Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[F:19][C:20](I)([F:25])[C:21]([F:24])([F:23])[F:22]>[Cu].CS(C)=O>[CH3:13][N:12]([CH3:14])[CH2:11][CH2:10][CH2:9][N:8]([CH3:15])[C:5]1[CH:6]=[CH:7][C:2]([C:20]([F:25])([F:19])[C:21]([F:24])([F:23])[F:22])=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: FC(F)(F)C(F)(F)I
Reactant: CN(C)CCCN(C)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cu]
Solvent: CS(C)=O
Product: CN(C)CCCN(C)c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 22 h

Procedure:
To a pressure vessel was added N-(4-Bromo-2-nitro-phenyl)-N, N′,N′-trimethyl-propane-1,3-diamine (Step 1, 5.0 g, 15.8 mmol), copper powder (10.0 g, 158 mmol), and 20 mL DMSO. Pentafluoroethyl iodide (7.8 g, 31.6 mmol) was bubbled in and the vessel sealed. The mixture was then heated to 120° C. and vigorously stirred for 22 h. The reaction was cooled to 0° C. and filtered through a Buchner funnel, rinsing with EtOAc. The filtrate was then washed once with saturated aqueous NaHCO3, twice with water, once with brine, and then dried over Mg2SO4. The crude mixture was then purified by silica gel chromatography using a 10% MeOH/CH2Cl2 gradient to yield the title compound as a brown oil. MS (M+H)+=356; Calc'd 355.30 for C14H18F5N3O2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: C1COCCO1
Product: Nc1nc(NCCCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and 3-phenylpropylamine in dioxane. ES-MS m/e (%): 331 (M{37C }+H+, 30), 329 (M{35Cl}+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[CH:16]1([C@H:19]([NH2:21])[CH3:20])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:21][C@@H:19]([CH:16]3[CH2:18][CH2:17]3)[CH3:20])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@@H](N)C1CC1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 500 mg, 1.821 mmol), (R)-1-cyclopropylethanamine HCl salt (277 mg, 2.277 mmol) and DIPEA (0.795 mL, 4.55 mmol) in NMP (5 mL) was heated to 100° C. for 4 hr. The reaction mixture was added 10 mL of water and stirred for 10 minutes. The solid was collected by vacuum filtration and dried to afford the title compound (485.4 mg, 79%). HPLC (condition G): retention time=2.29 min. LCMS (condition B): m/z 324.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (1 H, d, J=8.1 Hz), 8.22 (1 H, s), 7.84 (1 H, d, J=1.8 Hz), 6.99 (1 H, d, J=1.8 Hz), 3.78-3.91 (1H, m), 1.29 (3 H, d, J=6.2 Hz), 0.99-1.11 (1 H, m), 0.42-0.53 (2 H, m), 0.33-0.40 (1H, m), 0.22-0.29 (1 H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][OH:13].B(F)(F)F.CCOCC.[C:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=O)[CH2:24][CH3:25]>ClCCl>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][C:23]1([CH2:24][CH3:25])[C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH2:11][CH2:12][O:13]1)=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)[CH3:32]
Reactant: Cc1ccc2[nH]cc(CCO)c2c1
Reactant: CCOC(=O)CC(=O)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC1(CC)OCCc2c1[nH]c1ccc(C)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.7 %

Procedure:
To a solution of 2-(5-methyl-1H-indol-3-yl)-ethanol (0.48 g, 2.7 mmol) in dichloromethane (10 mL) was added boron trifluoride diethyl etherate (0.468 g, 3.3 mmol), followed by ethyl propionylacetate (0.649 g, 4.5 mmol). The mixture was stirred at room temperature for 5 hours. It was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.421 g (52%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3) δ 8.90 (br, 1H), 7.28 (s, 1H), 7.24 (d, 1H), 6.99 (d, 1H), 4.16 (m, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 2.98 (d, 1H), 2.88 (d, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.44 (s, 3H), 2.12 (m, 1H), 1.98 (m, 1H), 1.25 (t, 3H), 0.80 (t, 3H); ESI (−) MS m/e=300 (MH−).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11]
Reactant: O=[N+]([O-])O
Reactant: O=C1NCc2c(Br)cccc21
Agent: O=S(=O)(O)O
Product: O=C1NCc2c(Br)ccc([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A 0° C. solution of Example 1C (5 g, 23.6 mmol) in 10 mL sulfuric acid was treated with a solution of concentrated nitric acid (1.55 mL, 24.7 mmol) in 10 mL sulfuric acid via addition funnel. The resulting mixture was stirred at 0° C. for 1 hour, warmed to room temperature, stirred overnight, poured over ice, and filtered. The filter cake was washed with water and diethyl ether and then dried to give 5.39 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 4.39 (s, 2H); 7.88 (d, J=8.1 Hz, 1H); 8.05 (d, J=8.5 Hz, 1H); 9.17 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10](O)=[O:11])=[C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([F:21])=[C:6]([F:22])[CH:5]=1)(=O)[CH3:2].O.[NH2:24][NH2:25].Cl>C1COCC1.CCOC(C)=O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:8]1[C:7]([F:21])=[C:6]([F:22])[CH:5]=[C:4]2[C:9]=1[C:10](=[O:11])[NH:25][N:24]=[C:1]2[CH3:2]
Reactant: CC(=O)c1cc(F)c(F)c(Nc2ccccc2Cl)c1C(=O)O
Reactant: NN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1n[nH]c(=O)c2c(Nc3ccccc3Cl)c(F)c(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of 6-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (62 mg, 0.19 mmol, prepared by the procedures described in Example 1) and hydrazine monohydrate (0.031 mL, 0.63 mmol) in THF (3 mL) was added catalytic amount of 1 N aqueous HCl (0.15 mL, 0.15 mmol) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture was diluted with EtOAc, and washed with water (2×) and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (53 mg, 86%) that was used directly without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[N:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]3)[N:7]=2)[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=12
Reactant: NC1CCC(O)CC1
Reactant: Clc1nccc(-c2cnc3ccccn23)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: OC1CCC(Nc2nccc(-c3cnc4ccccn34)n2)CC1
Temperature: 105 °C
Reaction time: 5 h
Yield: 54.7 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (30 mg) and 4-amino-cyclohexanol (45 mg) in NMP (1 mL) was stirred at 105° C. for 5 h. The reaction mixture was then cooled to RT and titurated with water. The resulting solid was filtered, washed with water and dried. The product was purified by ISCO using 100% DCM to 15% MeOH/DCM, and the pure fractions combined, concentrated, and titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide 4-(4-imidazo[1,2-a]pyridin-3-yl-pyrimidin-2-ylamino)-cyclohexanol (compound 11, 22 mg).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[N:6]([CH2:17][C:18]([O:20]CC)=[O:19])[C:5]1=[O:23])=[N+:2]=[N-:3].[OH-].[Na+].Cl>CO.O>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[N:6]([CH2:17][C:18]([OH:20])=[O:19])[C:5]1=[O:23])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCc2ccc(OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)N(CC(=O)O)C(=O)C(N=[N+]=[N-])CC2
Reaction time: 2 h

Procedure:
A suspension of 3-azido-1-ethoxycarbonylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (13.8 g) in methanol (75 ml) was treated with a solution of sodium hydroxide (1.9 g) in water (75 ml). The reaction mixture was stirred at 40°-45° for 2 hours. Water (100 ml) was added and the mixture was acidified with concentrated hydrochloric acid (10 ml) and extracted with methylene chloride (3×75 ml). The combined methylene chloride solutions were dried over magnesium sulfate and evaporated at reduced pressure to give 3-azido-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 145°-147°.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[N:4][CH:3]=1.[CH:20]1([Mg]Br)[CH2:22][CH2:21]1>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([CH:20]2[CH2:22][CH2:21]2)([OH:8])[C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(c2ncc(Br)s2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexanecarboxylate (518 mg, 1.49 mmol) in anhydrous THF (16 ml) was treated dropwise over 20 min with cyclopropylmagnesium bromide (1.49 mmol, 0.5 M in tetrahydrofuran, 2.99 mL) at 0° C. under a nitrogen atmosphere. After stirring 1 h at room temperature, additional cyclopropylmagnesium bromide (2.23 mmol, 0.5 M in tetrahydrofuran, 4.48 mL) was added dropwise over 20 min at 0° C. and then the mixture was allowed to reach room temperature. After 4 h the mixture was diluted with saturated ammonium chloride and ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0% to 20% EtOAc in hexanes) to afford racemic ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)(cyclopropyl)hydroxymethyl]cyclohexanecarboxylate as a white solid. Two enantiomers were separated by chiral super critical fluid chromatography (Chiral Technology AS, 2.1×25 cm, 10 uM, 45/55 MeOH/CO2, Flow Rate: 70 mL/min, 14 min run time, WL: 220 nm) Elution was observed at 7.91 min and 10.78 min. Pooled fractions of each peak were concentrated under reduced pressure.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.[CH3:28][O:29][C:30]1[CH:42]=[CH:41][C:33]([CH2:34][C@H:35]([CH:38]([CH3:40])[CH3:39])[CH2:36]O)=[CH:32][C:31]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48]>ClCCl>[CH3:28][O:29][C:30]1[CH:42]=[CH:41][C:33]([CH2:34][C@H:35]([CH:38]([CH3:40])[CH3:39])[CH2:36][Br:20])=[CH:32][C:31]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48]
Reactant: COCCCOc1cc(C[C@@H](CO)C(C)C)ccc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCCOc1cc(C[C@@H](CBr)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
Triphenylphosphine (108.6 g) and, in portions, N-bromosuccinimide (73.7 g) are added in succession at 0° C., with stirring, to a solution of 2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butanol (102.2 g) in dichloromethane (2 liters). The batch is stirred for a further 18 hours at room temperature and is then concentrated under reduced pressure. The residue is purified by means of FC on silica gel (ethyl acetate/hexane 1:4). The title compound (102.2 g) is obtained in the form of a white solid: m.p. 52-53° C. (recrystallised from diethyl ether/hexane). Rf (ethyl acetate/hexane 1:1)=0.56. Anal. C17H27BrO3 (359.30): calc. C, 56.83; H, 7.57; Br, 22.24; found C, 56.81; H, 7.34; Br, 22.06.
Reaction SMILES: C([O:7][C:8]1[C:13](=[O:14])[N:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10][C:9]=1[C:19]([O:21]C)=O)(=O)C(C)(C)C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>CO>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:19]([C:9]2[N:10]=[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][N:12]3[C:13](=[O:14])[C:8]=2[OH:7])=[O:21])=[CH:26][CH:25]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc2ccccn2c(=O)c1OC(=O)C(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1nc2ccccn2c(=O)c1O
Temperature: 60 °C

Procedure:
Methyl 3-[(pivaloyl)oxy]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate was dissolved in methanol. p-Fluorobenzylamine (2 eqs.) was added and the reaction was stirred and heated to 60° C. for 2 hours. A precipitate had formed and further methanol and 1 eq. of triethylamine were added. After 2 more hours at 60° C. the reaction mixture was partitioned between EtOAc and 1 M HCl. The organic phase was extracted with 0.1 M aqueous NaOH. The aqueous phase was separated and acidified with 1 M HCl. The aqueous phase was extracted with EtOAc and the organic phase was dried over Na2SO4, filtered and concentrated to dryness. The title compound was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([OH:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:2][C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:12][C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c2ccccc2n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 186.4 %

Procedure:
2-carboxy-4-hydroxyquinoline (5 g, 1.0 eq) was dissolved in 50 mL DMF. Cesium carbonate (20 g, 2.3 eq) was added to the solution and the resulting reaction mixture was heated at 50° C. for 20 minutes. Benzyl bromide (10 g, 2.1 eq) was added. The resulting reaction mixture was stirred at 50° C. for 1 hour. Then the reaction mixture was poured into 500 mL ice-water, the precipitate was collected by filtration, and dried in vacuo to afford 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.1 g). 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.0 g) was dissolved in 50 mL THF, and 2 N LiOH solution (20 mL) was added, and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The solvent was then removed in vacuo, and the residue acidified by the addition of 2N NaHSO4 to pH 3–4. The white precipitate was collected to afford 2-carboxy-4-benzyloxyquinoline (7.2 g), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:42][Si:43]([CH3:50])([CH3:49])[CH2:44][CH2:45][O:46][CH2:47]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[N:37]([CH2:47][O:46][CH2:45][CH2:44][Si:43]([CH3:50])([CH3:49])[CH3:42])[C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (268 mg, 0.4 mmol) was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (142 μL, 0.8 mmol) to give 5-{4-[2-(4′-bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-2-(2-trimethylsilanyl-ethoxymethyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)C(C)C)(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>ClCCl.C(OCC)C>[Si:20]([O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][OH:10])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: OCc1ccccc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a solution of 1,2-benzenedimethanol (500 mg, 3.62 mmol), N,N-diisopropylethylamine (0.76 mL, 4.4 mmol) in 3.6 mL of dichloromethane was added tert-butyldimethylsilyl chloride (573 mg, 3.80 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 1 day. The reaction mixture was diluted with diethyl ether, and the solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 85/15) to obtain 2-[(tert-butyldimethylsilyloxy)methyl]benzylalcohol as a colorless oil (520 mg, 57%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH2:20][CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][N:21]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)[CH2:20][CH2:19]2
Reactant: O=[N+]([O-])c1cccc(CCBr)c1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCc1cccc([N+](=O)[O-])c1)CC2
Yield: 40.9 %

Procedure:
A mixture of 1-(2-bromoethyl)-3-nitrobenzene (2.3 g), 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride (2.3 g) and potassium carbonate (3 g) in DMF (50 ml) was heated at 50° for 12 h. The mixture was then filtered and the filtrate evaporated. The residue was then taken up in water, extracted with dichloromethane, dried, evaporated and purified by column chromatography eluting with dichloromethane/methanol (99:1) to give the title compound (1.4 g) as a yellow oil. NMR includes signals at d 3.6 (2H,s,N--CH2Ar), 3.75 (6H,s,OCH3).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23].O>C(Cl)Cl>[CH2:25]([O:24][C:22]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:23])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-benzyl-piperazine (1.97 ml) and NEt3 (1.9 ml) in DCM (100 ml) was added n-butyl chloroformate (1.47 ml). The mixture was stirred at RT for 2 h. Water was added, the org. phase separated, dried (Na2SO4) and evaporated off to give 3.13 g of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Br:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([CH:25]=[CH:26][C:18]=3[Br:17])[C:27]#[N:28])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: N#Cc1ccc(Br)c(C(=O)O)c1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3Br)CC2)c(F)c1
Yield: 49 %

Procedure:
Title compound was prepared according to procedure described in example K/step2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-bromo-5-cyano-benzoic acid, (49% yield, white solid, MS (m/e): 430 (M+, 100%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH3:8][O:9][C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13](B(O)O)=[CH:12][N:11]=1.O.C([O-])(O)=O.[Na+]>COCCOC.ClCCl>[CH3:8][O:9][C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([C:2]2[N:3]=[C:4]([CH3:7])[S:5][CH:6]=2)=[CH:12][N:11]=1
Reactant: Cc1nc(Br)cs1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: COc1ncc(-c2csc(C)n2)c(OC)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
4-bromo-2-methyl-1,3-thiazole (commercially available from Frontier, 300 mg, 1.685 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (5 ml). Pd(Ph3)4 (97 mg, 0.084 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 651 mg, 3.54 mmol) and 1M/H2O sol. of NaHCO3 (4.60 ml, 4.60 mmol) were added thereto. The reaction mixture was heated at 90° C. for 2.5 h and left at room temperature overnight. The mixture was then diluted with dichloromethane (20 ml) and washed with water (20 ml). The organic layer was separated through an hydrophobic frit and concentrated. The obtained crude was purified by flash chromatography eluting with Cyclohexane/AcOEt 8/2. 290 mg of the title compound were isolated as a white solid.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([N:7]([C:26]2[CH:31]=[CH:30][C:29](OC)=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:3][CH:2]=1.Cl.N1C=CC=CC=1.N1C=CC=CC=1.[F:53][C:54]([F:67])([F:66])[S:55]([O:58]S(C(F)(F)F)(=O)=O)(=[O:57])=[O:56]>>[F:53][C:54]([F:67])([F:66])[S:55]([O:58][C:29]1[CH:28]=[CH:27][C:26]([N:7]([C:4]2[CH:3]=[CH:2][C:1]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:6][CH:5]=2)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:31][CH:30]=1)(=[O:57])=[O:56]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(N(c2ccc(-c3ccccc3)cc2)c2c(-c3ccccc3)cccc2-c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(N(c2ccc(-c3ccccc3)cc2)c2c(-c3ccccc3)cccc2-c2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 14 h
Yield: 71.5 %

Procedure:
N-([1,1′-biphenyl]-4-yl)-N-(4-methoxyphenyl)-[1,1′:3′,1″-terphenyl]-2′-amine (13.6 g, 27.0 mmol) and pyridine hydrochloride (31.1 g, 270.0 mmol) were purged with nitrogen for overnight. The mixture was refluxed for 2 h. After cooling, the precipitate was filtered and washed by excess water. The solid dissolved in DCM was filtered through a silica pad and washed with DCM. The solvent was removed in vacuo. The residue was dissolved in DCM (100 mL) and cooled down to 0° C. After that, pyridine (8.7 mL, 108.0 mmol) and trifluoromethanesulfonic anhydride (9.1 mL, 54.0 mmol) were added at 0 0° C. The mixture was stirred for 14 h from 0° C. to room temperature. The reaction mixture was quenched by the addition of saturated K2CO3 solution and extracted with DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by re-crystallization in 20% toluene/heptane to afford 4-([1,1′-biphenyl]-4-yl([1,1′:3′,1″-terphenyl]-2′-yl)amino)phenyl trifluoromethanesulfonate (12.0 g, 72% yield over 2 steps) as a white solid.