Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:31]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:33]=[N:32][O:31][CH:35]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: OB(O)c1cnoc1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cnoc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), isoxazol-4-boronic acid (73 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (127 mg, 44%) as an orange solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])[C:4](OCC)=[O:5].C(N(CC)CC)C.Cl[Si](C)(C)C>O1CCCC1>[Si:12]([O:11][C@@H:9]([C@@H:3]1[CH2:2][NH:1][C:4]1=[O:5])[CH3:10])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCOC(=O)[C@@H](CN)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CNC1=O
Reaction time: 24 h
Yield: 47.3 %

Procedure:
To a solution of ethyl (2S,3R)-2-aminomethyl-3-(t-butyldimethylsilyloxy)butanoate (1.38 g) and triethylamine (0.84 ml) in tetrahydrofuran (10 ml) was added dropwise chlorotrimethylsilane (0.76 ml) at room temperature. After stirring for 1 day, the precipitate was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml) and 1.1N t-butylmagnesium chloride in tetrahydrofuran (15 ml) was added dropwise thereto at room temperature. After stirring for 30 minutes, the reaction mixture was quenched with water (10 ml), and diluted with ethyl acetate (50 ml) and 1N hydrochloric acid in water (20 ml). The aqueous layer was separated and extracted twice with ethyl acetate (25 ml×2) and the combined organic layer was washed in turn with 1N hydrochloric acid in water (20 ml), saturated aqueous sodium bicarbonate (20 ml), water (20 ml) and brine (20 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was column-chromatographed on silica gel (hexane-ethyl acetate=3:1) to give (3S)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-azetidin-2-one (0.543 g).
Reaction SMILES: C([O:8][C@@H:9]([C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)O)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH2:10]([C@H:9]([C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)[OH:8])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(c1ccccc1)[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Agent: [Pd]
Solvent: CC(=O)O
Product: O[C@H](Cc1ccccc1)[C@H]1COC2(CCCCC2)O1
Yield: 65.3 %

Procedure:
(iv)(a) A solution of 130 mg (0.35 mmol) of β(R)-benzyloxy-α(RS)-phenyl-1,4-dioxaspiro[4,5]decane-2(R)-ethanol in 3 ml of acetic acid was hydrogenated over 10% palladium-on-carbon under a pressure of about 4.1 atmospheres for 2 days. The catalyst was removed by filtration and the filtrate was evaporated. The crude product was purified by flash chromatography on silica gel using 2% methanol in dichloromethane for the elution. There were obtained 60 mg of α(R)-benzyl-1,4-dioxaspiro[4,5]decane-2(R)-methanol in the form of a colourless oil; MS: m/e 262 [M]+.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[NH:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[NH2:25]>C(O)(=O)C>[C:8]1([C:7]2[C:6]([CH2:5][C:4]([OH:3])=[O:23])=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:24]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[N:25]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)Cc1c(-c2ccccc2)nn(-c2cccnc2)c1-c1ccccc1
Yield: 61.2 %

Procedure:
8.7 grams 3,3-dibenzoyl-propionic acid ethyl ester, 5.0 grams 3-hydrazino-pyridine and 6.0 grams glacial acetic acid were mixed and the mixture heated to the boiling temperature under reflux for 5 hours. The reaction product was further processed by a procedure analogous to that described in Example (2a). 6.1 grams 3,5-diphenyl-1-(3-pyridyl)-pyrazol-4-acetic acid, melting at 185°-187° C., were obtained, representing a yield of 62%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[N:4][C:5](Br)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[F-].[Cs+]>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>[NH2:1][C:2]1[C:3]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[N:4][C:5]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(OC)nc2)c1N
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)nc2)c1N
Temperature: 80 °C
Yield: 67.6 %

Procedure:
A mixture of methyl 3-amino-6-bromo-6′-methoxy-2,3′-bipyridine-4-carboxylate (165 mg, 0.49 mmol), 4-methoxyphenylboronic acid (89 mg, 0.59 mmol), cesium fluoride (178 mg, 1.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) in a vial was flushed with nitrogen. Dimethoxyethane (2.4 mL) was added and the reaction was heated at 80° C. overnight. It was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic phase was separated, washed with brine, and dried with sodium sulfate. The solvent removed and the major product was isolated by silica gel radial chromatography (step gradient with hexane containing 5 to 20% ethyl acetate). This gave methyl 3-amino-6′-methoxy-6-(4-methoxyphenyl)-2,3′-bipyridine-4-carboxylate (121 mg, 68% yield) as a yellow solid. MS (ESI) m/z 366.1 (M+H). 1H NMR (CDCl3) δ ppm 8.57 (1H, d, J=2.44 Hz), 8.05 (1H, s), 7.96 (1H, dd, J=8.55, 2.44 Hz), 7.88-7.93 (2H, m), 6.92-6.97 (2H, m), 6.88 (1H, d, J=8.55 Hz), 5.88 (2H, s), 4.00 (3H, s), 3.96 (3H, s), 3.84 (3H, s).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:32])([F:19])[F:33])[CH:23]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Product: O=C(Cc1cccc(OC(F)(F)F)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-[3-(trifluoromethoxy)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.31 (d, J=7.7, 1H), 8.04 (d, J=7.8, 1H), 8.02-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.51 (t, J=7.9, 1H), 7.45-7.37 (m, 2H), 7.29 (d, J=8.2, 1H), 3.85-3.79 (m, 4H), 3.76 (s, 2H), 3.14-3.05 (m, 4H); MS (ESI−) M/Z 447 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:12](=[O:13])[CH2:11][CH2:10][S:9][C:8]1=[S:14].[BH4-].[K+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:14])[S:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: O=C1CCSC(=S)N1c1ccccn1
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCCCSC(=S)Nc1ccccn1
Reaction time: 1 h
Yield: 53.5 %

Procedure:
The procedure of Example 24 is followed, but a suspension of 3-(pyrid-2-yl)-2-thioxo-perhydro-1,3-thiazin-4-one (22.4 g) in methanol (300 cc) and a solution of potassium borohydride (10.8 g) in distilled water (75 cc) are used as the starting materials at a maximum of 40° C. The reaction is allowed to proceed for 1 hour at between 25° and 40° C. The reaction mixture is evaporated to dryness and the residue (21.5 g) is dissolved in a mixture of ethyl acetate (70 cc) and cyclohexane (30 cc). The solution is chromatographed on silica (0.2-0.5 mm) (300 g) distributed in a column of diameter 4.5 cm. Elution is carried out with a mixture of ethyl acetate (520 cc) and cyclohexane (180 cc), this eluate being discarded, and then with a mixture of ethyl acetate (1,660 cc) and cyclohexane (540 cc). The eluate which is collected is evaporated to dryness under reduced pressure (20 mm Hg) at 45° C. 3-Hydroxypropyl pyrid-2-yldithiocarbamate (12.2 g), which melts at 93° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([CH3:26])([CH3:25])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([CH3:26])([CH3:25])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(Cc1c[nH]c2c(C=CS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(Cc1c[nH]c2c(CCS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Yield: 79.5 %

Procedure:
To a solution of {2-[7-(2-methanesulfonyl-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (0.40 g, 1.02 mmol) in methanol (20.0 mL) is added 10% Pd/C (0.10 g) in methanol (2.0 mL). The reaction mixture is purged with hydrogen and hydrogenation is carried out with a hydrogen balloon overnight. The reaction mixture is filtered and the filtrate is evaporated to dryness to give 320 mg of {2-[7-(2-methanesulfonyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (80%). FDMS m/e=395.2 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>C(#N)C>[CH3:1][O:2][C:3]([C@H:4]([NH:5][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:10]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: COC(=O)[C@@H](CC(C)C)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a solution of D-Leucine methylester (1.58 g, 10.9 mmol) in acetonitrile (35 mL) was added 1,3-propanesultone (1.21 g, 9.9 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, recrystallized from EtOH and dried in vacuo, affording the title compound (1.59 g, 60%). 1H NMR (D2O, 500 MHz) δ ppm 3.98 (m, 1H), 3.70 (s, 3H), 3.11 (m, 2H), 2.85 (m, 2H), 2.00 (m, 2H), 1.72 (m, 1H), 1.60 (m, 2H), 0.81 (m, 6H). 13C (D2O, 125 MHz) δ ppm 170.51, 58.78, 53.69, 47.97, 45.36, 38.09, 24.34, 22.07, 21.51, 20.82. [α]D=+13.1° (c=0.0019 in water), ES-MS 266 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([NH2:23])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([NH:23][C:37](=[O:39])[CH3:38])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2
Reactant: NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Yield: 95 %

Procedure:
A solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-amine (6 mg, 0.011 mmol, 1 eq.) in 1 mL of acetic anhydride and 1 mL of pyridine was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 6 mg (95%) of desired N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}acetamide. Compound was determined to be 95% pure by 1H NMR. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.95-2.11 (m, 3 H) 2.15-2.39 (m, 2 H) 2.60 (d, J=13.56 Hz, 2 H) 3.69 (br. s., 2 H) 5.23 (br. s., 2 H) 5.71 (br. s., 1 H) 7.10-7.60 (m, 13 H) 8.31-8.48 (m, 1 H), [M−H]− 554.5.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[N:12][C:10]=3[NH:11][C:7]=2[CH:6]=[N:5][C:4]=1[C:16]#[N:17])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:25][C:14]1[CH:13]=[N:12][C:10]2[NH:11][C:7]3[CH:6]=[N:5][C:4]([C:16]#[N:17])=[C:3]([CH2:1][CH3:2])[C:8]=3[C:9]=2[CH:15]=1
Reactant: CCc1c(C#N)ncc2[nH]c3ncccc3c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c(C#N)ncc2[nH]c3ncc(Br)cc3c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To a solution of 5-ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (48 mg, 0.21 mmol) in DMF (1 mL) was added NBS (54 mg, 0.30 mmol) then the reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with saturated aqueous sodium carbonate (10 mL). The aqueous phase was washed with DCM (2×10 mL), the combined organic phase was washed with saturated brine (2×10 mL) and concentrated in vacuo to afford the title compound as a yellow solid (50 mg, 79%). LCMS (Method B): RT=3.34 min, M+H+=301/303.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].C([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=O)C>>[O:33]=[C:29]1[NH:30][CH2:31][CH2:32][N:28]1[C:2]1[CH:7]=[C:6]([N:30]2[CH2:31][CH2:32][NH:28][C:29]2=[O:33])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Br)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3N3CCNC3=O)CC2)c(C)c1
Yield: 26.9 %

Procedure:
Using (2,4-dibromophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (258 mg) described in Preparation Example 237 and 1-acetylimidazolidin-2-one (219 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (71 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[C:28]([O:36][CH3:37])=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[F:26][C:27]1[C:28]([O:36][CH3:37])=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1c(F)cccc1B(O)O
Solvent: CN(C)C=O
Product: COc1c(F)cccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 3-fluoro-2-methoxyphenylboronic acid (CAS RN 762287-59-2) and using DMF as reaction solvent. Off-white solid (27%). MS (ESI): m/z=473.2 [M+H]+.
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[Cl:10][C:11]1[C:19]2[O:18][CH:17]([CH3:20])[CH2:16][C:15]=2[C:14]([N:21]=[C:22]=[O:23])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:10][C:11]1[C:19]2[O:18][CH:17]([CH3:20])[CH2:16][C:15]=2[C:14]([N:21]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:22]2=[O:23])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CNC
Reactant: CC1Cc2c(N=C=O)ccc(Cl)c2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1Cc2c(N3C(=O)CN(C)C3=O)ccc(Cl)c2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.30 g of sarcosine ethyl ester hydrochloride was added over 5 minutes to a mixture of 2.10 g of 34A, 1.52 g of triethylamine and 60 mL of methylene chloride, under nitrogen at 25°-30° C. The mixture was stirred at room temperature for 24 hours, then diluted with 100 mL of methylene chloride, washed with water, then brine, dried (MgSO4) and stripped of solvent. The residue was dissolved in 70 mL of a 1:1 v:v mixture of ethanol and 2N hydrochloric acid. The solution was refluxed for 4 hours, the resulting mixture was stirred at room temperature overnight, stripped of volatiles, diluted with water and extracted with methylene chloride. The extract was dried (MgSO4) and stripped of solvent. The residue was purified by flash chromatography over silica gel with a 1:2 v:v mixture of hexane and ethyl acetate as eluent to give the title compound, as a glass/sticky solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:10]([O:9][C:3]1[C:2]([Br:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ncc(Cl)cc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: Clc1cnc(OCc2ccccc2)c(Br)c1
Temperature: 70 °C

Procedure:
A mixture of 3-bromo-5-chloro-2-hydroxypyridine (81 g), benzyl bromide (52 mL) and silver carbonate (97 g)in benzene (1 L) was heated at 70° C. for 1 h. The mixture was cooled to r.t. and then filtered through a bed of celite. The filtrate was concentrated and the residual off-white solid was recrystallized from hexane to provide the title compound as a white solid (102 g).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11](=[O:17])[CH2:10]2.O>CS(C)=O>[O:17]1[CH2:2][C:11]21[CH:12]1[CH2:15][CH2:16][N:9]([CH2:14][CH2:13]1)[CH2:10]2
Reactant: O=C1CN2CCC1CC2
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C1CN2CCC1C1(CO1)C2
Temperature: 67.5 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A mixture of trimethylsulfoxonium iodide (16.10 g, 73.2, mmol) and a dispersion of sodium hydride (60% in oil, 3.00 g, 75.0 mmol) in anhydrous dimethyl sulfoxide was stirred at room temperature under nitrogen for 30 minutes. Quinuclidin-3-one (7.05 g, 56.3 mmol) was then added as a solid portionwise, and the resulting mixture was stirred at 65-70° C. under nitrogen for 1 hour. The reaction mixture was cooled, water was added (200 mL), and the resulting solution was extracted with chloroform (3×200 mL). The chloroform extracts were combined, and back-extracted with water (4×200 mL). The chloroform layer was then dried (MgSO4), filtered, and evaporated under reduced pressure to afford spiro[1-azabicyclo[2.2.2]octane-3,2'-oxirane] (6.51 g, 46.8 mmol, 83%) as a clear, colorless liquid. To a stirred solution of spiro[1-azabicyclo[2.2.2]octane-3,2'-oxirane] (5.3 g, 38.1 mmol) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added dropwise a solution of borane in tetrahydrofuran (1.0 M, 38.1 mL, 38.1 mmol), and resulting solution was stirred at 0° C. under nitrogen for 30 minutes. Brine (100 mL) was added cautiously to the reaction solution, and the resulting aqueous mixture was extracted with ethyl acetate (2×100 mL). The organic extracts were combined, dried (MgSO4), filtered, and evaporated under reduced pressure to afford the title compound (4.3 g, 28.1 mmol, 74%) as a white solid: electrospray MS 152 ([M-H]+, 15).
Reaction SMILES: B(Br)(Br)[Br:2].CO[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])[O:16][CH3:17].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:2][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: BrB(Br)Br
Reactant: COCc1ccccc1NC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1ccccc1CBr
Reaction time: 2 h

Procedure:
38.6 g (150 mmol) of boron tribromide are added dropwise to 10 g (51 mmol) of methyl N-(2-methoxymethylphenyl)-carbamate (Example 2b) in 100 ml of methylene chloride. Stirring is carried out for 2 hours, after which the vigorously stirred reaction mixture is added dropwise to a solution of 11.8 g (0.17 mol) of NaHCO3 in water. The organic phase is separated off and the aqueous phase is extracted once with methylene chloride and once with ethyl acetate. The combined organic phases are dried over MgSO4 and evaporated down. 9.5 g (39 mmol=76%) of the title compound are obtained as a colorless solid. mp.=132° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[S:17][C:18]=1[Cl:19]>>[Br:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[S:17][C:18]=1[Cl:19]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(Br)c(Cl)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-bromo-5-chlorothiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (40.9 mg) with purity >90%. MS pos) m/z 445.0, 447.0.
Reaction SMILES: [C:1]([CH:5]1[C:9](O)=[CH:8][O:7][C:6]1=[O:11])([CH3:4])([CH3:3])[CH3:2].O.[NH2:13][NH2:14]>CCO>[C:1]([C:5]1[C:6](=[O:11])[N:13]=[N:14][C:9]=1[CH2:8][OH:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)C1C(=O)OC=C1O
Solvent: O
Solvent: CCO
Product: CC(C)(C)C1=C(CO)N=NC1=O
Yield: 101.9 %

Procedure:
3-tert-Butyl-4-hydroxy-2-furanone (6.6 g, 42 mmol) was dissolved in EtOH (75 mL) with hydrazine hydrate (6.6 mL, 0.21 mol) and was heated at reflux for 16h. The solvent was evaporated and the residue azeotroped with xylene ( 3×50 mL) to afford the title compound (7.2 g, 100%) as a colourless solid. mp 169-172° C. 1H NMR (360 MHz, d6-DMSO) δ1.26 (9H, s), 4.41 (2H, d, J=5.2 Hz), 4.97-5.01 (1H, m), 9.30 (1H, br s), 11.05 (1H, br s). MS (ES+) 171 (M+1).