Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.FC(F)(F)S(O[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[O:19][CH:10]3[CH:9]=[CH:8][C:7]4[C:12]([N:11]3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]2=3)=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:16][CH:15]=1
Reactant: COc1cccc2cccnc12
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(C2OC3C=Cc4ccccc4N3c3ccccc32)cc1
Yield: 65 %

Procedure:
Following the general procedure, treatment of 8-methoxyquinoline (0.086 g, 0.50 mmol) and 4-chlorobenzaldehyde (0.105 g, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=70/30) of the crude reaction mixture afforded 5-(4-chlorophenyl)-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as inseparable mixture of diastereomers as a white solid (0.121 g, 65% yield, dr determined by 1H NMR analysis of crude reaction mixture is 1:1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C@H:6]1[C@H:11](OS(C)(=O)=O)[CH2:10][CH2:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7]1>CN(C=O)C.O.C(Cl)Cl>[N:1]([C@H:11]1[CH2:10][CH2:9][N:8]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:7][C@H:6]1[F:5])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)[C@H](F)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](N=[N+]=[N-])[C@H](F)C1
Temperature: 115 °C

Procedure:
Sodium azide (4.045 g, 62.22 mmol) was added to a solution of (trans)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (3.700 g, 12.44 mmol) dissolved in DMF (25 mL). The reaction was heated to 115° C. for 24 hours. The mixture was cooled and diluted with water and methylene chloride. After separation, the organic layer was dried over Na2SO, filtered and concentrated in vacuo to provide the desired product (quantitative yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].CO.C(N(CC)CC)C.ClC1C=C(Cl)C(Cl)=CC=1[O:26][C:27](=O)[CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C)C=O>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:27](=[O:26])[CH2:28][NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31]
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)CNC(=O)OC(C)(C)C

Procedure:
Prepare a solution of 1.98 g. of glycine methyl ester hydrochloride in dimethylformamide containing 8 ml. of methanol and 1.42 g. of triethylamine. Cool and stir the solution while adding 5.0 g. of t-butoxycarbonylglycine-2,4,5-trichlorophenyl ester in 25 ml. of dimethylformamide. Stir the reaction mixture overnight, filter and evaporate the filtrate to dryness under reduced pressure. Chromatograph the residue on 150 g. of silica gel and collect the desired product which is eluted by an ethyl acetate:chloroform (1:9) mixture. Evaporate the eluate to dryness and crystallize from hexane to obtain the title product (m.p. 132°-135° C.).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[C:10]([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:12][C:13]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:8].Br[CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48].C(O)(=O)C>CN(C)C=O.O>[C:7]([C:9]1[C:10]([CH:25]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:37][N:38]2[C:42](=[O:43])[C:41]3[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]2=[O:48])=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:12][C:13]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:8]
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CN1C(=O)c2ccccc2C1=O)c1ccc2ccccc2c1
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
A dry 40 mL vial charged with a mixture of potassium tert-butoxide (0.110 g, 0.984 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) was cooled to −50° C. with an acetonitrile-dry ice bath under nitrogen. To the vial was added a suspension of ethyl 4-cyano-5-morpholin-4-yl-3-(2-naphthylmethyl)thiophene-2-carboxylate (0.200 g, 0.492 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) dropwise. After 10 min of stirring the resulting black solution, a solution of N-bromomethylphthalimide (0.142 g, 0.590 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise and the mixture was stirred at −52° C.˜−45° C. for 90 min. The reaction was quenched with acetic acid (0.084 mL, 1.5 mmol) and warmed up to r.t. The solution was diluted with water (˜30 mL), and the resulting pale yellow solid was collected by filtration. The crude solid was dissolved in DCM (30 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification on a silica gel column (continuous gradient of EtOAc/hexane 0˜50%) afforded the title product (0.126 g, yield 45.3%). LCMS: (FA) ES+ 566. 1H NMR (400 MHz, d-chloroform) δ: 7.95 (s, 1H), 7.90-7.75 (m, 5H), 7.73-7.63 (m, 2H), 7.50-7.40 (m, 3H), 6.03 (m, 1H), 4.87-4.73 (m, 2H), 4.20-4.10 (m, 2H), 3.82-3.75 (m, 4H), 3.51-3.42 (m, 4H), 1.20-1.13 (m, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1O)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].I[CH3:18].CN([CH:22]=[O:23])C>>[C:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:18][O:23][CH3:22])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CI
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1O
Agent: [H-]
Agent: [Na+]
Product: COC[C@H]1CCCCN1C(=O)OC(C)(C)C
Yield: 85 %

Procedure:
A suspension of sodium hydride (0.13 g, 5.4 mmol) in DMF (4 mL) was cooled with ice and a solution of the intermediate alcohol of Step 2 (0.97 g, 4.5 mmol) in DMF (1 mL) was added dropwise. After stirring for 30 min at room temperature iodomethane (0.96 g, 6.8 mmol) was added and the mixture was stirred over night. The mixture was quenched with saturated NH4Cl-solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure to leave the crude (R)—N-Boc-2-methoxymethylpiperidine (0.88 g, 85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH2:10].I.CS[C:14]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[N:15]=1.C(O)C.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH:10][C:14]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[N:15]=1
Reactant: NCCOc1ccccn1
Reactant: CSC1=Nc2cccc3cccc1c23
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)=O
Product: c1ccc(OCCNC2=Nc3cccc4cccc2c34)nc1

Procedure:
A mixture consisting of 3.0 grams of 2-(2-pyridinyloxy) ethylamine, 6.5 grams of 2-methylthiobenz(cd)indole hydriodide, and 150 ml of ethanol was stirred and heated under reflux, utilizing the conditions of Example 16. The crude free base (weight, 7.1 grams) was dissolved in 20 ml of acetone and added to a stirred boiling solution of 5.5 grams of fumaric acid in 1200 ml of acetone. After cooling the precipitate of the title compound was collected, washed with acetone, and dried; yield, 7.6 grams; mp 184° C.-185° C. with decomposition.
Reaction SMILES: [NH:1]([C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([S:17][CH3:18])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:21]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[NH:1]([C:8]1[C:13]([C:14]([NH2:21])=[O:15])=[CH:12][N:11]=[C:10]([S:17][CH3:18])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CSc1ncc(C(=O)O)c(Nc2ccccc2)n1
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ncc(C(N)=O)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
The compound prepared in Example 92 (2.15 g), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (1.74 g) and 1-hydroxybenzotriazole hydrate (1.39 g) were combined in N,N-dimethylformamide (20 mL). The mixture was stirred for 2 hours at room temperature and then concentrated aqueous ammonium hydroxide (15 mL) was added slowly. The reaction was stirred for one hour and then was diluted with ethyl acetate and sequentially washed with water and brine. The organics were dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (2.06 g) having the following physical data.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[NH:6][C:7]2[CH:36]=[CH:35][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH2:26][CH2:25][N:24]([C:27](=[O:34])[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[CH2:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:37])[CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([NH:4][C:5](=[O:38])[NH:6][C:7]2[CH:36]=[CH:35][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH2:26][CH2:25][N:24]([C:27](=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:37])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CCC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.5 %

Procedure:
To a stirred suspension of 272 (120 mg, 0.223 mmol) in THF/MeOH (5/5 mL) was added NaOH 1M (3 mL, 3.00 mmol). The reaction mixture was stirred at RT for 16 h and concentrated. The residue was then diluted with water and extracted with DCM/MeOH. The organic layer was successively washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 15/85 over 20 CV) to afford a material that upon trituration with AcOEt afforded the title compound 273 (10 mg, 0.019 mmol, 9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.90-8.79 (bs, 1H), 8.35 (d, =5.6 Hz, 1H), 7.64-7.56 (m, 1H), 7.32-7.29 (m, 1H), 7.27-6.96″(m, 4H), 6.68-6.60 (m, 1H), 6.48-6.40 (m, 1H), 5.14-5.01 (m, 1H), 3.94-3.88 (m, 1H), 3.68-3.48 (m, 2H), 2.63-2.56 (m, 2H), 2.50-2.30 (m, 3H), 2.20-2.08 (m, 1H), 1.92-1.79 (m, 1H), 0.57-0.52 (m, 2H), 0.34-0.30 (m, 2H). MS (m/z): 525.39 (M+H).
Reaction SMILES: [Si:1]([O:18][C@H:19]1[CH2:24][C@@H:23]([C:25](O)=[O:26])[C@H:22]([C:28](=[O:37])[N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH3:30])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][C@:39]1([C:44]([O:46][CH3:47])=[O:45])[CH2:41][C@H:40]1[CH:42]=[CH2:43].[Si](O[C@H]1C[C@@H](C(OC(C)(C)C)=O)[C@H](C(=O)N(CCCCC=C)C)CC1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[Si:1]([O:18][C@H:19]1[CH2:24][C@@H:23]([C:25]([NH:38][C@:39]2([C:44]([O:46][CH3:47])=[O:45])[CH2:41][C@H:40]2[CH:42]=[CH2:43])=[O:26])[C@H:22]([C:28](=[O:37])[N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH3:30])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC
Reactant: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)O
Agent: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Product: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)N[C@]1(C(=O)OC)C[C@H]1C=C

Procedure:
Compound 41 was synthesized from compound 40 and (1R,2S)-methyl 1-amino-2-vinylcyclopropanecarboxylate as described for compound 39 to yield compound 41 as a yellow oil in 76% yield. MS (ESI, EI+): m/z=645 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28](C(O)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].[C:38](=[O:41])([O-])[OH:39].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([C:38]([OH:39])=[O:41])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: O=C([O-])O
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 1-{4-[(R)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-phenyl}-piperidine-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a yellow semisolid, MS (ESI−): m/z=490.3 ([M−H]−).
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH:26][CH3:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]>C(O)C.[Pt]=O>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH3:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC=Cc1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Agent: O=[Pt]
Solvent: CCO
Product: CCCc1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
In 7 ml of ethanol was dissolved 757 mg of N-acetyl-N-[2-(propen-1-yl)benzyl]-2-phenoxyaniline (a mixture of the geometrical isomers at a ratio of about 3:2), and 15 mg of platinum oxide was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The catalyst in the reaction solution was removed by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:4) to give 647 mg of N-acetyl-N-(2-propylbenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:14][C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][C:16]=1[O:17][CH2:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[CH:10]=[O:9]
Reactant: C[Si](C)(C)CCCCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCC[Si](C)(C)C
Temperature: 80 °C
Yield: 89.1 %

Procedure:
3-chloropropyltrimethylsilane (33.14 g, 0.22 mol) was added dropwise over 20 minutes to a mixture of vanillin (30.4 g, 0.2 mol) and potassium carbonate (30.4 g, 0.22 mol) in 150 ml of dry DMF heated to 80° C. under nitrogen. The mixture was maintained for 4 hours at 95°-110° C. The reaction mixture was cooled and poured into ice-cold water. The aqueous phase was extracted three times with dichloromethane. The organic phases were dried over sodium sulfate and concentrated under vacuum. After distillation under vacuum (0.04 mm Hg), 47.5 g (yield: 89%) of 3-methoxy-4-(3-trimethylsilanylpropyloxy) benzaldehyde were obtained in the form of a slightly pinkish oil distilling at 1120-114° C. and employed without further purification in the following step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH:9](=O)[CH2:10][CH3:11].[C:13](=[O:15])=[O:14]>>[F:1][C:2]1[C:3]([F:8])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[C:13]([OH:15])=[O:14]
Reactant: CCC=O
Reactant: O=C=O
Reactant: Fc1ccccc1F
Product: CCCc1ccc(C(=O)O)c(F)c1F

Procedure:
2,3-Difluoropropylbenzene is obtained by lithiating o-difluorobenzene at -70° to -80° and reacting with propionaldehyde, dehydrating the secondary alcohol produced and subsequently hydrogenating the double bond. Re-metallation and reaction with dry ice gives 2,3-difluoro-4-propylbenzoic acid. From this acid, 4-(4'-pentylbiphenyl) 2,3-difluoro-4-propylbenzoate, C 74° Sc 86° N 160.1° I, is obtained analogously to Example 1 by esterification using 4-pentyl-4'-hydroxybiphenyl anddicyclohexylcarbodiimide.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH3:7].[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12].C[O:15][CH:16]=[C:17]([C:22]([O:24]C)=[O:23])[C:18](OC)=O.[OH-].[Li+]>Cl.C1COCC1.O>[CH2:9]([N:13]1[C:4]([CH2:5][CH2:6][CH3:7])=[C:3]([CH2:2][CH3:1])[CH:18]=[C:17]([C:22]([OH:24])=[O:23])[C:16]1=[O:15])[CH2:10][CH2:11][CH3:12]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: CCCC(=O)CCC
Reactant: CCCCN
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1c(CCC)c(CC)cc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under the nitrogen gas atmosphere, a solution of 4-heptanone (5.0 mM, 35.75 mmol), n-butylamine (4.25 mL, 4.29 mmol), and three drops of concentrated hydrochloric acid was stirred for 18.5 hours at room temperature. After that, water was added and the mixture was extracted with ethyl acetate. After the organic layer had been washed with water and then dried with anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The obtained oily matter was dissolved in 2-methoxyethyl ether (40 mL), and heated and stirred with dimethyl methoxymethylenemalonate (5.66 g, 32.5 mmol) at 120° C. for 3 hours. After the solvent had been removed by distillation under reduced pressure, the residue was refined with silica gel (100 g) column chromatography (ethyl acetate-hexane of 1:1 in mixing ratio and then that of 2:1), and a ark reddish-brown oily substance was obtained. The substance was dissolved in THF (20 mL) without purification, and a 1M lithium hydroxide aqueous solution (15.18 mL) and water (4.82 mL) were added, and then the mixture was stirred for 2 hours at room temperature. After that, the mixture was diluted with water and washed with diethyl ether. After 2M hydrochloric acid had been added to the water layer to acidify it, the water layer was extracted with ethyl acetate. The organic layer was washed with water and then dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and a pale yellow solid (AA03, 1.68 g, 18%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[O:33]1[CH2:38][CH2:37][N:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.O1CCOCC1.C(OCC)(=O)C>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39]([N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[O:40])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)N1CCOCC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (339 mg), triethylamine (0.18 ml), 4-dimethylaminopyridine (5 mg) and morpholinocarbonyl chloride (0.15 ml) in 1,4-dioxane (4 ml) was stirred at 80° C. for 2 hours. Then the mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (ethyl acetate) to give 2-benzyl-4-[3-(morpholinocarbonylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (242 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@@H:18]([CH2:26][OH:27])[NH:17]1.C(N(CC)CC)C>CN1CCCC1=O.CO>[NH2:15][C:4]1[N:3]=[C:2]([N:17]2[C@H:18]([CH2:26][OH:27])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=1
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCN(c2cc(N3Cc4ccccc4C[C@H]3CO)nc(N)n2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (20 mg, 87.8 mmol), (3 S)-1,2,3,4-tetrahydroisoquinolin-3-ylmethanol (21.5 mg, 132 mmol, Aldrich, Cat. 494186) and triethylamine (0.5 mL, 4 mmol) in N-methylpyrrolidinone (1 mL) was heated at 120° C. overnight. The reaction mixture was diluted in MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=355.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].FC(F)(F)C(O)=O.[CH2:21]([N:28]([CH2:34]OC)[CH2:29][Si](C)(C)C)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.C(OC(=O)C)C>[CH2:21]([N:28]1[CH2:29][CH2:10][CH:9]([C:7]2[CH:6]=[CH:5][C:4]([N+:11]([O-:13])=[O:12])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:34]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=Cc1ccc([N+](=O)[O-])c(OC)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 127.8 %

Procedure:
2-Methoxy-1-nitro-4-vinyl-benzene (435 mg, 2.43 mmol) was dissolved in dichloromethane (2 ml), trifluoro acetic acid (80 μl, 1.0 mmol) was added, followed by slow addition of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (715 mg, 3.01 mmol). Stirring was continued for 2 h at room temperature. Another portion of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (300 mg, 1.26 mmol) was added and stirring continued for another 30 minutes. The reaction mixture was diluted with ethylacetate (25 ml), washed with aqueous NaHCO3 (15 ml). The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield an oil (970 mg). The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-50%). Fractions containing the product were combined, the solvent evaporated to yield an oil (320 mg, 46%).
Reaction SMILES: C[C:2]([CH3:15])(CC(C)CCN=C=O)CN=C=O.[OH:16][CH2:17][CH2:18][O:19][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22]>>[C:20]([O:19][CH2:18][CH2:17][O:16][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:2][CH3:15])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)OCCO
Reactant: CC(CCN=C=O)CC(C)(C)CN=C=O
Product: C=C(C)C(=O)OCCOCCOCCOCC

Procedure:
Diurethane di(meth)acrylate from 2,2,4-trimethylhexamethylene diisocyanate and 2-hydroxyethyl(methacrylate)