Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH:15]=[O:16])=[CH:10][C:9]=3[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])=[N:7][C:6]=12.[CH2:33]([S:35]([N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:8]1[C:9]2[CH:10]=[C:11]([CH:15]=[O:16])[CH:12]=[CH:13][C:14]=2[C:2]2[N:3]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[N:4]=[C:5]([NH:44][CH:41]3[CH2:42][CH2:43][N:38]([S:35]([CH2:33][CH3:34])(=[O:36])=[O:37])[CH2:39][CH2:40]3)[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(C=O)ccc32)c1Br
Reactant: CCS(=O)(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(Nc2nn(COCC[Si](C)(C)C)c3c2nc(-c2c(F)cccc2F)c2cc(C=O)ccc23)CC1
Yield: 45.9 %

Procedure:
A 50 ml three-necked flask equipped with a magnetic stirrer and with an argon intake is charged with 350 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-2H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde, prepared in step 5 of example 2, in 7.8 ml of 1,4-dioxane. 195 mg of 1-ethylsulphonylpiperidin-4-ylamine, 880 mg of caesium carbonate, 59 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 15 mg of palladium(II) acetate are added. The mixture is heated at reflux for 2 h. After cooling, the mixture is poured into water and extracted with AcOEt. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. It is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of cyclohexane and AcOEt (75/25 by vol.), to give 195 mg of 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde (yellow foam). LC-MS-DAD-ELSD 628=(M−H)(+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[C:4]([O:21][CH3:22])[CH:3]=1.C1COCC1.C(=O)([O-])O.[Na+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>C(OCC)(=O)C.O>[CH2:37]([O:36][C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9]2)=[C:4]([O:21][CH3:22])[CH:3]=1)=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(N)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 4-(4-amino-2-methoxy-phenyl)piperidine-1-carboxylate (Preparation Example 413) (4.25 g) and THF (100 mL), sodium hydrogen carbonate (1.28 g) and water (30 mL) were added, followed by dropwise addition of benzyl chloroformate (1.98 mL) under ice cooling and stirring overnight. After addition of water and extraction with ethyl acetate, the extract was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to give tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate (4.92 g) as a colorless amorphous.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:20]1[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:19]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccco2)n1
Product: c1coc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)c1
Yield: 31 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2-furyl)oxazole to give 2-(2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 31%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 92-93° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)ccc1Oc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 60 h
Yield: 84.4 %

Procedure:
Methyl 5-fluoro-2-hydroxybenzoate (2.65 g, 15.6 mmo.) and 1-fluoro-2-nitrobenzene (2.02 g, 14.2 mmol) were dissolved in acetonitrile (30 mL) and cesium carbonate (6.10 g, 18.7 mmol) was added. The reaction mixture was stirred at 80° C. for 60 hours. The mixture was cooled down to room temperature and poured into ethyl acetate. This organic mixture was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography with 10-20% ethyl acetate in hexanes and triturated in ethanol to afford the title compound 18 (3.49 g, 84%) as white solid. LRMS (ESI): (calc) 291.05 (found) 292.2 (MS)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:16]([O-])=O.Cl>>[NH2:16][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Oc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Agent: Cl
Product: Nc1ccc(Oc2ccc(Cl)cc2)cc1N

Procedure:
1.2 G. of 2-amino-4-(p-chlorophenoxy)-1-nitrobenzene in 3 ml. concentrated hydrochloric acid is treated with a solution of 6 g. stannous chloride in 6 ml. concentrated hydrochloric acid on the steam bath for 5 minutes. The mixture is cooled, decanted and the residue washed with 6 ml. 6N hydrochloric acid. The residue is treated with potassium bicarbonate and chloroform, filtered, and the chloroform layer repeated and dried over magnesium sulfate. Evaporation leaves 1,2-diamino-4-(p-chlorophenoxy)-benzene as a gum.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])=[CH:8]2)=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:50][NH:51][OH:52]>CN(C=O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:51]([OH:52])[CH3:50])=[O:18])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(COCCN3CCCC3=O)cn(Cc3ccc(F)cc3)c2cn1
Reactant: CNO
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(O)C(=O)c1cc2c(COCCN3CCCC3=O)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a stirring solution of 1-(4-fluorobenzyl)-3-{[2-(2-oxopyrrolidin-1-yl)ethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (0.817 g, 1.99 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.418 g, 2.38 mmol) in DMF (20 mL) was added N-methyl morpholine (0.2409, 2.38 mmol). After stirring at room temperature for 2 hours, N-methyl hydroxylamine hydrochloride (1.66 g, 19.9 mmol) was added. The reaction stirred for 16 hours at room temperature. After stirring for 16 hours, the reaction was concentrated in vacuo yielding a yellow oil. The oily residue was partitioned between a saturated sodium bicarbonate solution and ethyl acetate (50:50, 50 mL: 50 mL). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×100 mL). The organic phases were combined, washed with brine (100 mL), and dried over Na2SO4. The solution was filtered, concentrated, and triturated with diethyl ether to yield a pale yellow solid. The solid was recrystalized from isopropyl alcohol to give 1-(4-fluorobenzyl)-N-hydroxy-N-methyl-3-{[2-(2-oxopyrrolidin-1-yl)ethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxamide as clear needles (0.425 g, 49% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.76-1.85 (m, 2H) 2.13 (t, J=8.08 Hz, 2H) 3.26-3.35 (m, 8H) 3.51 (t, J=5.43 Hz, 2H) 4.65 (s, 2H) 5.54 (s, 2H) 7.16 (t, J=8.84 Hz, 2H) 7.36 (dd, J=8.59, 5.56 Hz, 2H) 7.86 (s, 1H) 8.01 (s, 1H) 8.89 (s, 1H)
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]1[CH:35]=[C:34]([CH:36]2[CH2:38][CH2:37]2)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH:36]1([C:34]2[N:33]=[CH:32][N:31]=[C:30]([N:20]3[CH2:21][CH2:22][C:16]4[C:15]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[N:14][C:13]([C:10]5[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=5)=[N:18][C:17]=4[CH2:19]3)[CH:35]=2)[CH2:38][CH2:37]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Clc1cc(C2CC2)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cc(C4CC4)ncn2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0597 g, 0.156 mmol), 4-chloro-6-cyclopropylpyrimidine (0.046 g, 0.30 mmol), N,N-Diisopropylethylamine (0.0570 mL, 0.327 mmol), and dry N,N-Dimethylformamide (0.84 mL, 11 mmol) were combined, the reaction was microwaved on 200 watts, 120° C. for 20 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.37 (s, 1H), 8.21 (d, J=8.8, 2H), 7.50 (d, J=8.8, 2H), 6.91 (s, 1H), 6.21 (t, J=5.5, 1H), 4.70 (s, 2H), 3.88 (s, 2H), 3.73 (d, J=4.5, 4H), 3.48 (d, J=4.3, 4H), 3.16-3.08 (m, 2H), 2.75 (s, 2H), 2.01-1.91 (m, 1H), 1.06 (t, J=7.2, 3H), 1.02-0.88 (m, 4H). LC/MS-m/z+501.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([O:25][CH3:26])[C:17]([CH3:24])=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:26][O:25][C:16]1[C:17]([CH3:24])=[C:18]2[C:23](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:15]=1)[N:22]=[CH:21][CH:20]=[CH:19]2
Reactant: COc1cc(N2CCN(Cc3ccccc3)CC2)c2ncccc2c1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(N2CCNCC2)c2ncccc2c1C
Yield: 87.9 %

Procedure:
A mixture of methanol (15mL), 10% Pd/C (0.12 g), 1-benzyl-4-(6-methoxy-5-methylquinolin-8-yl)piperazine (0.8 g, 2.3 mmol), and ammonium formate (0.88 g, 13.9 mmol) were refluxed for 45 minutes. The reaction mixture was filtered through celite and concentrated. The residue was diluted with 1 N aqueous NaOH (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were washed with water (50 mL) and brine(50 mL), then were dried over anhydrous Na2SO4, filtered, and concentrated to give 0.52 g (61%) of the title compound as a thick oil. MS (ES) m/z: 258 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][N:38]=1)CCC.[Cl-].C(N(CC)CC)C>CN(C)C=O.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:34]1[S:35][CH:36]=[CH:37][N:38]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ncnc(N)c1-c1nccs1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 13.3 %

Procedure:
60 mg (0.07 mmol) of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one, 43 mg (0.11 mmol) of 2-(tributylstannyl)thiazole, 2.0 mg (0.01 mmol) of bis-triphenylphosphinepalladium(II) chloride, 4.4 mg (0.02 mmol) of copper (I) iodide and 32 μl (0.23 mmol) of triethylamine in dimethylformamide (1.5 mL) were heated to 120° C. for 20 minutes with microwave irradiation under nitrogen atmosphere. The reaction mixture was filtered through Celite® and washed with methanol. The solvent of the filtrates were evaporated in vacuum and the residue was dissolved in ethyl acetate and washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) and then by preparative HPLC (Waters XBridge C18 OBD column, mixture of eluents NB from 50% B to 65% B, in a 10 min. gradient) to give 4 mg (13% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH2:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: OCc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncccc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
2-Chloro-3-pyridinol (500 mg, 3.86 mmol) was dissolved in 20 mL of tetrahydrofuran along with 4-pyridyl methanol (465 mg, 4.26 mmol) and triphenylphosphine (1.15 g, 4.38 mmol). To this solution was added diisopropylazodicarboxylate (840 μL, 4.27 mmol). The reaction was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was removed under vacuum and the residue was dissolved in 50 mL of ethyl acetate. The reaction mixture was washed 4 times with 25 mL portions of water. Then, the product was extracted by washing 3 times with 25 mL portions of 0.5 M HCl. The acidic washes were neutralized with 1.0 M NaOH and the product was extracted back into ethyl acetate with 3 washes of 25 mL. The combined organic fractions were dried with magnesium sulfate and concentrated under vacuum to give 620 mg of 2-chloro-3-(pyridin-4-ylmethoxy)pyridine as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([N:2]([C@@H:3]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:4]([O:6][CH3:7])=[O:5])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 50 °C
Yield: 165.5 %

Procedure:
Methyl 2(S)-amino-3-cyclohexylpropionate hydrochloride (150 g) was dissolved in N,N-dimethylformamide (1200 ml). Thereto was added pulverized potassium carbonate (330.7 g), and benzyl bromide (254.6 g) was dropwise added to the obtained suspension while stirring. After the dropwise addition, the inner temperature was raised to 50° C., and the reaction mixture was stirred at said temperature for 9 hours. The reaction mixture was cooled and filtered. Water (600 ml) and diisopropyl ether (600 ml) were added to the filtrate for partition, and the organic layer was separated. The water layer was re-extracted with diisopropyl ether (300 ml), and the combined organic layer was washed with 5% hydrochloric acid (600 ml), 5% aqueous sodium hydrogencarbonate (600 ml), and 25% aqueous sodium chloride sequentially and dried over magnesium sulfate. The solvent was distilled away to give 204.6 g of methyl 2(S)-(N,N-dibenzylamino)-3-cyclohexylpropionate.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[F:35][C:36]1[CH:37]=[C:38]([OH:42])[CH:39]=[CH:40][CH:41]=1>>[F:35][C:36]1[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=1)[O:42][C:23]1[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=1[O:21][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: Oc1cccc(F)c1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2Oc2cccc(F)c2)c1
Yield: 40 %

Procedure:
The compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester is reacted with 3-fluorophenol as in Example 45 to afford 0.106 g (40%) of the title compound. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z mass calculated for C30H25O5F4 541.1638, found 541.1625.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]([C:43]4([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44]4)=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: NC(=O)C1(c2ccc(Br)cn2)CCCC1
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CCCC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 62 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclopentanecarboxylic acid amide following a procedure analogous to that described in Example 1. Yield: 62% of theory; LC (method 2): tR=2.02 min; Mass spectrum (ESI+): m/z=542 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CS(O[C:9]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH3:11])[CH3:10])(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([NH:3][CH2:11][CH:9]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH3:2]
Reactant: CC(C)(OS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CCN
Solvent: Cc1ccccc1
Product: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 24 h

Procedure:
Ethylamine (18.75 cc) is added to a solution of 2-(2-cyano-10-phenothiazinyl)-2-propyl methanesulphonate, D series (10 g) in toluene (100 cc), and this mixture is brought to a temperature in the region of 105° C. for 24 hours. After being cooled, the reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl ether (250 cc) and extracted successively with N aqueous hydrochloric acid solution (2×100 cc). The combined aqueous phases are alkalinized with caustic soda (d=1.33) to pH 13 and extracted with ethyl ether (2 x 200 cc). The combined organic phases are washed successively with distilled water (50 cc) and with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40.° C. 10-(1-Ethylamino-2-propyl)- 2-phenothiazinecarbonitrile D series (5 g) is thereby obtained in the form of an orange oil. This product is dissolved at a temperature in the region of 60° C. in ethanol (17 cc) and this solution is poured into a solution of fumaric acid (1.9 g) in ethanol (17 cc) at the same temperature, crystallization is then primed and the mixture is left for 16 hours at a temperature in the region of 20° C. The solid is drained, washed with ethanol (2×2 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. 10-(1-Ethylamino-2-propyl)-2-phenothiazinecarbonitrile acid fumarate, D series (4 g) is thereby obtained in the form of a yellow solid, m.p. 208° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][C:46](=[O:48])[CH3:47])=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:41](=[O:42])[C:40]1[CH:44]=[C:36]([CH2:35][C:29]2[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=2[CH3:49])[CH:37]=[CH:38][C:39]=1[O:45][C:46](=[O:48])[CH3:47]
Reactant: Nc1ccccn1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccn3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.1 %

Procedure:
2-Aminopyridine (0.282 g, 3.000 mmol), triethylamine (0.304 g, 3.000 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.507 g, 3.000 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.374 g, 1.000 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.140 g, 0.311 mmol, 31%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:11](=O)[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>O1CCCC1>[N:7]1([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(CN1CCN(C(=O)c2ccccc2)CC1)N1CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCN(CCN3CCC3)CC2)cc1
Temperature: 25 °C
Yield: 104.3 %

Procedure:
Lithium aluminium hydride (405 mg) was suspended in tetrahydrofuran (10 ml) under a nitrogen atmosphere with stirring in an ice water bath, 1-(azetidin-1-yl)-2-(4-benzoylpiperazin-1-yl)ethanone (730 mg) and tetrahydrofuran (5 ml×3) was added thereto. The reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was allowed to cool down to room temperature, and water (0.4 ml), a 5N aqueous solution of sodium hydroxide (0.4 ml) and water (1.2 ml) were added thereto, followed by stirring for 13 hours. The insoluble matter in the reaction mixture was removed by filtration through celite, and washed with ethyl acetate (100 ml). The solvent was distilled off under reduced pressure to give a crude product of the title compound (687 mg) as a pale yellow oil.