Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:11]1([CH2:10][C:8]2[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CS(=O)(=O)c1nsc(CC2CCCCC2)n1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(CC2CCCCC2)n1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
300 mg of 3-methylsulfonyl-5-(cyclohexyl)methyl-1,2,4-thiadiazole and 89 mg of 2-butyn-1-ol were dissolved in 2.5 g of N,N-dimethylformamide, 55 mg of sodium hydride (60% in oil) was added thereto, and the reaction mixture was stirred for 30 minutes under ice-cooling. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 222 mg of 5-(cyclohexyl)methyl-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (5)).
Reaction SMILES: O=[C:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].Cl.[Br:13][C:14]1[CH:30]=[CH:29][C:17]([CH2:18][N:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)N)=[CH:16][CH:15]=1.[C:31](O)(=O)C>>[Br:13][C:14]1[CH:30]=[CH:29][C:17]([CH2:18][N:19]2[C:21]3[C:26](=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:3]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:31])=[O:8])=[C:2]2[CH3:11])=[CH:16][CH:15]=1
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Reactant: COC(=O)CCCCC(C)=O
Reactant: CC(=O)O
Agent: Cl
Product: CCOC(=O)CCCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 100 °C

Procedure:
A mixture of methyl 6-oxoheptanoate (3.1 g, 19.5 mmol), acetic acid (100 mL) and hydrazine from Example 1, Step 5 (5.0 g, 16.3 mmol) was heated at 100° C. overnight. The acetic acid was removed in vacuo and the residue was added to a 0° C. mixture of EtOH (150 mL) and acetyl chloride (5 mL). The resulting mixture was refluxed for 1 h, then most of the solvent was removed by distillation and further concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated NaHCO3, the organic layer washed with water, brine and dried over MgSO4. Purification by flash chromatography (30% ethyl acetate in hexane) provided 4.68 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](F)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:16][NH2:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:17][CH3:16])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(-c2cccnc2Cl)ccn1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(-c2cccnc2Cl)ccn1
Temperature: 80 °C

Procedure:
To 2-chloro-2′-fluoro-[3,4′]bipyridinyl (5.30 g, 25.4 mmol), methylamine hydrochloride (9.00 g, 133 mmol) and K2CO3 (28.1 g, 203 mmol) was added DMSO (70 mL). The mixture was heated overnight at 80° C. in a sealed tube. The cooled mixture was diluted with water (300 mL) and the resulting solid was filtered, washed with water and dried to yield (2-chloro-[3,4′]bipyridinyl-2′-yl)-methyl-amine. MS m/z=220 [M+1]+. Calc'd for C11H10ClN3: 219.68.
Reaction SMILES: Br[C:2]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.O=C1CC(=O)CN(C(OCC2C=CC=CC=2)=O)C1.[CH3:32][N:33]1[CH2:45][C:44]2NC3C=CC=C4C(=O)[NH:47][N:48]=[C:35]([C:36]=2C=34)[CH2:34]1>>[F:13][C:9]1[CH:8]=[C:3]2[C:4](=[O:6])[NH:47][N:48]=[C:35]3[C:36]4[C:2]2=[C:11]([NH:12][C:44]=4[CH2:45][N:33]([CH3:32])[CH2:34]3)[CH:10]=1
Reactant: COC(=O)c1cc(F)cc(N)c1Br
Reactant: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Agent: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Product: CN1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 55 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoate and benzyl 3,5-dioxopiperidine-1-carboxylate according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 10.1 (s, 1H), 7.36 (dd, 1H, J=1.8, 9.6 Hz), 7.20 (dd, 1H, J=1.8, 10.2 Hz), 3.75 (s, 2H), 3.24 (s, 2H), 2.44 (s, 3H). MS (ESI) m/e [M+1]+ 259.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@:12]1([C:17]1[NH:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[C:24]=2[CH:25]=1)[CH3:16])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:16][C@:12]1([C:17]2[NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[C:24]=3[CH:25]=2)[CH2:13][CH2:14][CH2:15][NH:11]1
Reactant: COC(=O)c1cccc2[nH]c([C@@]3(C)CCCN3C(=O)OCc3ccccc3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc2[nH]c([C@@]3(C)CCCN3)cc12
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A stirred mixture of (R)-methyl 2-(1-(benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (307 mg, 0.78 mol), methanol (10 mL), and 10% palladium on carbon (50 mg) was treated with a balloon-pressure of hydrogen at room temperature. After 2 hours, the mixture was filtered through Celite and the filtrate was concentrated to give (R)-methyl 2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (190 mg, 94%). 1H NMR (CDCl3-d1) δ 10.9 (s, 1H), 7.86 (d, 1H, J=7.8 Hz), 7.63 (d, 1H, J=7.8 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.14 (s, 1H), 3.96 (s, 3H), 3.40-3.43 (m, 1H), 3.12-3.15 (m, 1H), 2.78-2.81 (m, 1H), 2.23-2.26 (m, 3H), and 1.94 (s, 3H). MS (ESI) m/e [M+1]+ 259.0.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH2:13])[N:8]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>[N+](C1C=CC=CC=1)([O-])=O.C(#N)C.O>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH:13][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])[N:8]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)n1c(N)cc(=O)n1-c1ccccc1
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: C=C(C)C(=O)Nc1cc(=O)n(-c2ccccc2)n1C(=O)OCC

Procedure:
123.5 g (0.5 mole) of 1-phenyl-2-ethoxycarbonyl-3-amino-3-pyrazolin-5-one (compound 2) are dissolved at room temperature in a solution of 133.5 g (1 mole) of anhydrous aluminium chloride and 15 ml of nitrobenzene in 500 ml of acetonitrile. The resulting solution is mixed with 57.5 g (0.55 mole) of methacryloyl chloride and is then refluxed for 3 h. The reaction mixture is poured out in 1 l of water and the precipitate formed is separated. The product is recrystallized from benzene/hexane (1:1).
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:10][CH2:9][C:8]([CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][CH2:6]1)([CH3:4])[CH3:3].O.NN>CO>[NH2:12][CH2:11][C:8]1[CH2:9][CH2:10][C@H:5]([C:2]([OH:1])([CH3:3])[CH3:4])[CH2:6][CH:7]=1
Reactant: CC(C)(O)[C@@H]1CC=C(CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(O)[C@@H]1CC=C(CN)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A mixture of 0.62 g (2.1 mmol) (S)-2-[4-(1-hydroxy-1-methyl-ethyl)-cyclohex-1-enyl-methyl]-isoindole-1,3-dione and 20 ml MeOH was cooled to 0° C. Thereafter, 0.2 ml (6 mmol) hydrazine hydrate was added and the resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then concentrated in vacuo; triturated with CHCl3; filtered and then concentrated to a filtrate yielding 0.31 g (63%) solid product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:24][CH2:25]1
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3cnccn3)CC2)cc1
Yield: 69.9 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.6 g), 1-(pyrazin-2-yl)piperazine (1.3 g) and potassium carbonate (1.6 g) in dimethylformamide (20 ml) was stirred at 70-80° C. for 7 hr. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give a pale-yellow solid (1.8 g). The obtained pale-yellow solid was crystallized from hexane-ethyl acetate to give the title compound (1.2 g) as pale-yellow crystals, m.p.=118-119° C.
Reaction SMILES: [OH:1][CH:2]([CH2:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.[OH:27]O.O.N>C(O)(=O)C>[OH:1][CH:2]([CH2:18][S:19]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)=[O:27])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1
Reactant: OO
Reactant: COc1ccccc1N1CCN(CC(O)CSc2ccc(F)cc2)CC1
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1N1CCN(CC(O)CS(=O)c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1.85 g of 1-[2-hydroxy-3-(p-fluorophenylthio)propyl]-4-(o-methoxyphenyl)piperazine in 20 ml of glacial acetic acid is added dropwise 1.2 g of 35 % aqueous hydrogen peroxide solution under cooling, and the mixture is stirred at a temperature of 20° to 30°C for 1 hour. The reaction mixture is poured into water, neutralized with aqueous ammonia and extracted with benzene. The organic layer is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue is crystallized by cooling to give 1-[2-hydroxy-3-(p-fluorophenylsulfinyl)propyl]-4-(o-methoxyphenyl)piperazine, M.P. 164° to 165°C. Recrystallization from benzene gives white crystals, M.P. 167.5° to 168.5°C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:26]1[S:25][CH:29]=[CH:28][CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cccs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mix carbon tetrabromide (49.8 g, 150 mmol) and methylene chloride (75 mL) and cool to 0° C. Add, by dropwise addition, a solution of triphenylphosphine (78.6 g, 300 mmol) in methylene chloride (75 mL). Stir at 0° C for 30 minutes. Add, by dropwise addition, a solution of 2-thiophenecarboxaldehyde (8.75 g, 78.8 mmol) in methylene chloride (75 mL). Remove the cooling bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2].[Cl-].[OH:31][NH3+:32].C([O-])(=O)C.[Na+]>O.CCO>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=[N:32][OH:31])=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2]
Reactant: [NH3+]O
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc21
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NO)c3)cc21
Yield: 130 %

Procedure:
1.2 g (2.9 mmol) of the compound from Example 70, 0.4 g (6 mmol) of hydroxylammonium chloride and 0.48 g (6 mmol) of sodium acetate in 45 ml of H2O/EtOH (2:1) were refluxed for 30 minutes. The organic solvent was removed under reduced pressure, and the resulting aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to yield 1.6 g (70%) of the product. Melting point>250° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[CH:6][CH:5]=1.[C:34](O)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[N:29]1([CH2:28][CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C:11]3[C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[S:14][C:10]=3[C:7]3[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:34]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)=[O:41])=[CH:5][CH:6]=3)=[CH:25][CH:24]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)c1ccncc1
Reactant: NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 33 %

Procedure:
A solution of 2-[4-(2-aminoethyl)phenyl]-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (111 mg) in dichloromethane (3.0 mL) was treated isonicotinic acid (35 mg) and DCC (50 mg) sequentially and allowed to stir at ambient temperature for 25 h. The reaction mixture was then concentrated and fractionated by column chromatography with Et3N:MeOH:EtOAc (5:10:85) to afford the product (45 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:23])=[C:4]([C:13]([NH:15][C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.C(O[C:33](=[O:35])[CH3:34])(=O)C>>[C:7]([NH:1][C:2]1[C:3]([I:23])=[C:4]([C:13]([NH:15][C:16]([CH2:17][O:18][C:33](=[O:35])[CH3:34])([CH2:19][O:20][C:17](=[O:18])[CH3:16])[CH2:21][O:22][C:13](=[O:14])[CH3:4])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:8])[CH3:6]
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(CO)(CO)CO)c1I
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(COC(C)=O)(COC(C)=O)COC(C)=O)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Amino-2,4,6-triiodo-N-[tris(hydroxymethyl)methyl]isophthalamic acid (50.0 g., 0.076 mol.) was added in one portion to a stirred solution of sulfuric acid (0.36 ml.) in acetic anhydride (136.0 ml.). The temperature of the reaction mixture rose briefly to 82° and dissolution was effected. As the reaction mixture cooled to room temperature, the product began to precipitate at 47° and the mixture was diluted with toluene (100 ml.). The mixture was stirred at room temperature for 1 hr., and filtered. The filter cake was washed with toluene (50 ml.), dried, dissolved in hot methanol (300 ml.), and treated with charcoal (6 g.). After removal of the charcoal, the product precipitated from the cold solution and was collected and dried (70°) to give white crystalline 5-acetamido-2,4,6-triiodo-N-[tris(acetoxymethyl)methyl]-isophthalamic acid (38.8 g.) m.p. 248-251 (dec., uncorr.). (Yield, 62%). This material was pure by TLC analysis (benzene, 2-butanone, 88% formic acid; 60:25:20) and its structure was confirmed by IR and NMR.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1.C(O)(=O)C.[CH3:28][C:29]1[N:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][N:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:2][C@@H:3]1[CH2:7][N:6]([CH2:35][C:32]2[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=2)[CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1
Reactant: Cc1ncc(C=O)cn1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Temperature: 50 °C
Yield: 24.6 %

Procedure:
To a solution of 6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrogen chloride (493 mg) in 1,2-dichloroethane (10 mL) was added acetic acid (174 mg), 2-methylpyrimidine-5-carbaldehyde (236 mg) and sodium triacetoxy borohydride (635 mg). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated onto silica gel and purified by CombiFlash chromatography to provide the title compound (146 mg). 400 MHz 1H NMR (CDCl3) δ 8.63 (s, 2H), 8.01 (s, 1H), 4.82-4.76 (m, 1H), 4.12-4.08 (m, 2H), 3.68 (d, J=5.0 Hz, 3H), 3.64-3.54 (m, 2H), 3.28 (t, J=8.3 Hz, 1H), 3.04 (d, J=9.9 Hz, 1H), 2.89-2.86 (m, 1H), 2.71 (s, 3H), 2.66-2.62 (m, 1H), 2.49-2.27 (m, 3H), 1.97 (t, J=7.9 Hz, 1H), 1.91-1.83 (m, 2H), 1.19 (d, J=7.05 Hz, 3H). MS: (M+H m/z 410.2).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:34]1[CH:35]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:31]=[C:32]([CH3:37])[N:33]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(OC(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example M193) (230 mg, 0.423 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (97 mg, 54%).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:19][CH:18]=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]12([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH3:16])[C:27](=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCNCCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)CCCCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CCCCc1ccncc1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
N,N-Dimethylformamide (8.4 ml) was added to a mixture of 2-(1-adamantyl)-N-propylethylamine (Intermediate No. 1-6, 0.37 g, 1.7 mmol) and 5-(4-pyridyl)valeric acid (Intermediate No. 5-1, 0.30 g, 1.7 mmol), and the whole was stirred at room temperature. N-Methylmorpholine (0.27 ml, 2.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2.0 mmol) were added thereto successively, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate (20 ml) was added to the residue, and the whole was washed with a saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (5 ml) successively. The organic layer was dried over sodium sulfate, and ethyl acetate was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography to give the target compound (0.21 g, 33%) as a colorless oily matter.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][C:24]2([CH2:32][O:33][CH3:34])[CH3:31])#[CH:20]>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.[Cu]I.CN(C=O)C>[CH3:34][O:33][CH2:32][C:24]1([CH3:31])[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:19]#[C:20][C:2]3[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)[CH:22]=2)[O:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(COC)CCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC1(C)CCOc2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Reaction time: 0.25 h

Procedure:
In 11 ml of abs. DMF was successively dissolved 1.061 g (1.25 eq.) of methyl 4-iodo-benzoate, 114 mg (0.05 eq.) of bis (triphenylphosphine)palladium(II) chloride, 74.1 mg (0.12 eq.) of CuI, and 1.13 ml (2.5 eq.) of triethylamine. 701 mg (3.24 mmol) of the above prepared 6-ethynyl-4-methoxymethyl-4-methyl-chroman, dissolved in 2.7 ml of abs. DMF, was added within 1 h via dropping funnel. After 0.25 h, the reaction was quenched by pouring the reaction mixture onto crushed ice/ HCl. Extraction with diethylether, washing the organic phase twice with water, drying it over magnesium sulfate, filtration and evaporation of the solvent yielded after flash chromatography (SiO2, hexane/ ethylacetate 92/8) 630 mg of the title compound as yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](O)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([N:13]1[CH2:14][CH:15]2[CH:11]([CH2:10][N:9]([C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16]2)[CH2:12]1)=[O:21]
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1c(F)cccc1F
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4c(F)cccc4F)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 23 and 2,6-difluorobenzoic acid. MS (ESI): mass calculated for C19H20F2N4O, 358.16; m/z found 359.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.34 (tt, J=8.4, 6.4, 1H), 6.93 (s, 2H), 6.30 (s, 1H), 4.12-3.76 (m, 3H), 3.75-3.45 (m, 4H), 3.36-2.88 (m, 3H), 2.30 (s, 6H).
Reaction SMILES: F[C:2]1(F)[CH2:7][CH2:6][CH:5]([CH:8]=[CH:9][C:10](Cl)=O)[CH2:4][CH2:3]1.[CH2:14](OC(C1CCC(F)(F)CC1)=O)C.CC1(C=O)CCOCC1.[N+:36]([C:39]1[CH:40]=[C:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]([F:55])([F:54])[F:53])[CH:42]=[CH:43][C:44]=1[NH2:45])([O-])=O>>[CH:5]1(/[C:8](/[CH3:14])=[CH:9]/[C:10]2[NH:45][C:44]3[CH:43]=[CH:42][C:41]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=4[C:52]([F:55])([F:54])[F:53])=[CH:40][C:39]=3[N:36]=2)[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Cl)C=CC1CCC(F)(F)CC1
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: CC1(C=O)CCOCC1
Product: C/C(=C\c1nc2cc(-c3ccccc3C(F)(F)F)ccc2[nH]1)C1CCCCC1

Procedure:
(E)-2-(2-Cyclohexyl-propenyl)-5-(2-trifluoromethyl-phenyl)-1H-benzimidazole was prepared from 3-(4,4-difluoro-cyclohexyl)-acryloyl chloride (prepared from 4,4-difluoro-cyclohexanecarboxylic acid ethyl ester utilizing a procedure analogous to the preparation of 4-methyl-tetrahydro-pyran-4-carbaldehyde in Example 9) and 3-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (prepared as described in Example 3, STEP A) as described in Example 9, STEPS A-C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15]OC)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[I:18][Si](C)(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][I:18])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[Si](C)(C)I
Reactant: COCCCc1cc(C(=O)OC)cc(Br)c1C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(C)c(CCCI)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chloroform (0.1 M) solution of methyl 3-bromo-5-(3-methoxypropyl)-4-methylbenzoate (1 eq.) from the previous step was added iodotrimethylsilane (10 eq.). The resulting red solution was stirred at RT in darkness for 18 h. The reaction was quenched with methanol before the volatiles were removed in vacuo. The resulting residue was then taken up in ether, washed sequentially with 10% aq. HCl, 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as an orange oil.