Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([N:8]1[C@@H:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]1=[O:41])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1>[Si:1]([N:8]1[CH:11]([S:12][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]([CH:32]([OH:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]1=[O:41])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](C(=O)Cc2ccccc2)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(C(O)Cc2ccccc2)C1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 95.5 %

Procedure:
trans 1-(t-butyldimethylsilyl)-3-phenylacetyl-4-tritylthio-2-azetidinone (28.8 g, 50 mmol) and NaBH4 (0.5 g, 0.25 mole) in THF (200 ml) were stirred at room temperature for 18 h. The mixture was poured onto ice-1N HCl and extracted with CH2Cl2. The CH2Cl2 solution was washed with brine and dried (Na2SO4). It was evaporated to give an amorphous solid (27.7 g). A portion of the solid (23.0 g) was chromatographed on SiO2 and eluted with hexane:ether to give off-white solid (14.4 g) which was found to be a mixture of (1'R,3S,4R and 1'S,3R,4S) and (1'S,3S,4R and 1'R,3R,4S) isomers in the ratio of 1:1 (60%). 1Hmr (CDCl3) δ: 7-7.7 (20H, m), 4.37 (1/2H, d), 4.18 (1/2H, d), 3.3-3.8 (H, m), 3.45 (1/2H, dd), 3.1 (1/2H, dd), 2.7 (2H, m), 0.87 (9H, d) and 0.25 ppm (6H, s).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([NH:20][CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:34]=[C:33]3[C:29]([N:30]=[CH:31][N:32]3[C@@H:35]3[CH2:39][C@H:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[C@@H:37]([OH:45])[C@H:36]3[OH:46])=[C:28]([NH:47][CH2:48][CH:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:27]=2)=[O:25])=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:34]=[C:33]3[C:29]([N:30]=[CH:31][N:32]3[C@@H:35]3[CH2:39][C@H:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[C@@H:37]([OH:45])[C@H:36]3[OH:46])=[C:28]([NH:47][CH2:48][CH:49]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:27]=2)=[O:25])[CH2:15][CH2:16]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(C(=O)OCc5ccccc5)CC4)nc32)[C@H](O)[C@@H]1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCNCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-[3-(2-{[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carbonyl]-amino}-ethyl)-ureido]-piperidine-1-carboxylic acid benzyl ester (Example 108) (0.145 g, 0.174 mmol) in methanol (1 ml) under an atmosphere of Argon is treated with palladium hydroxide on carbon (0.054 g, 20% w/w carbon). The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature for 72 hours and then filtered. The filtrate is concentrated in vacuo to yield the title compound as a green oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.[N+](=[CH2:24])=[N-].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([O:20][CH3:24])=[O:19])=[CH:16][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cccnc1S2
Reactant: C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C(C)c1ccc2c(c1)C(=O)Cc1cccnc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 54 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]-thiepin-8-yl)-propionic acid in ethanol was added 5 ml of diazomethane etherial solution and the mixture was stirred at room temperature for 1 hour. To this was added acetic acid to decompose an excess reagent, then saturated sodium hydrogen-carbonate solution to make the solution alkaline, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 51 mg of oily substance, which was chromatographed over silica gel, eluted with benzene/chloroform (1/1) to obtain the colorless oily substance, which was crystallized from ethanol to give 40 mg of methyl 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]thiepin-8-yl)-propionate as colorless crystals having a melting point of 98°-99.5° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[CH:11]=[O:12])O1.Br[C:23]1[C:24]([O:30][CH3:31])=[N:25][CH:26]=[C:27]([Br:29])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>COCCOC.O.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:29][C:27]1[CH:28]=[C:23]([C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:10]=2[CH:11]=[O:12])[C:24]([O:30][CH3:31])=[N:25][CH:26]=1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2C=O)OC1(C)C
Reactant: COc1ncc(Br)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1C=O
Temperature: 85 °C
Reaction time: 8 h

Procedure:
2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzaldehyde (1.59 g, 4.4 mmol), 3,5-dibromo-2-methoxy-pyridine (1.19 g, 4.4 mmol), and potassium carbonate (2.17 g, 15.6 mmol) were combined in DME (13 mL) and H2O (6 mL). The solution was purged with N2 for 30 minutes, and dichlorobis(triphenylphosphine)palladium(II) (0.156 g, 0.22 mmol) was added. The reaction was stirred at 85° C. overnight, and then cooled to room temperature and worked-up with EtOAc and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give 2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzaldehyde, which was repurified by preparative HPLC.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1C

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2-methylphenyl)-5-(pent-1-enyl)pyridine (Example 141) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.76 (t, J=6.6 Hz, 3 H), 1.0-1.40 (m, 19 H), 1.97 (s, 3 H), 2.0 (m, 1 H), 2.35 (m, 1 H), 3.22 (m, 1 H), 3.42 (m, 1 H), 4.16 (dd, J=12.0, 5.0 Hz, 1 H), 4.40 (dd, J=12.0, 5.0 Hz, 1 H), 7.0-7.10 (m, 1 H), 7.20-7.40 (m, 3 H). FAB-MS: calculated for C24H5NO 354; found 354 (M+H, 100%). Rf=0.32 (10% ethyl acetate/n-hexane). mp 81-83° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7]2[C:12]3=[N:13][CH:14]=[C:15]([C:16]#[N:17])[N:11]3[N:10]=[C:9]([S:18][CH3:19])[N:8]=2)[CH2:5][CH2:4]1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>CN(C=O)C>[CH:3]1([N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:7]2[C:12]3=[N:13][CH:14]=[C:15]([C:16]#[N:17])[N:11]3[N:10]=[C:9]([S:18][CH3:19])[N:8]=2)[CH2:4][CH2:5]1
Reactant: COc1ccc(CCl)cc1
Reactant: CSc1nc(NC2CC2)c2ncc(C#N)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nc(SC)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
(I2C): Sodium hydride (60% in mineral oil, 0.890 g, 22.02 mmol) was added to a solution of 4-(cyclopropylamino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.39 g, 13.76 mmol) in DMF (110 mL) at room temperature and the resulting mixture was stirred for 30 min. 1-(chloromethyl)-4-methoxybenzene (3.05 mL, 22.02 mmol) was added and the reaction mixture was heated at 80° C. for 2 h. The reaction solution was quenched with ethyl acetate/sodium bicarbonate saturated solution. The organic phase was separated, washed with 10% lithium chloride solution, dried and concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (220 g column, eluting with 5-20% ethyl acetate/hexanes). 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (4.59 g) was obtained as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)=[O:7].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2cccc(N)c2)cc1OC
Yield: 38.9 %

Procedure:
To a solution of 3,4-dimethoxy-3'-nitrobenzophenone (0.5 g, 1.7 mmol) in 40 mL of ethyl acetate was added 0.05 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 1.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 10% ethyl acetate/methylene chloride) to afford 0.17 g (38%) of the product as a yellow solid: mp 157-175 ° C.; 1H NMR (CDCl3) δ 7.56-6.80 (m, 7H); 3.95 (s, 3H), 3.94 (s, 3H); 13C NMR (CDCl3) δ 195.7, 152.9, 148.9, 146.4, 139.3, 130.3, 128.9, 125.4, 120.1, 118.4, 115.6, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C15H15NO3. Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.00; H, 6.10; N, 5.13.
Reaction SMILES: S(Cl)([Cl:3])=O.F[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH:11]([C:16]([OH:18])=O)[CH2:10][CH2:9]2>C1(C)C=CC=CC=1.CN(C=O)C>[O:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:11]1[C:16]([Cl:3])=[O:18]
Reactant: O=C(O)C1CCc2cc(F)ccc2O1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCc2ccccc2O1
Temperature: 65 °C
Reaction time: 1.17 h
Yield: 124.8 %

Procedure:
Thionylchloride (109.21 g, 918 mmol) was added under nitrogen atmosphere at 20-25° C. to a suspension of 6-fluorochroman-2-carboxylic acid (90.00 g, 459 mmol) and DMF (1.68 g, 23 mmol) in toluene (635 ml). Afterwards, the suspension was heated to an internal temperature of 60-70° C., whereupon a clear yellow solution was obtained under simultaneous evolution of a gas. The reaction was completed within 70 min at this temperature, and the mixture was then concentrated in vacuum (bath temperature 45-50° C., pressure≦35 mbar) to yield the chroman-2-carboxylic acid chloride as a yellow oil (112.65 g). The crude product was dissolved in methylene chloride (65 ml) and added slowly under nitrogen atmosphere to a solution of Meldrum's acid (70.90 g, 482 mmol) and pyridine (72.62 g, 918 mmol) in methylene chloride (261 ml) at an internal temperature of 0-10° C. The reaction mixture was allowed to warm to 20-25° C. within 50 min. and stirred at this temperature for additional 30 min. Methylene chloride (325 ml) and water (325 ml) were then added to the formed brown suspension. The two phase mixture was stirred for 5 min, separated, and the organic layer was subsequently extracted twice with water (200 ml each), then with 2N aqueous HCl solution (250 ml) and finally with water (250 ml). After drying over Na2SO4, the organic layer was filtrated and concentrated in vacuo (≦50 mbar) to give a brown, viscous oil (170.76 g), which crystallized after 10 min at room temperature. The solid was slurried at 20-25° C. in diisopropyl ether (500 ml) for 2 h. After filtration of the suspension, the wet product was washed with diisopropyl ether (70 ml) and dried in vacuo (13 h at 40° C.) to give a yellow-ocher colored solid (yield: 114.71 g, HPLC-purity: 96.98%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28](C)[CH:29]=1>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:16]
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccccc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3,5-dimethylphenylboronic acid in step 1.F.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>C(Cl)(Cl)Cl>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33][C:34]([NH:20][C:19]1[CH:21]=[C:22]([CH3:23])[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[CH3:24])=[O:35]
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Nc4ccc(F)cc4F)cc3C)c2cc1OC
Yield: 97 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (200 mg) was dissolved in chloroform (15 ml), and 2,4-difluorophenyl isocyanate (88 μl) was then added to the solution. The mixture was heated under reflux for one hr. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (4/1) to give 287 mg (yield 97%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([NH:6][CH:7]([C:14]1([N:19]([CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCCCC>[Cl:1][C:2]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([NH:6][CH:7]([C:14]1([N:19]([CH2:21][CH2:22][OH:23])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN(CCO)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (±)-2-chloro-N-[{1-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)(methyl)amino]cyclopentyl}(phenyl)methyl]-3-(trifluoromethyl)benzamide D30 (0.390 g; 0.685 mmol) in THF (10 ml) was added tetrabutylammonium fluoride (1M solution in THF 1.6 ml; 1.6 mmol). The reaction mixture was allowed to stir at room temperature for 4 h. The desired product was isolated by column chromatography on silica using 20% to 50% ether in n-pentane, the solvent was reduced in volume by evaporation in vacuo and loaded onto an SCX cartridge. Washing with DCM, then methanol followed by elution with 1M ammonia in methanol afforded the title product (170 mg, 73%). Mass Spectrum (Electrospray LC/MS). Found 455 (MH+). C23H2635ClF3N2O2 requires 454. Ret. time: 2.09 min.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]3[C:27]4[CH:28]=[CH:29][C:30]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6C(OC(C)(C)C)=O)=[N:35][CH:36]=5)=[CH:31][C:26]=4[CH2:25][N:24]([CH3:49])[CH2:23][C:22]=3[CH:50]=2)=[CH:15][N:14]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl.CO>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]3[C:27]4[CH:28]=[CH:29][C:30]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][NH:38]6)=[N:35][CH:36]=5)=[CH:31][C:26]=4[CH2:25][N:24]([CH3:49])[CH2:23][C:22]=3[CH:50]=2)=[CH:15][N:14]=1
Reactant: CN1Cc2cc(-c3cnc(C4CCCN4C(=O)OC(C)(C)C)[nH]3)ccc2-c2ccc(-c3cnc(C4CCCN4C(=O)OC(C)(C)C)[nH]3)cc2C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CN1Cc2cc(-c3cnc(C4CCCN4)[nH]3)ccc2-c2ccc(-c3cnc(C4CCCN4)[nH]3)cc2C1
Temperature: 50 °C
Yield: 147.7 %

Procedure:
To the solution of 3,9-bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine (24 mg) in DCM/MeOH (1.6 ml/0.75 ml) was added hydrochloric acid in dioxane (0.44 ml, 1.7 mmol). The mixture was heated at 50° C. for 3 hours and the solvents were evaporated under reduced pressure. The mixture was diluted with water and acetonitrile, and was freezer-dried to give 3,9-bis-[2-(pyrrolidin-2-yl)-3H-imidazol-4-yl]-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine as brown powder (25 mg). m/z: 480.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=[C:7]([CH2:22][O:23][CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:6]=1)=[O:4]>CO>[CH3:29][Si:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][O:25][CH2:24][O:23][CH2:22][C:7]1[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1nc(COCOCC[Si](C)(C)C)ccc1C(=O)c1ccc2c(c1)OCO2
Solvent: CO
Product: C[Si](C)(C)CCOCOCc1ccc(C(=O)c2ccc3c(c2)OCO3)c(C(=O)O)n1

Procedure:
6-(2-Trimethylsilylethoxymethoxymethyl)-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-carboxylic acid methyl ester was subjected to alkaline hydrolysis in methanol to give 6-(2-trimethylsilylethoxymethoxymethyl)-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-2-carboxylic acid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4]CC1>CC#N.Cl>[F:17][C:16]([F:18])([F:19])[C:15]([NH:14][CH:11]([CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)[CH2:12][CH3:13])=[O:20]
Reactant: CCC(NC(=O)C(F)(F)F)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: CCC(NC(=O)C(F)(F)F)C1CCC(=O)CC1

Procedure:
A solution of N-(1-{1,4-dioxaspiro[4.5]decan-8-yl}propyl)-2,2,2-trifluoroacetamide (89 mg, 0.30 mmol, 1.00 equiv) in CH3CN (5 mL) and HCl (2M, 1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of aq. sodium bicarbonate (1M). The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35].N>C(Cl)Cl.C(O)(=O)C>[CH3:31][O:32][CH2:33][C:34]([NH:21][C:17]1[CH:16]=[C:15]([O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:20]=[CH:19][N:18]=1)=[O:35]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Reactant: COCC(=O)Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a stirred solution of 4-(4-nitronaphthalen-1-yloxy)pyridin-2-amine (10) (40.0 g, 135 mmol) and DIPEA (48.1 mL, 270 mmol) in DCM (600 mL) at 0° C., under nitrogen, was added dropwise methoxyacetyl chloride (18.53 ml, 203 mmol). The mixture was warmed to RT and after 1 hr a solution of ammonia (100 mL, 7 M in MeOH) was added and stirring continued for 30 min, during which time a precipitate formed. The mixture was evaporated in vacuo and water (1 L) was added to the residue to provide a red suspension. Glacial acetic acid was added dropwise until a yellow colour persisted (˜5 mL). The solid was collected by filtration and washed with water (300 mL) to afford 2-methoxy-N-(4-(4-nitronaphthalen-1-yloxy)pyridin-2-yl)acetamide (11) (44.1 g, 90%) as a yellow solid: m/z 354 (M+H)+ (ES+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[C:12]1([CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[I:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:20])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][CH3:23])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(N)ccc1I
Reactant: CCC(C(=O)Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
0.823 g (3.14 mmol) of the compound from Example 4A are dissolved in 10 ml of dichloromethane at RT, and 0.688 mg (3.77 mmol) of 2-phenylbutyryl chloride and 0.298 mg (3.77 mmol) of pyridine are added. The mixture is stirred at RT over after. Ethyl acetate is added, and the mixture is extracted with water. The organic phases are dried over magnesium sulfate and freed of solvent under reduced pressure. The residue is purified by chromatography on a silica gel column (mobile phase ethyl acetate:cyclohexane 2:1). 0.943 g (72% of theory) of product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:29]5[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=5[F:27])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: COc1ccc(B(O)O)c(F)c1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(OC)cc5F)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-4-methoxy-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.92 min; Mass spectrum (ESI+): m/z=505 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[NH2:12].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=[S:23]>C1COCC1>[NH2:12][C:3]1[C:4]([F:11])=[C:5]([F:10])[C:6]([F:9])=[C:7]([F:8])[C:2]=1[NH:1][C:22]([NH:21][C:15]1[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])=[S:23]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1c(N)c(F)c(F)c(F)c1F
Solvent: C1CCOC1
Product: Nc1c(F)c(F)c(F)c(F)c1NC(=S)Nc1c(Cl)cccc1Cl
Yield: 88.4 %

Procedure:
1-(2-Amino-3,4,5,6-tetrafluorophenyl)-3-(2,6-dichlorophenyl)thiourea was obtained by boiling a mixture of 1 g of 1,2-diamino-3,4,5,6-tetrafluorobenzene with 1.13 g of 2,6-dichlorophenyl isothiocyanate in 30 ml of anhydrous THF for 4 hours. After distilling off the solvent, the thiourea was brought to crystallization under diisopropyl ether and 1.88 g of 1-(2-amino-3,4,5,6-tetrafluorophenyl)-3-(2,6-dichloro-phenyl)thiourea were obtained as a crystalline solid. M.p.: >300° C.