Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:28])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[F:24])[C:11]=2[C:25](=[O:27])[NH2:26])C=CC=CC=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1>>[F:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:25]([NH2:26])=[O:27])=[C:10]([NH:9][C:8]([NH:39][CH2:38][CH2:37][CH2:36][N:33]2[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]2)=[O:28])[S:14][N:13]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: Cc1ccc(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1ccc(COc2nsc(NC(=O)NCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2-fluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 465 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][CH3:14].[N+:15]([C:18]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21])([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:19]=1[C:20]([O:1][CH:2]1[C:8]([CH3:9])([CH3:10])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][CH3:14])=[O:21])([O-:17])=[O:16]
Reactant: COC1C=C(C)C(=O)CC(C)(C)C1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: COC1C=C(C)C(=O)CC(C)(C)C1OC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 61.5 %

Procedure:
5-Hydroxy-4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU154) obtained in Example 4 (5.95 g, 30 mM) was treated with 2,4-dinitrobenzoic acid according to the procedures described in Example 20. The mixture was re-crystallized twice from a mixed solution of ethyl acetate and hexane to obtain 7.24 g (61.5%) of 5-(2,4-dinitrobenzoyloxy)-4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU407) as reddish needles. Melting point: 147.5° to 149° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](OC)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:15].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(=O)OCC>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:15]
Reactant: COC(=O)c1ccc2c(c1)nc(C)n2C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2cc(CO)ccc2n1C
Reaction time: 1 h

Procedure:
To a solution of Methyl 1,2-dimethyl-1H-benzo[d]imidazole-5-carboxylate (500 mg, 2.448 mmol) in THF (24.5 ml) Lithiumaluminium hydride (1 M in THF, 2.44 ml) was added at 0° C. After 2 hours sodium sulfate decahydrate and citric acid was added to the reaction to destroy the excess of lithiumaluminiumhydride. After 1 hour, methanol (25 ml) was added and the fine suspension was filtered off. The filtrate was evaporated under reduced pressure to afford a brown solid. EA (50 ml) was added and the suspension was treated in an ultra sonic bath. The solid was filtered off and this procedure was repeated twice. The yellow filtrate was evaporated under reduced pressure to afford crude (1,2-Dimethyl-1H-benzo[d]imidazol-5-yl)methanol.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([N:29]([CH3:31])[CH3:30])[N:4]=1.Br>C(O)(=O)C>[CH3:30][N:29]([CH3:31])[C:5]1[NH:4][C:3](=[O:2])[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=1
Reactant: COc1nc(N(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc(-c2cnc(N(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 74 %

Procedure:
A solution of 4-methoxy-N,N-dimethyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.060 g, 0.144 mmol) in acetic acid (5 mL) was treated with HBr (0.065 mL, 0.575 mmol), heated at 90° C. for 6 h, cooled to RT and quenched with ice water. The solution was treated with NaHCO3 and NaCl, extracted with 1:1 THF/EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN (1 mL), allowed to stand at RT and the resulting solid was collected via filtration to afford 2-(dimethylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (43 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 8.73 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.30 (m, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.51 (m, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.62 (br s, 1H), 3.85 (s, 3H), 3.12 (s, 6H), 2.35 (s, 3H); MS (ESI) m/z: 404.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:19]([CH3:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([OH:14])[C:8]=1[CH3:15])=O.N#N>C1COCC1>[F:1][C:2]1[C:19]([CH3:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[CH:16][C:3]=1[CH2:4][NH:6][C:7]1[C:8]([CH3:15])=[C:9]([OH:14])[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(C)ccc(O)c2C)c1F
Agent: N#N
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(O)c2C)c1F
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)-N-(3-hydroxy-2,6-dimethyl-phenyl)-3-methyl-benzamide (270 mg, 0.7 mmol, 1.0 eq) in THF (15 mL) was added a solution of BH3 (1M in THF, 4.4 mL, 4.4 mmol, 6.0 eq) dropwise under N2. The reaction mixture was heated at 60° C. overnight. After cooling, the resulting mixture was quenched by the addition of water and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 30:1 to 20:1) to give the title compound as a colorless oil (106 mg, 41%).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26].Cl>C(=O)([O-])O.[Na+].O1CCCC1>[CH2:28]([O:27][C:25]([S:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])=[O:26])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1c(NC(=O)C(CS)Cc2ccccc2)cccc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)C(CSC(=O)OCC(C)C)Cc2ccccc2)cccc1C(=O)O
Yield: 36 %

Procedure:
3-[(2-Mercaptomethyl-3-phenylpropionyl)amino]-2-methylbenzoic acid (compound of Example 7) (0.66 g) is dissolved in a mixture of saturated aqueous sodium hydrogen carbonate solution and tetrahydrofuran (1 ml), and to the mixture is added a solution of isobutyl chloroformate (0.33 g) in tetrahydrofuran (5 ml) with stirring under ice cooling, and the mixture is stirred under ice cooling for 30 minutes and further at room temperature for one hour. The reaction mixture is acidified with 4N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and the precipitates are separated by filtration to give the title compound (0.31 g). m.p.: 165°-167° C. (amorphous) IR (KBr; cm-1): 1700, 1650
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH:6]=[CH:7][CH:8]=1.[S:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[S:22].NCCC(O)=O>C(O)(=O)C>[S:22]=[C:21]1[NH:23][C:24](=[O:25])/[C:26](=[CH:12]/[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=2)/[S:20]1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccccc1Nc1cccc(C(F)(F)F)c1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: O=C1NC(=S)S/C1=C\c1ccccc1Nc1cccc(C(F)(F)F)c1
Yield: 66.4 %

Procedure:
To a room temperature solution of 2-[[3-(trifluoromethyl)phenyl]amino]benzaldehyde (749 mg, 2.83 mmols) and rhodanine (398 mg, 2.99 mmols) in 20 mL of acetic acid is added β-alanine (382 mg, 4.29 mmols). The solution is heated at reflux for 45 min. During this time a thick precipitate forms. The mixture is filtered hot, washing with an additional 10 mL of acetic acid, to provide 715 mg (66%) of (Z)-2-thioxo-5-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methylene]-4-thiazolidinone as a bright red-orange solid; mp=234°-236° C. Calc'd for C17H11F3N2OS2:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
2-Chloro-5-nitropyridine (5.0 g, 31.5 mmol) and tetrakis(triphenylphosphine)palladium (0.35 g, 0.3 mmol) were added to 1,2-dimethoxyethan (50 ml), then degassed and purged with nitrogen three times under reduced pressure. Under nitrogen atmosphere the mixture was stirred at room temperature for 20 minutes, 4-methylphenylboronic acid (4.29 g, 31.5 mmol) and 2M aqueous sodium carbonate (31.5 ml) were poured in, and the temperature was raised to 80° C. After the reaction at 80° C. for 3 hours, the mixture was cooled to room temperature and extracted with addition of ethyl acetate and water. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The products were purified by column chromatography to give the title compound (5.4 g, 80.0% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][CH2:20][C:21]([OH:23])=O)[C:10]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:48]1([CH2:54][CH2:55][CH2:56][NH2:57])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][CH2:20][C:21]([NH:57][CH2:56][CH2:55][CH2:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:23])[C:10]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCc1ccccc1
Reactant: Cc1c(CCC(=O)O)nc2ccccc2c1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CCC(=O)NCCCc2ccccc2)nc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
3-[4-(Benzyloxy)-3-methylquinolin-2-yl]propionic acid (213 mg) and 1-hydroxybenzotriazole hydrate (107 mg) were dissolved in DMF (4 mL). 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg), 3-phenylpropylamine (134 mg), and N,N-diisopropylethylamine (0.14 mL) were added thereto, and the mixture was stirred at room temperature for 72 hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (200 mL). The organic layer was washed sequentially with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1) to obtain 3-[4-(benzyloxy)-3-methylquinolin-2-yl]-N-(3-phenylpropyl)propanamide (90 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=O)[CH2:2][CH:3]=[CH2:4].C([O-])(=O)C.[Na+].Cl.[NH2:15][OH:16]>C(O)C.O>[CH2:1]([O:5][CH2:6][CH:7]=[N:15][OH:16])[CH2:2][CH:3]=[CH2:4]
Reactant: NO
Reactant: C=CCCOCC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCCOCC=NO
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
(But-3-en-1-yloxy)acetaldehyde (C6) (40 g from the preceding step, ≦312 mmol) was dissolved in a 2:1 mixture of ethanol and water (700 mL). Sodium acetate (128 g, 1560 mmol) was added, and the mixture was stirred for 20 minutes. Hydroxylamine hydrochloride (98%, 66.4 g, 936 mmol) was then added, and the reaction mixture was heated to 60° C. for 18 hours, at which point it was cooled to room temperature and concentrated under reduced pressure to remove ethanol. The aqueous residue was poured into water (500 mL) and extracted four times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 40% ethyl acetate in heptane) afforded the product as an oil, presumed from the 1H NMR spectrum to be a mixture of E and Z oximes. Yield: 24 g, 0.19 mmol, 60% over three steps. 1H NMR (400 MHz, CDCl3) δ 2.33-2.41 (m, 2H), 3.51-3.57 (m, 2H), [4.11 (d, J=5.7 Hz) and 4.36 (d, J=3.7 Hz), total 2H], 5.04-5.16 (m, 2H), 5.76-5.89 (m, 1H), [6.92 (t, J=3.7 Hz) and 7.51 (t, J=5.6 Hz), total 1H].
Reaction SMILES: [CH:1]1([C:7]2[N:8]=[C:9]3[CH:14]=[N:13][C:12]4[N:15](S(C5C=CC(C)=CC=5)(=O)=O)[CH:16]=[CH:17][C:11]=4[N:10]3[CH:28]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1>[CH:1]1([C:7]2[N:8]=[C:9]3[CH:14]=[N:13][C:12]4[NH:15][CH:16]=[CH:17][C:11]=4[N:10]3[CH:28]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nc(C4CCCCC4)cn23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1cc2c(ncc3nc(C4CCCCC4)cn32)[nH]1
Yield: 13.9 %

Procedure:
7-Cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.13 g, 0.33 mmol) was dissolved in 1,4-dioxane (5 mL) and aqueous NaOH (2N, 0.5 mL) was added. The mixture was heated at reflux for about 30 min. The organic solvent was removed under reduced pressure. The aqueous phase was neutralized with 1 N aqueous HCl and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by RP-HPLC (Table 2, Method h) to yield 7-cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as an off-white solid (0.011 g, 14%): LC/MS (Table 2, Method a) Rt=2.06 min; MS m/z: 241 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)[C@@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 30.7 %

Procedure:
A solution of (R)-2-(4Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole). 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2.25 hours with nitrogen bubbling through it. A solution of dipropylamine (5.04 g, 0.050 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was refluxed under nitrogen for two days. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. It was then dried over magnesium sulfate, charcoaled, filtered, and evaporated to an oil which crystallized upon trituration with isopropyl ether. The solid was collected by filtration and dried under high vacuum at 50° C. overnight to give 1.96 g (31%) of title compound, mp 95°-97° C.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(C2CC2)ccc1F
Yield: 84.7 %

Procedure:
Degas the solution of cyclopropyl boronic acid (0.585 g, 6.80 mmol) in dry toluene (6 mL) for 30 minutes. Then added tetrakis(triphenylphosphine) Palladium (0.090 g, 0.089 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (1.0 g, 4.56 mmol) to the solution. The reaction mass was again degassed for 30 minutes and then added potassium carbonate (0.0628 g, 4.55 mmol). The reaction mass was refluxed for 48 h. The excess of solvent was removed under vacuum and the reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography to afford 0.700 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.74-0.76 (m, 2H), 1.00-1.02 (m, 2H), 2.08 (m, 1H), 7.45-7.48 (m, 2H), 7.83 (d, J=6.9 Hz, 1H); MS [M+H]+: 164.13.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH2:29])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>ClCCl.CO>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: OC1CCN(c2ccnc(Cl)n2)CC1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Nc2nccc(N3CCC(O)CC3)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 1-(2-chloropyrimidin-4-yl)-4-piperidinol (120 mg, 0.534 mmol) and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (109 mg, 0534 mmol) using in analogous manner the procedure described in example 43b). Obtained after trituration in dichloromethane/methanol (19:1 v/v) as a white solid (117 mg, 57%). MS ISP (m/e): 381.1 [(M+1-1)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.24 (s, 1H), 7.97 (d, 1H), 7.84 (d, 1H), 7.63 (s, 1H), 7.26 (dd, 1H), 7.18 (d, 1H), 7.03 (s, 1H), 6.31 (d, 1H), 4.77 (d, 1H), 4.07 (m broad, 2H), 3.78 (s, 3H), 3.77 (m, 1H), 3.25 (m broad, 2H), 2.14 (s, 3H), 1.78 (m broad, 2H), 1.36 (m broad, 2H). Mp 197-200° C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:11]([C:13]1[CH2:14][O:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=2)#[N:12].[OH-].[Na+]>C(OCC)C.O1CCCC1.O>[NH2:12][CH2:11][CH:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:23])[CH:20]=2)[O:15][CH2:14]1
Reactant: N#CC1=Cc2cc(F)ccc2OC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NCC1COc2ccc(F)cc2C1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
In an argon atmosphere, a mixture of 0.89 g (6.66 mmol) of aluminium trichloride in 40 ml of absolute diethyl ether is added dropwise while stirring at room temperature to a suspension of 1.52 g (40 mmol) of lithium aluminium hydride in 50 ml of absolute diethyl ether. Subsequently, a solution of 3.5 g (20 mmol) of 3-cyano-6-fluoro-2H-chromene in 50 ml of absolute tetrahydrofuran is added dropwise within a period of 20 minutes to the diethyl ether solution. The reaction mixture is then boiled under reflux for 16 hours. After cooling to room temperature, the reaction mixture is carefully decomposed with 1.52 ml of water, 1.52 ml of sodiumhydroxide solution (15%) and 4.6 ml of water. The resulting precipitate is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether and the etheral solution is washed with water and then extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline with sodium hydroxide solution (30%) while cooling and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 1.89 g of 3-aminomethyl-6-fluoro-chroman in the form of a light-yellow oil. 3-Aminomethyl-6-fluoro-chroman hydrochloride, prepared therefrom with hydrochloric acid in diethyl ether, crystallizes from methanol/acetone and has a melting range of from 208° to 211°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C@H:17]3[C@@H:24]4[C@@H:20]([CH2:21][NH:22][CH2:23]4)[CH2:19][CH2:18]3)[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.[C:34](=O)([O:42]C1C=CC([N+]([O-])=O)=CC=1)[O:35][CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1.C1CCCCC1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C@H:17]3[C@@H:24]4[C@@H:20]([CH2:21][N:22]([C:34]([O:35][CH2:36][C:37]5[N:38]=[CH:39][S:40][CH:41]=5)=[O:42])[CH2:23]4)[CH2:19][CH2:18]3)[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2cccc(O[C@@H]3CC[C@@H]4CNC[C@@H]43)c2)cc1
Reactant: O=C(OCc1cscn1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(-c2cccc(O[C@@H]3CC[C@@H]4CN(C(=O)OCc5cscn5)C[C@@H]43)c2)cc1
Yield: 62.3 %

Procedure:
The process is performed according to the procedure described in Example 1, step 1.3. Starting with 0.053 g (0.19 mmol) of (3aR,4R,6aS)-4-[(4′-ethoxybiphenyl-3-yl)oxy]octahydrocyclopenta[c]pyrrole, obtained in step 14.3., 0.04 mL (0.23 mmol) of N,N-diisopropylethylamine and 0.068 g (0.21 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate (WO 2008/013 834), and after chromatography on silica gel, eluting with a 95/5 and then a 90/10 mixture of cyclohexane and ethyl acetate, 0.055 g (63%) of expected product is obtained in the form of an oil.