Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:8]=[C:9]([C:13]#[C:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH:10]=[N:11][CH:12]=1>CO>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]=[N:11][CH:10]=[C:9]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(C#Cc2cncc(C3CCCN3C)c2)cc1
Solvent: CO
Product: COC(=O)c1ccc(CCc2cncc(C3CCCN3C)c2)cc1
Reaction time: 24 h

Procedure:
A mixture of YH19 (0.15 g, 0.468 mmol) and Pd(C) (10%, 20 mg) in MeOH (10 mL) was hydrogenated at atmospheric pressure and room temperature for one day. The catalyst was removed by filtration through Celite and the filtrate was concentrated. The residue was chromatographed [SiO2, CHCl3/MeOH (60:1)] to give 0.15 g (95%) of YH22; 1H NMR (400 MHz, CDCl3) δ 8.38 (br s, 2H), 7.91-7.80 (m, 2H), 7.40 (s, 1H), 7.16-7.14 (m, 2H), 3.85 (s, 3H), 3.23-3.16 (m, 1H), 3.05-2.87 (m, 5H), 2.30-2.22 (m, 1H), 2.18-2.08 (m, 1H), 2.09 (s, 3H), 1.92-1.84 (m, 1H), 1.81-1.72 (m, 1H), 1.67-1.57 (m, 1H); 13C NMR (400 MHz, CDCl3) δ 166.9, 148.6, 147.3, 146.2, 138.3, 136.5, 134.5, 129.7, 128.0, 68.6, 56.9, 51.9, 40.2, 37.4, 35.0, 34.4, 22.4;
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)=O.[C-]#N.[K+].CN(C)[C:17]1([C:22]#[N:23])[CH2:21]CC[CH2:18]1>O>[CH3:18][C:17]([N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)([CH3:21])[C:22]#[N:23]
Reactant: C1CCNCC1
Reactant: CN(C)C1(C#N)CCCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C#N)N1CCCCC1
Yield: 77 %

Procedure:
The title compound (2.33 g, 77%) was prepared from piperidine hydrochloride (2.43 g, 20 mmol), acetone (1.16 g, 20 mmol) and potassium cyanide (1.30 g, 20 mmol) in water (10 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.46 (2H, m), 1.50 (6H, s), 1.63 (4H, m), 2.59 (4H, m).
Reaction SMILES: C(N)C1C=CC=CC=1.C(O[C:17]([N:19]([CH2:21][C:22]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([C:34]([NH:36][C@H:37]([P:39](=[O:42])([OH:41])[OH:40])[CH3:38])=[O:35])[CH2:31][CH2:32][CH3:33])=[O:28])[CH3:26])=[O:23])C)=O)C1C=CC=CC=1>>[NH:19]([CH2:21][C:22]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([C:34]([NH:36][C@H:37]([P:39](=[O:40])([OH:42])[OH:41])[CH3:38])=[O:35])[CH2:31][CH2:32][CH3:33])=[O:28])[CH3:26])=[O:23])[CH3:17]
Reactant: CCC[C@H](NC(=O)[C@H](C)NC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CCC[C@H](NC(=O)[C@H](C)NC(=O)CNC)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 5(A)(iii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-sarcosyl-L-alanyl-L-norvalyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(N-sarcosyl-L-alanyl-L-norvalylamino)-ethylphosphonic acid of melting point 291°-292° C. (decomposition); [α]D20 =-110°; [α]36520 =-391° (c=0.26% in water).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=C(C3C=CC=CC=3)C3C=CC=CC=3)[N:16]=2)[CH2:10][C@@H:9]1[CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].Cl.ON>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)[CH2:10][C@@H:9]1[CH3:35])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1C[C@@H](Oc2cccc(N=C(c3ccccc3)c3ccccc3)n2)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: C[C@H]1C[C@@H](Oc2cccc(N)n2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 4-[6-(benzhydrylidene-amino)-pyridin-2-yloxy]-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 62, 1.19 g) in methanol (30 mL), add sodium acetate (0.497 g), and hydroxyamine hydrochloride (0.316 g) and stir at room temperature. After 1 hr., partition between dichloromethane and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column, eluting with dichloromethane-2M NH3 in methanol, gradient) to give the title compound (0.687 g). 1H NMR (CDCl3): 7.33 (t, 1H), 6.03 (m, 21), 5.25 (m, 1H), 4.33 (m, 3H), 3.87 (m, 1H), 3.25 (m, 1H), 1.91 (m, 3H), 1.73 (m, 1H), 1.46 (s, 9H), 1.27 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10]Cl.[Na+].[I-:14]>CC#N>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][I:14]
Reactant: [I-]
Reactant: Nc1ccc(F)cc1C(=O)CCl
Agent: [Na+]
Solvent: CC#N
Product: Nc1ccc(F)cc1C(=O)CI
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.9 %

Procedure:
To a solution of 23.463 g (125.069 mM) of 2'-amino-2-chloro-5'-fluoroacetophenone in 436 ml of CH3CN is added 56.2 g (375.2 mM) of NaI, and the mixture is stirred at room temperature for 45 min. and concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, washed with aqueous Na2S2O3, and brine in order, dried and concentrated to give 29.97 g (Yield: 85.9%) of 2'-amino-5'-fluoro-2-iodoacetophenone as yellow crystals.
Reaction SMILES: [CH:1]([C:4]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1)[C:5]#[N:6])([CH3:3])[CH3:2].[CH2:35]=O.[BH4-].[Na+]>CO>[CH:1]([C:4]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)([CH2:7][CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1)[CH3:35])[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: COc1cc(C(C#N)(CCCNCCCOc2cccc(CO)c2)C(C)C)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(C#N)(CCCN(C)CCCOc2cccc(CO)c2)C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
A solution of 2.80 g of alpha-isopropyl-alpha-[3-[N-[3-(3-hydroxymethylphenoxy)propyl]amino]propyl]-3,4,5-trimethoxyphenyl acetonitrile and 4.84 g of 37% formalin in 70 ml of methanol was refluxed for 1 hour. After cooling, to the solution was added 2.25 g of sodium borohydride and the solution was stirred for 1 hour at room temperature. The solvent was removed and to the residue was added water. The solution was extracted with chloroform and the extract was washed with water, dried, and evaporated. The residue was chromatographed on silica gel using 10% methanol-chloroform as an eluent to give 0.74 g of the desired compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11]O)=[CH:8][C:6]=2[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>C(Cl)Cl>[Br:39][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (1.46 g, 5.11 mmol) in anhydrous DCM (30 mL) at 0° C. were added triphenylphosphine (1.74 g, 6.64 mmol) and carbon tetrabromide (2.03 g, 6.13 mmol). The resulting brown solution was stirred at RT for 5 h, before additional quantities of triphenylphosphine and carbon tetrabromide were added (0.4 g and 0.34 g, respectively) and stirring was continued at RT for 1 h. The reaction mixture was concentrated in vacuo and DCM and EtOAc were added. The resultant white precipitate was collected by filtration and air dried to give the title compound as a white solid (0.82 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]2=[N:6][CH:7]=1.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]3=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CCC(=O)NC1COc2cc(N)cnc2C1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)cnc2C1

Procedure:
Following the same procedure as described in example 31.5, a portion of crude N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)-propionamide (100 mg, 0.45 mmol) in CH2Cl2/pyridine 9/1 (20 ml) was treated with 4-isopropylbenzenesulfonyl chloride (130 μl, 0.72 mmol). Purification by flash column chromatography (CH2Cl2:methanol, 97:3) gave the title compound (85 mg, 47% for steps 31.4 and this step) as a gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:17][C:18]1[CH:35]=[CH:34][C:21]2[N:22]([CH2:32][CH3:33])[C:23](=[O:31])[C:24]([CH3:30])([CH3:29])[C:25](=[O:28])[N:26]([CH3:27])[C:20]=2[CH:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:39]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[N:7]([CH2:17][C:18]1[CH:35]=[CH:34][C:21]2[N:22]([CH2:32][CH3:33])[C:23](=[O:31])[C:24]([CH3:29])([CH3:30])[C:25](=[O:28])[N:26]([CH3:27])[C:20]=2[CH:19]=1)[CH2:8][C:9]1[C:10]([CH3:16])=[N:11][C:12]([O:15][CH3:39])=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3ccc(=O)[nH]c3C)C(=O)OC(C)(C)C)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3ccc(OC)nc3C)C(=O)OC(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-6-oxo-1,6-dihydropyridin-3-ylmethyl) carbamic acid tert-butyl ester (536 mg) was dissolved in DMF (20 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 56.1 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.081 ml) was added thereto, and the mixture was stirred at 0° C. for 0.5 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (550 mg) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.2 g) in dry N,N-dimethylformamide (5 mL) was heated at 60° C. with anhydrous potassium carbonate (0.315 g) for 1 hour and allowed to cool to room temperature before adding 3-(bromomethyl)tetrahydro-2H-pyran (0.112 g). The reaction mixture was heated at 50° C., overnight. The reaction mixture was quenched with water (20 mL) and extracted into ethyl acetate (3 times, 75 mL combined volume). The organic phase was separated, combined and passed through a hydrophobic frit to dry. The organic phase was evaporated under reduced pressure to give a yellow oil which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a white solid (105.4 mg).
Reaction SMILES: C1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12]C3C=CC(S(N4CCC(O)CC4)(=O)=O)=CC=3)[N:11]=2)CCC1.CS(CC1C=CC(N)=CC=1)(=O)=O>>[N:9]1[C:8]2[NH:29][CH:30]=[CH:31][C:7]=2[C:6]([NH2:5])=[N:11][C:10]=1[NH2:12]
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Agent: CS(=O)(=O)Cc1ccc(N)cc1
Product: Nc1nc(N)c2cc[nH]c2n1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, 4-(methylsulfonylmethyl)aniline and 2-Chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave N4-cyclobutyl-N2-(4-methylsulfonylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine (MS calcd for C18H21N5O2S 371.5. found [MH] 372.1; UV 205.1, 273.6, 304.5 nm).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:15]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20][C:19]=2[C:18](B(O)O)=[CH:17][CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[CH:15]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20][C:19]=2[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:17][CH:16]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3sc3ccccc34)cc12
Temperature: 80 °C
Yield: 79 %

Procedure:
Into a 200 mL three-neck flask were placed 3.0 g (12 mmol) of 3-bromocarbazole, 2.8 g (12 mmol) of dibenzothiophene-4-boronic acid, and 0.15 g (0.5 mol) of tri(ortho-tolyl)phosphine, and the air in the flask was replaced with nitrogen. To this mixture were added 40 mL of toluene, 40 mL of ethanol, and 15 mL (2.0 mol/L) of an aqueous solution of potassium carbonate. In the flask, the mixture was degassed by being stirred under reduced pressure. After the degassing, the air in the system was replaced with nitrogen, and 23 mg (0.10 mmol) of palladium(II) acetate was added to this mixture, and then the mixture was refluxed at 80° C. for 4 hours. After the reflux, the mixture was cooled to room temperature, whereby a solid was precipitated. About 100 mL of toluene was added to the mixture in which the solid was precipitated, and the resulting mixture was heated and stirred, so that the precipitated solid was dissolved. While kept hot, the obtained suspension was filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina. The solid obtained by concentration of the obtained filtrate was recrystallized from toluene, so that 3.4 g of a white solid which was the object of the synthesis was obtained in 79% yield. The reaction scheme of Step 1 is illustrated in the following scheme (a-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:21])([CH3:20])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][NH:27][C:28]2=[O:33]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:19][C:12]1([C:15]([F:16])([F:18])[F:17])[CH2:11][C:10]([CH3:20])([CH3:21])[C:4]2[C:5](=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:13]1[NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][NH:27][C:28]2=[O:33]
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2c(=O)[nH]ncc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ncc12
Yield: 10.9 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 287 mg of 5-amino-phthalazin-1-one. As in Example 3, 320 mg of the imine is reacted by reaction with 7.2 ml of titanium tetrachloride (1 M in dichloromethane) in 20 ml of dichloromethane, and 80 mg of the title compound is obtained.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][N:5]=1)([CH3:3])[CH3:2].CC([O-])(C)C.[K+].C1(P(O[NH2:36])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[NH2:36][N:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1n[nH]c(=O)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1nn(N)c(=O)c2ccccc12
Reaction time: 0.75 h
Yield: 109.2 %

Procedure:
A mixture of the product of Example 1A (30.0 mg, 0.159 mmol) and KOtBu (1 M in THF, 0.32 mL, 0.32 mmol) in THF (1 mL) was stirred for 45 minutes, and O-(diphenylphosphoryl)hydroxylamine (57.6 mg, 0.247 mmol) [Klotzer, W.; Stadlwieser, J.; Raneburger, J. Organic Syntheses 1986, 64, 96-103] was added and stirred overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated to give 35.3 mg of crude product as a tan solid, which was used without purification. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (dd, 1H), 8.09 (d, 1H), 7.92 (ddd, 1H), 7.84 (ddd, 1H), 6.31 (s, 2H), 3.63 (quin, 1H), 1.30 (d, 6H); LC/MS (APCI) M/Z 204.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH3:11])[C:3]=12.[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]c2ncnc(Cl)c12
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (150.4 mg, 0.89 mmol, Example 3) and potassium carbonate (187 mg, 1.35 mmol) in dimethylformamide (6 mL) was added iodomethane (225 mg, 1.59 mmol, Aldrich). The reaction mixture was stirred at room temperature for 2 hours before it was diluted with ethyl acetate, washed with water, brine, dried and concentrated. The crude product was purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 162.3 mg).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[C:3]=[CH:4][CH2:5][C:6](=[O:8])[CH3:7]>[Pd]>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)CC=C=C(C)CCCC(C)CCCC(C)C
Agent: [Pd]
Product: CC(=O)CCCC(C)CCCC(C)CCCC(C)C

Procedure:
In analogy to the procedure and apparatus described in Example 1 but employing a 0.5% (wt./wt.) Pd on Al2O3 catalyst (DEGUSSA, E257H/D) 6,10,14-trimethyl -pentadeca-4,5-diene-2-one was hydrogenated to produce 6,10,14-trimethyl-pentadecane-2-one (phytone). The process parameters were as stated below:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.[C:11]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:17])[CH3:16])=[C:4]([F:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5.10 g (24.9 mmol) (4-bromo-2-fluoro-phenyl)-methanol in 30 mL DMF is added subsequently 4.06 g (26.1 mmol) tert-butyl-chloro-dimethyl silane, 2.57 g (37.3 mmol) imidazole and 456 mg (3.73 mmol) DMAP. The reaction mixture is stirred overnight at RT and the solvent is evaporated. The residue is diluted with EtOAc, washed five times with water and the combined organic phase is dried over MgSO4, filtered and the solvent is evaporated.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH:15]=1.[CH2:17](Br)[CH:18]=[C:19]([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.CC(OC)(C)C>[CH3:9][C:10]1[C:11](=[O:16])[CH:12]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:13][CH2:14][CH:15]=1
Reactant: CC1=CCCCC1=O
Reactant: CC(C)=CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)=CCC1CCC=C(C)C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LDA (prepared from BuLi, 1.6 M in hexane, 75 ml, 0.12 mol and diisopropylamine, 12.2 g, 0.12 mol) in THF (50 ml) was added 2-methyl-cyclohex-2-enone (11.0 g, 0.1 mol) at −78° C. The mixture was stirred for 1 h at −78° C. and prenyl bromide 17.88 g, 0.12 mol) was added. The mixture was stirred over night, while the temperature was allowed to rise to room temperature. MTBE (50 ml) and sat. NH4Cl were added, the organic phase was separated and washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled in a Kugelrohr oven to yield 9.8 g (55%) of a slightly yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH3:11].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][C:13](=[O:16])/[CH:14]=[CH:15]/[C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH3:11]
Reactant: Cc1c[nH]c2c(Br)cc(F)cc12
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cc(F)cc2c(C)c[nH]c12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a mixture of 7-Bromo-5-fluoro-3-methyl-1H-indole, [which was prepared analogous to I-30, according to the method of Dobbs, A., J. Org. Chem., 66, 638-641 (2001)], (870 mg, 3.8 mmol) and methyl acrylate (819 mg, 9.5 mmol) in triethylamine (4 ml), palladium(II) acetate (112 mg, 0.5 mmol) and tri-o-tolylphosphine (428 mg, 1.42 mmol) was added under argon at rt The reaction mixture was stirred at 100° C. for 3 hrs in a sealed pressure tube and then cooled to rt The reaction mixture was diluted with CH2Cl2 (70 ml), washed with water (3×40 ml), brine, and dried over sodium sulfate. After removal of solvent, the residue purified by column chromatography on silica gel with methanol/dichloromethane as an eluent to give 690 mg of compound I-33 as a solid. 1H-NMR (500 MHz, CDCl3).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:14][CH2:15][CH3:16].COC(O)C1C=C([N+]([O-])=O)C=CC=1OC>>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:14][CH2:15][CH3:16])=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCCI
Agent: COc1ccc([N+](=O)[O-])cc1C(O)OC
Product: CCCOc1ccc([N+](=O)[O-])cc1C=O
Yield: 72 %

Procedure:
This compound was prepared by the reaction of 2-hydroxy-5-nitrobenzaldehyde and 1-iodopropane using a similar procedure as described in the preparation of 2-methoxy-5-nitrobenzaldehyde methyl hemiacetal. Yield was 72%: MP 51-52° C.; 1H NMR (500 MHz, CDCl3) δ 10.46 (s, 1H), 8.68 (d, 1H, J=2.9 Hz), 8.39 (dd, 1H, J=2.7 and 9.1 Hz), 7.08 (d, 1H, J=9.1 Hz), 4.16 (t, 2H, J=6.2), 1.93 (m, 2H), 1.98 (t, 3H, J=7.37).