.18 (m, 2H), 2.85 (s, 3H), 3.15-3.28 (m, 6 H), 5.09 (s, 2H), 7.38-7.50 (m, 5H). LRMS (ESI+) for C21H35N2O2+ (347.3); Found: 347 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.O1CCCC1.O>[CH:27]1([C:30]([O:26][CH:23]([C:5]2[C:6]3[N:7]4[CH2:14][CH2:13][CH2:12][N:11]([C:15]5[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=5)[C:8]4=[N:9][C:10]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:24][CH3:25])=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(O)C1CC1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(OC(=O)C1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 71.7 %

Procedure:
A mixture of 1-[9-chloro-1-(3,5-dichloropyridin-2-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (112 mg, 0.272 mmol), cyclopropanecarboxylic acid (35.1 mg, 0.408 mmol), 4-dimethylaminopyridine (49.8 mg, 0.408 mmol), triethylamine (76 μL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg, 0.544 mmol) in tetrahydrofuran (2.0 mL) was stirred at room temperature for 13 hr. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (93.5 mg, 0.195 mmol, 72%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][OH:14])[C:9]([O:11][CH3:12])=[O:10].[C:15](=O)(O)[O-].[K+].S(OC)(OC)(=O)=O.O>C(#N)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C([O-])O
Reactant: COC(=O)C(=NO)c1ccccc1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC#N
Product: CON=C(C(=O)OC)c1ccccc1O

Procedure:
1.7 g (0.0075 mol) of methyl 2-(2-hydroxyphenyl)-2-hydroxyimino-acetate (HPLC: 86.4% Z, log p=1.70) (Example VII-1d from process step 7) in 40 ml of acetonitrile are heated under reflux with 0.77 g (0.0076 mmol) of potassium bicarbonate and 1.1 g (0.0087 mol) of dimethyl sulphate for 10 hours. The reaction mixture is poured into water, the product is extracted with diethyl ether and the solvent is distilled off under reduced pressure. This gives 1.2 g of crude product which, according to HPLC, contains 46% of methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.38. This crude product is chromatographed over silica gel using a mixture of 7 parts of n-hexane and 3 parts of acetone. This gives 0.8 g of a product which, according to HPLC, contains 54.4% methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.39.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16](Cl)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[N:18]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CCN(CC)CC.O>CC(O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([NH:26][CH2:25][CH2:24][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccn2c(-c3cccc(Br)n3)cnc12
Reactant: NCCN1CCOCC1
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: Brc1cccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Temperature: 25 °C

Procedure:
A mixture of 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine (from Example 38 supra) (3.09 g, 10.0 mmol), 2-morpholin-4-yl-ethylamine (2.6 g, 20.0 mmol), NEt3 (2.02 g, 20.0 mmol) in 2-propanol (300 mL) was stirred and heated at reflux for 16 hours. The solution was then cooled to room temperature and poured into water. The resulted solid was filtered and washed with water. The crude product was purified by chromatography (CH2Cl2:CH3OH, 20:1) to give [3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 2.5 g, 62%). LC-MS: [M+H]+ 403.
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][OH:12].N1C=CC=CC=1>C(O)C>[C:1]1(=[N:11][OH:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCCC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CCCCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution containing cyclooctanone (12.6 g, 0.1 mol) and hydroxylamine hydrochloride (14.0 g, 0.2 mole) in a mixture of pyridine (40 mL, 0.5 mole) and ethanol (50 mL) was stirred at ambient temperature for about 15 hours. The solvent was then removed by rotary evaporation. The residue was dissolved in diethyl ether (300 mL) then washed with hydrochloric acid (2×100 mL). The aqueous layer was extracted with diethyl ether (2×150 mL). The ether extracts were combined, dried over magnesium sulfate then concentrated to provide cyclooctanone oxime as a white solid.
Reaction SMILES: CO.[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:4]=1.C=O.[CH:20]([O-])=O.[NH4+]>O>[CH3:20][NH:16][C:15]1[C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH3:17])[CH:8]=[CH:7][CH:6]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(Nc2ncccc2N)c1
Reactant: O=C[O-]
Agent: C=O
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CNc1cccnc1Nc1cccc(C)c1
Reaction time: 3 h

Procedure:
600 mL of methanol and 24 mL water were added to a 3-neck 2 L round bottom flask. Nitrogen was bubbled directly into the solution. Palladium on carbon was added (10%, 10.35 g, 9.73 mmol) while bubbling continued. Next, N2-(m-tolyl)pyridine-2,3-diamine (19.38 g, 97 mmol) and formaldehyde (37%, 14.48 mL, 195 mmol) were added. The reaction mixture was stirred under nitrogen for 3 h. Next, nitrogen was bubbled into the solution and ammonium formate (123 g, 1945 mmol) was added slowly. The reaction mixture was stirred under nitrogen overnight at room temperature. The reaction mixture was filtered through Celite® and the Celite® was washed with dichloromethane. The filtrate was washed with water twice, and the organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified using column chromatography eluting with 30% ethyl acetate/hexanes to isolate the desired product. The product was combined with material from other reactions and purified by column chromatography eluting with 30% ethyl acetate/hexanes. A dark reddish-brown solid was obtained. The solid was recrystallized from boiling hexanes with a small amount of ethyl acetate to dissolve the solid. The product was filtered off as needles with some reddish color which were washed with hexanes, obtained 15.1 g.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4]Br.[Mg].[CH3:18][O:19][C:20]1[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH3:30])[C:21]=1[CH2:31][CH2:32][C@:33]1([CH3:36])[O:35][CH2:34]1.[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:18][O:19][C:20]1[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH3:30])[C:21]=1[CH2:31][CH2:32][C@:33]([CH3:36])([OH:35])[CH2:34][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: COc1c(C)c(C)c(OC)c(CC[C@@]2(C)CO2)c1C
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)c1C
Reaction time: 8 h

Procedure:
5.8 mmol of (3R,7R)-3,7,11-trimethyldodecyl bromide are heated at reflux for 1/4 hour in 20 ml of ethyl acetate with activated magnesium. Then, there are added at 0° C. 1 g of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-epoxybutane and 0.9 g of copper(I)-2-propylacetylide [or 1.2 g of copper(I) bromide/dimethyl sulphide complex]. The temperature of the reaction mixture is subsequently left to rise to room temperature and the mixture is stirred overnight. 10 ml of ammonium chloride are than added and the mixture is extracted with ethyl ether. The extract is dried and concentrated, and the residue is distilled in a bulb-tube (b.p.0.01 =140° C.). There are obtained 1.28 g (72%) [or 1.41 g (79%)] of (3R,7R,11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-3,7,11,15-tetramethylhexadecan-3-ol as a colourless oil.