Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([CH2:21]O)[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH3:23])=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:5]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:16]3[CH:15]=[C:20]([Cl:3])[CH:19]=[C:18]([CH3:21])[C:17]=3[N:14]=[C:13]2[CH3:23])=[CH:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc2ccc(CO)cc2n1Cc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)cc2c1nc(C)n2Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (2 ml) is added to a chloroform solution (30 ml) of 1-(biphenyl-4-ylmethyl)-6-hydroxymethyl-2-methylbenzimidazole (3.62 g), and the solution is stirred for one hour at 60° C. A sodium bicarbonate aqueous solution is added and the reaction is halted. The chloroform layer is washed with water and dried. After removing the solvent through evaporation under reduced pressure, ethyl acetate is added and crystallization is performed. After the crystals are separated through filtration and washed with ethyl acetate, they are dried and thus, 1-(biphenyl-4-ylmethyl)-6-chloro-methyl-2-methylbenzimidazole (2.04 g) is obtained. 1H-NMR (CDCl3, δ): 2.67 (3H, s), 4.71 (2H, s), 5.40 (2H. s), 7.12 (2H, d, J=8.2 Hz), 7.31-7.38 (3H, m), 7.43 (3, s), 7.52-7.58 (4H, m), 7.75 (1H, d, J=8.2 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].[SH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])([O-:3])=[O:2]
Reactant: COC(=O)CS
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CSCc1ccccc1[N+](=O)[O-]

Procedure:
A mixture of o-nitrobenzylchloride (17.2 g), methyl mercaptoacetate (8.9 ml), and potassium carbonate (27.6 g) was refluxed with stirring in acetone (200 ml) for 6 hours. The reaction mixture was filtered and evaporated to leave the title compound as an oil.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: BrCc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Brc1ccc(Cn2cncn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
DMF and KOH (3.3 g, 58 mmol) were stirred together at rt for 5 minutes before adding 1,2,4-triazole (1 g, 14.5 mmol). After a further 30 minutes, the reaction mixture was cooled to 0° C. and 1-bromo-4-bromomethyl-benzene (7.2 g, 29 mmol) was added dropwise over 5 minutes. The reaction mixture was heated to 60° C., then cooled to rt, extracted with ethyl acetate and water, and subsequently dried over K2CO3. The solvent was evaporated to yield yellow-white crystals, which, upon repeated recrystallisation, (ethylacetate/isohexane) yielded 0.60 g of the sub-title compound as white crystals (62% isolated yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:29])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[CH3:27][O:26][C:24]([CH:23]([OH:28])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:29])=[CH:17][CH:18]=1)=[O:25]
Reactant: COC(=O)C(O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 68.9 %

Procedure:
A mixture of 1.16 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 1.71 g of methyl 3-[4-(2-oxopropoxy)phenyl]lactate (prepared as described in Preparation 6) and 40 ml of benzene was heated under reflux for 3.5 hours, whilst the water being formed during the reaction was continuously removed. After completion of the reaction, the benzene used in the reaction was removed by distillation under reduced pressure, and the residue was dissolved in 50 ml of absolute methanol. 2.04 g of sodium cyanoborohydride were added, whilst ice-cooling, to the solution, and the resulting mixture was allowed to react overnight at room temperature. At the end of this time, methanol was removed by distillation under reduced pressure, and the resulting residue was mixed with ethyl acetate and with an aqueous solution of sodium chloride. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 1.9 g of the title compound having an Rf=0.30 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5].[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH:24]=1)[CH2:30][O:31][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Reactant: OCc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1OCc1cc(F)ccc1O
Temperature: 100 °C
Yield: 3.6 %

Procedure:
To a solution of 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (211.2 mg, 0.70 mmol) and 4-fluoro-2-(hydroxymethyl)phenol (100 mg, 0.70 mmol) in N-methyl pyrrolidinone (3 mL) was added cesium carbonate (687.8 mg, 2.1 mmol) and the mixture was heated at 100° C. for 2 hours. The reaction was cooled to 25° C., filtered and purified by reverse phase HPLC using a gradient of acetonitrile/water (10 to 99%) and HCl as a modifier to yield 2-[(5-fluoro-2-hydroxy-phenyl)methoxy]-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (159) (10.5 mg, 3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 10.49 (s, 1H), 10.04 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.33-7.23 (m, 2H), 7.05-6.91 (m, 2H), 6.91-6.79 (m, 2H), 6.61 (dd, J=7.4, 2.4 Hz, 1H), 4.96 (s, 2H) ppm. ESI-MS m/z calc. 422.09. found 423.3 (M+1)+; Retention time: 1.83 minutes (3 minutes).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH:15]([O:18][C:19]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:20]=1[C:21](Cl)=[O:22])([CH3:17])[CH3:16].N1C=CC=CC=1>O1CCOCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][C:21](=[O:22])[C:20]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:19]=1[O:18][CH:15]([CH3:16])[CH3:17])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: Cc1ccc(OC(C)C)c(C(=O)Cl)c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC(=O)c2cc(C)ccc2OC(C)C)c(C(C)=O)c1
Yield: 113.6 %

Procedure:
Methyl 3-acetyl-4-hydroxy-benzoate (6 g) in dioxane (100 ml) was reacted with 2-isopropoxy-5-methyl-benzoyl chloride (10 g) in the presence of pyridine (10 ml) at room temperature for 16 hours. After dilution with water, the precipitate was extracted with ethyl acetate and the organic solution was washed with 5% NaHCO3 and water and then evaporated to dryness to give methyl 3-acetyl-4-(2'-isopropoxy-5'-methyl-benzoyloxy)-benzoate (13 g, oil), which was dissolved in methyl-ethyl-ketone (200 ml) and treated with anhydrous potassium carbonate (22 g) under stirring at the reflux temperature for 4 hours.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]([CH3:22])([CH3:21])[CH:14]=3)=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[N:30]([Si](C)(C)C)=[C:31]=[O:32]>ClCCl>[CH3:21][C:15]1([CH3:22])[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:13]([C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH2:1][N:2]([C:31]([NH2:30])=[O:32])[CH2:3][CH2:4]3)=[O:12])=[CH:14]1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC1(C)C=C(C(=O)c2ccc3c(c2)CCNC3)C(C)(C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C=C(C(=O)c2ccc3c(c2)CCN(C(N)=O)C3)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of the product of Example 10j (59 mg, 0.2 mmol) in dichloromethane (5 mL) was added triethylamine (110 mg, 1.0 mmol) and isocyanatotrimethylsilane (94 mg, 0.8 mmol) and stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (47 mg, Yield: 69%). Mp=78.6-79.7° C.; Rf 0.3 (10:1 dichloromethane/methanol); 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.17 (d, J=7.6 Hz, 1H), 5.79 (s, 1H), 4.63 (s, 2H), 4.52 (s, 2H), 3.64 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H), 1.59 (s, 4H), 1.24 (s, 6H), 1.06 (s, 6H) ppm; Mass spectrum (ESI +ve) m/z 341 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl[CH:19]([C:22]1([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][CH:29]=[CH:28]3)[CH2:24][CH2:23]1)[CH:20]=O.C(N(CC)CC)C>C(O)(C)C>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([C:22]3([C:19]4[N:3]5[N:4]=[C:5]([C:8]6[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=6)[CH:6]=[N:7][C:2]5=[N:1][CH:20]=4)[CH2:24][CH2:23]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 110 °C
Yield: 44.1 %

Procedure:
A mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate (160 mg, 0.70 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (200 mg, 0.83 mmol) in isopropyl alcohol (6 mL) was heated at 110° C. for 24 h. The mixture was adjusted to pH 9 by adding triethylamine and then the volatiles were removed under reduced pressure. The residue was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-60%) to afford the desired product (130 mg, 44%). LCMS: (M+H)=421.1.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:29])[CH2:13][O:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[C:17]([C:26](O)=[O:27])[CH:16]=1)=[O:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@H:64]([C:74]([O:76][CH3:77])=[O:75])[CH2:65][CH2:66][C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70].Cl>CN(C=O)C>[CH3:77][O:76][C:74](=[O:75])[C@@H:64]([NH:63][C:26]([C:17]1[CH:16]=[C:15]([O:14][CH2:13][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:5](=[O:6])[NH:4][CH2:3][CH2:2][F:1])=[O:29])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=1)=[O:27])[CH2:65][CH2:66][C:67]([O:68][C:69]([CH3:71])([CH3:72])[CH3:70])=[O:73]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
To a solution of 950 mg 5-[2-((S)-2-(2-Fluoro-ethylcarbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 15 ml DMF were added 0.39 ml DIPEA, 893 mg HATU and 596 mg H-Glu(OtBu)-OMe hydrochloride. After stirring for 24 h the solution was concentrated, taken up with dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 1.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:12][C:13]1[CH:18]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Nc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-aminobenzoate (0.500 g; 3.31 mmol), 3-fluorobenzeneboronic acid (0.925 g; 6.62 mmol), copper acetate (1.20 g; 6.62 mmol) and pyridine (0.535 mL; 6.62 mmol) in dichloromethane (15 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.O=[C:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(O)(=O)C.[BH]C#N.[Na]>C(O)C>[CH2:27]([O:26][C:24]([CH:23]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CSc2ccccc21
Reactant: CCCCCCCCC(=O)C(=O)OCC
Agent: [BH]C#N
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCCCC(NC1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O)C(=O)OCC
Reaction time: 3 h
Yield: 84.3 %

Procedure:
1.3 g of 3-amino-5-t-butoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 3.0 g of ethyl 2-ketodecanoate were dissolved in 10 ml of ethanol. After the addition of 0.3 ml of acetic acid, the resulting mixture was stirred for 3 hours. Then, a solution of 420 mg of sodium boron cyanide hydride in 7 ml of ethanol was added dropwise thereto. After this mixture was allowed to stand overnight, it was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and then concentrated. The residue was purified by silica gel column chromatography using a 7:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.8 g of the desired compound in the form of an oily material.
Reaction SMILES: O[CH:2]1[CH2:5][C:4]([CH2:20][C:21]#[N:22])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1.COCCN(CCOC)S(F)(F)[F:29].C(O)C>ClCCl>[F:29][CH:2]1[CH2:5][C:4]([CH2:20][C:21]#[N:22])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(O)C1
Solvent: ClCCl
Solvent: CCO
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(F)C1

Procedure:
A solution of 3-hydroxy-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.01 g, 0.00003 mol) (a mixture of cis/trans isomers) in dichloromethane (3 mL), contained in a Teflon bottle equipped with a nitrogen inlet tube and stirring bar, was treated with 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (0.03 mL, 0.0002 mol) at rt. Ethanol (0.002 mL, 0.00003 mol) was added, and the mixture was stirred at rt over weekend. The reaction was evaporated to dry and the residue was purified with prep. HPLC (pH=10) to give a mixture of two isomers. LCMS calculated for C15H14FN6(M+H)+: 297.1. Found: 297.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ncccn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(3-Chloro-phenylethynyl)-2-methyl-1H-imidazole (200 mg, 0.92 mmol) was dissolved in 5 mL dimethyl formamide. Potassium carbonate (255 mg, 1.85 mmol) and 2-chloro-pyrimidine (159 mg, 1.38 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was poured into 70 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from diisopropyl ether and the desired compound was obtained as an off-white solid (212 mg, 78%), MS:m/e=295.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].N1C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[Cl:27]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:29])=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C1Cc2ccccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1Cc2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indoline-2-carboxylic acid methyl ester (33.0 g, 149.7 mmol) was dissolved in DCM (400 ml), and pyridine (37.8 ml, 463.2 mmol) was added thereto. A solution of 3,4-dichlorobenzenesulfonyl chloride (24.1 ml, 154.4 mmol) dissolved in DCM (100 ml) was then added, and the mixture was stirred overnight under reflux and then cooled to room temperature. The mixture was diluted with DCM and washed in succession with 0.5 M KHSO4, saturated NaHCO3 solution and saturated NaCl solution. The organic phase was dried (sodium sulfate) and concentrated in vacuo.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=2)[CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:14]([C:10]1[C:11]([CH3:13])=[N:12][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][CH:9]=1)=[O:16])(=[O:30])=[O:31]
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Reactant: Cc1nc(-c2cccnc2)ncc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cccnc3)nc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A mixture of 2-(3-pyridyl)-4-methylpyrimidine-5-carboxylic acid (215 mg, 1 mmol, prepared according to the general procedure described in Example 42, steps 1 and 2) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) in dry DMF (12 mL) is treated with of diisopropylethylamine (0.18 mL) and stirred at room temperature for 30 min. 3-Methylsulfamoylbenzylamine hydrochloride (355 mg, 1.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue partitioned between EtOAc and saturated NaHCO3. The organic phase is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 2% MeOH in EtOAc to afford 2-(3-pyridyl)-4-methyl-pyrimidine-5-carboxylic-acid-3-methylsulfamoyl-benzylamide (180 mg, 45%) as a solid. MS: 398 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.43 (s, 3H), 2.65 (s, 3H), 4.60 (d, 2H), 7.57-7.71 (m, 4H), 7.79 (s, 1H), 8.68-8.72 (d, 1H), 8.72-8.78 (d, 1H), 8.93 (s, 1H), 9.34 (t, 1H), 9.53 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.Br[CH2:14][CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:17][CH2:16][CH2:15][CH2:14][N:10]1[N:11]=[N:12][C:8]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([I:1])[CH:7]=2)=[N:9]1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Ic1cncc(-c2nn[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cncc(I)c2)n1
Temperature: 80 °C

Procedure:
The reaction mixture of 3-iodo-5-(2H-tetrazol-5-yl)pyridine (273 mg, 1 mmol, 1 eq), (3-bromopropoxy)-tert-butyldimethylsilane (0.31 mL, 1.3 eq), potassium carbonate (207 mg, 1.5 eq) in anhydrous DMF (4 mL) under nitrogen atmosphere was stirred and heated at 80° C. for 5 hours. The mixture was then diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, aqueous ammonium chloride, brine, and dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated under reduced pressure, and the resulting brown oily residue was subject to a gradient column chromatography (EtOAc-Hex 1:50 to 1:4) giving 3-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)-5-iodopyridine as a soft white solid in the amount of 395 mg.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]=O)=[CH:15][CH:14]=1>>[I:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]2[CH2:7][CH2:8][NH:9][CH:21]([CH2:20][CH2:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:23])[F:24])=[CH:14][CH:15]=3)[C:6]=12
Reactant: Cc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Product: Cc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 110° C.; 8 bars; 10 min.) between 2-(4-iodo-2-methyl-imidazol-1-yl)-ethylamine (373.8 mg; 1.489 mmol) and 3-(4-trifluoromethyl-phenyl)-propionaldehyde (301 mg; 1.489 mmol) afforded 1-iodo-3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by FC (DCM/MeOH=25/1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][C:18](Br)=[O:19].O>ClCCl>[Br:16][CH2:17][C:18]([NH:4][C:3]1[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=1[F:9])=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2,6-difluoroaniline (1.12 g) and potassium carbonate (1.8 g) in 50 mL dichloromethane was added bromoacetyl bromide (1.5 mL) and the mixture was stirred at room temperature for 17 h. Water was added and the mixture stirred for several hours then the phases were separated on a hydrophobic frit and the organic layer was evaporated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane to give the sub-titled compound (0.92 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5](=[O:15])[CH2:6][CH:7]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH2:9].C1(C)C=CC(S([N:26]=[N+:27]=[N-])(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:16])[C:4](=[N+:26]=[N-:27])[C:5](=[O:15])[CH2:6][CH:7]([O:10][Si:11]([CH3:13])([CH3:14])[CH3:12])[CH:8]=[CH2:9]
Reactant: C=CC(CC(=O)CC(=O)OC)O[Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Product: C=CC(CC(=O)C(=[N+]=[N-])C(=O)OC)O[Si](C)(C)C
Yield: 83 %

Procedure:
In accordance with the process of Example 2, 3-oxo-5-trimethylsilyloxy-6-heptenoic acid methyl ester (360 mg; 1.47 m mol), p-toluenesulfonyl azide(290 mg; 1.47 m mol) and triethylamine (150 mg; 147 m mol) were used as starting materials to obtain 330 mg of 2-diazo-3-oxo-5-trimethylsiloxy-6-heptenoic acid methyl ester as yellow oily product.