Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.C([O-])(=O)C.[K+].[O:29]=[C:30]1[NH:35][C:34](=[O:36])[C:33](B(O)O)=[CH:32][NH:31]1>CN(C)C=O.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>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:33]5[C:34](=[O:36])[NH:35][C:30](=[O:29])[NH:31][CH:32]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: O=c1[nH]cc(B(O)O)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3c[nH]c(=O)[nH]c3=O)cc1-2
Temperature: 25 °C

Procedure:
9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (500 mg, 1.3 mmol) and potassium acetate (380 mg, 3. 8 mmol) were suspended in N,N-dimethylformamide (5 mL) and water (5 mL) and degassed by bubbling N2 for 5 min. Charged with 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylboronic acid (250 mg, 1.6 mmol) and then tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol). The reaction was microwaved at 300 watts, 140° C. for 20 minutes. Subsequently after cooling to r.t. and diluting with water (20 mL), the mixture was extracted with ethyl acetate. The combined organics portions were concentrated and purified by reverse phase HPLC to provide 506 as a white crystalline compound (70 mg, 10% yield). LC/MS (ESI+): m/z 423.1 (M+H). 1H NMR (500 MHz, DMSO) δ 1.22 (s, 2H), 8.71 (s, 1H), 8.11 (s, 1H), 7.65 (s, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 5.92-5.81 (m, 1H), 4.38 (s, 2H), 3.45 (s, 2H), 1.55 (d, J=6.5 Hz, 4H)
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[CH2:7]([NH:9][CH2:10][CH2:11][NH2:12])[CH3:8].[H][H]>C(O)C.[Pd]>[CH2:7]([NH:9][CH2:10][CH2:11][NH:12][CH2:3][C:2]([OH:6])=[O:5])[CH3:8]
Reactant: CCNCCN
Reactant: O=CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCNCCNCC(=O)O
Reaction time: 18 h

Procedure:
A solution of glyoxylic acid hydrate (9.2 g, 0.10 mol) and N-ethylethylenediamine (8.82 g, 0.10 mol) in ethanol (150 ml) was hydrogenated in a Paar apparatus at 20°-25° and an initial pressure of 51 psi with 5% Pd on carbon (2.0 g) as catalyst. After 18 hours, hydrogen uptake was complete. Catalyst was removed by filtration through a pad of diatomaceous earth and the filtrate concentrated to give N-(2-ethylaminoethyl)glycine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][C:4]=2[CH:3]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Solvent: O
Product: COc1ccc(-c2cc3cc(Br)ccc3o2)cc1
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 4-Bromo-2-Iodophenol [207115-22-8] (0.9 g, 3.0 mmol), 4-Methoxyphenylacetylene (0.43 g, 3.3 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give a solid which was triturated with MeOH, filtered to give a solid (0.4 g, 45%): Mp=192-194° C.; 1H NMR (CDCl3) δ 7.77 (d, 2 H, J=9.1 Hz), 7.66 (s, 1 H), 7.37-7.32 (m, 2 H), 6.98 (d, 2 H, J=9.1 Hz), 6.82 (d, 1 H, J=0.8 Hz), 3.87 (s, 3 H).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:3].F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([O:45]C)=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.C1COCC1>[CH3:1][N:2]([CH3:3])[C:43]([C:40]1[S:39][C:35]2[N:36]=[CH:37][N:38]=[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[O:47][CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[C:34]=2[C:41]=1[CH3:42])=[O:45]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C(=O)N(C)C)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. Dimethylamine (2M in THF, 1.0 mL, 2.0 mmol was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the product purified by reverse phase preparative HPLC to yield white solid (0.017 g, 30%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C1(C)C=CC=CC=1.[CH3:18][C:19](=[O:22])[CH2:20][CH3:21]>O>[CH3:18][C:19]([OH:22])([CH2:20][CH3:21])[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: CCC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)(O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
Phenylacetylene (500 g, 4.2 mol) was added to a mixture of potassium hydroxide flake (290 g) and toluene (3 L). 2-Butanone (425 g, 5.9 mol) was added over 45 minutes keeping the temperature below 30° C. with periodic cooling and the resulting mixture agitated for 20 h at room temperature. Water (1 L) was added, the toluene solution washed until neutral, the solvent evaporated, and the residue distilled to give 517 g (71% yield) of 3-methyl-1-phenyl-1-pentyn-3-ol; bp 107°-110° C./3 mm; IR (film) 3400, 1150, 1000, 920 cm-1 ; NMR (CDCl3) 1.1 (3H, t), 1.6 (3H, s), 1.8 (2H, q), 2.2 (1H, s), 7.2-7.6 (5.H, m) δ; MS (m/e) 174, 156, 145, 43.
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: N#Cc1ccc(Cl)nc1
Product: CN(CCNc1ccc(C#N)cn1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methylamine and 2-chloro-5-cyanopyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]-methyl{2-[(5-cyano(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[K+].[K+]>>[N:21]1([CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:7]=2[CH3:20])[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(SCCCn2ccnc2)ccnc1CSc1ccncc1
Yield: 32 %

Procedure:
According to the procedure indicated in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with imidazole (2.0 equivalents) and potassium carbonate and subsequent chromatography on silica gel (dichloromethane/acetone/NH3 aq) gives, after crystallization from diisopropyl ether, the title compound; m.p. 117-119° C.; yield 32% of theory.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[OH:11].O[CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1.CN1CCCC1=O>[Br:18][C:14]1[CH:13]=[C:12]([CH:10]([O:11][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCC(O)CC1
Reactant: OC(c1cccc(Br)c1)c1nc2ccccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: CN1CCCC1=O
Product: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
A mixture of 1H-benzimidazol-2-yl(3-bromophenyl)methanol (12.9 g), 4-hydroxy-1-methylpiperidine (4.86 g) and para-toluenesulfonic acid (24 g) in chlorobenzene (60 mL) and N-methylpyrrolidone (6 mL) is heated under reflux for 120 h in a Dean Stark apparatus. Solvent is removed by evaporation. To the residue is added water which is made alcaline by addition of sodium hydroxide solution, then extracted with ethyl acetate. The pooled organic extracts are washed with water, treated with activated charcoal, dried over magnesium sulfate and concentrated under reduced pressure. The residue is triturated in diethyl ether to give 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][CH:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH:19]1([C:25]([NH:14][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N+:1]([O-:3])=[O:2])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(Cc1ccccc1[N+](=O)[O-])c1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(NC(Cc1ccccc1[N+](=O)[O-])c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.0 g of 2-nitro-α-phenylphenethylamine in 75 ml of toluene is added dropwise to a stirred, cooled solution of 14.4 ml of cyclohexylcarbonyl chloride in 75 ml of toluene and 25 ml of pyridine. After complete addition the mixture is stirred at room temperature for 2 hours. The mixture is allowed to stand overnight, after which the tan precipitate is collected and washed with 100 ml of ether. The precipitate is recrystallized from 350 ml of methanol to give yellow needles, mp 210°-212° C. of N-cyclohexanecarbonyl-2-nitro-α-phenylphenethylamine.
Reaction SMILES: [NH2:1][C:2]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:4](OCC)=[O:5].C[O-:14].[Na+].C1C[CH2:25][N:24]2C(=NCCC2)CC1>CN(C)C=O>[F:12][C:9]([F:10])([F:11])[C:2]1[NH:1][C:25](=[O:14])[NH:24][C:4](=[O:5])[CH:3]=1
Reactant: C[O-]
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Reactant: C1CCC2=NCCCN2CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)[nH]1

Procedure:
In the method of Schema I, a 2-fluoro-5-(optionally substituted)-nitro-benzene was reacted with an appropriately substituted amine, for example, 2-propynylamine, under basic conditions, affording the corresponding N-substituted-4-optionally substituted-2-nitroaniline (1), for example, N-(2-propyn-1-yl)-4-fluoro-2-nitroaniline. Intermediate (1) was in turn reduced with either iron powder and acetic acid in ethyl acetate or with tin(II) chloride dihydrate and sodium borohydride in ethanol, yielding the corresponding 2-(substituted amino)-5-optionally substituted aniline (2), for example, 2-(2-propyn-1-ylamino)-5-fluoroaniline. The so-prepared aniline (2) was then cyclized with either trifluoroacetic acid (when R1 is --CF3) or acetic acid (when R1 is --CH3), affording the corresponding 1-substituted-2-(methyl or trifluoromethyl)-5-optionally substituted benzimidazole (3), for example, 1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazole. Nitration of the benzimidazole (3) with 70% nitric acid in concentrated sulfuric acid yielded an isomeric mixture of 1,2-disubstituted-4-nitro-5-optionally substituted benzimidazole (4A) and 1,2-disubstituted-5-optionally substituted-6-nitrobenzimidazole (4B). The nitrobenzimidazole isomers (4A) and (4B) were separated by column chromatography, and isomer (4B), for example, 2-propyn-1-yl-2-trifluoromethyl-5-fluoro-6-nitrobenzimidazole, was reduced with iron powder in ethyl acetate and acetic acid, affording the corresponding 1,2-disubstituted-5-optionally substituted-6-aminobenzimidazole (5). Intermediate (5) was then treated with ethyl chloroformate in pyridine, yielding the corresponding 1,2-disubstituted-5-optionally substituted-6-ethoxycarbonylaminobenzimidazole [generic structure (6), where V is C--R1 ]. The 6-substituted-aminobenzimidazole (6) was, in turn, cyclized with ethyl 3-amino-4,4,4-trifluoro-2-butenoate and sodium methoxide in the presence of DBU in N,N-dimethylformamide, affording the corresponding 3-(1,2-disubstituted)-5-optionally substituted benzimidazol-6-yl)-6-trifluoromethyluracil (7). The intermediate uracil (7) was in turn alkylated with an appropriate alkyl halide and potassium carbonate in acetone, yielding the desired 1-alkyl-3-(1,2-disubstituted-5-optionally substituted benzimidazol-6-yl)-6-trifluoromethyluracil (II), for example, 1-methyl-3-[1-(propyn-2-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil (Compound 12). Example 1 provides a detailed description of how these reactions were conducted.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].Cl.CN(C)[CH:24]=[O:25]>>[CH2:17]([NH:20][C:24](=[O:25])[O:16][CH2:15][C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:18][CH3:19]
Reactant: CCCN
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: CN(C)C=O
Agent: Cl
Product: CCCNC(=O)OCc1c2ccccc2cc2ccccc12
Reaction time: 1 h
Yield: 93 %

Procedure:
To the solution dissolved 8.92 g of N,N′-carbonyldiimidazole (55 mmol; produced by Wako Pure Chemical Industries, Ltd.) into 40 mL of dimethylformamide (DMF), 10.4 g of 9-anthracenemethanol (50 mmol; produced by Wako Pure Chemical Industries, Ltd.) was added under cooling with ice, then, the solution was reacted by stirring for 1 hour at the same temperature. Subsequently, 4.13 g of mono-n-propylamine (70 mmol; produced by Wako Pure Chemical Industries, Ltd.) was added to this solution, and the solution was reacted by stirring for 2 hours at room temperature. After completing reaction, the reaction solution was poured into 210 mL of 1.8% hydrochloric acid, the resultant crystal was filtered, then, the resultant crystal was dried, the crystal after drying was added to 70 mL of toluene, and was hot-dissolved to hot-filtered at the temperature of 100° C. Subsequently, the filtrate obtained by filtration was cooled with ice, and the precipitated crystal was filtered, then, the resultant crystal was dried to obtain 13.6 g of 9-anthrylmethyl N-n-propylcarbamate (yield: 93%) represented by the above-described formula [14] as yellow crystal. Measurement results of 1H-NMR and melting point are shown as the follows:
Reaction SMILES: CCOCC.Br[C:7]1[C:20]2[O:19][C:18]3[C:13](=[CH:14][C:15]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][C:17]=3Br)[C:12]([CH3:27])([CH3:26])[C:11]=2[CH:10]=[C:9]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:8]=1.[Li]CCCC.[Si:37]([Cl:41])(Cl)([CH3:39])[CH3:38]>CCCCCC>[Cl:41][Si:37]([CH3:39])([CH3:38])[C:7]1[C:20]2[O:19][C:18]3[C:13](=[CH:14][C:15]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][C:17]=3[Si:37]([Cl:41])([CH3:39])[CH3:38])[C:12]([CH3:27])([CH3:26])[C:11]=2[CH:10]=[C:9]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:8]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: CC(C)(C)c1cc(Br)c2c(c1)C(C)(C)c1cc(C(C)(C)C)cc(Br)c1O2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)c1cc2c(c([Si](C)(C)Cl)c1)Oc1c(cc(C(C)(C)C)cc1[Si](C)(C)Cl)C2(C)C
Temperature: -65 °C

Procedure:
The reaction outlined in the reaction scheme below is as follows: Et2O (125 mL) and 4,5-dibromo-2,7-di(tert-butyl)-9,9-dimethylxanthene (9.54 g, 19.9 mmol) were combined and cooled to −65° C. A hexane solution of BuLi (19.2 mL, 47.7 mmol) was added dropwise over 5 min and the colorless suspension was allowed to warm to −30° C. over a period of 45 min during which time the starting material dissolved (at about −40° C.). After 15 min at −30° C. the solution was cooled to −80° C. and cold SiMe2Cl2 (20.5 g, 159 mmol) was added in one portion.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=O)[CH2:15][CH2:16][CH3:17])[CH:8]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1cc(Oc2ccc(N)cc2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCNc1cc(Oc2ccc(N)cc2)ccn1
Temperature: 25 °C

Procedure:
After dissolving 80 mg of 4-(4-aminophenoxy)-2-butyrylaminopyridine in 8 ml of tetrahydrofuran, 67 mg of lithium aluminum hydride was added while stirring at room temperature, and the mixture was stirred at 70° C. for 10 minutes. Water was added, extraction was performed with ethyl acetate, and then silica gel was added to the extract and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purified by column chromatography (ethyl acetate) to obtain 54 mg of the target substance as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=C([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)C#N)[CH:4]=[CH:5][N:6]=1.[OH-:19].[Na+].[O:21]1[CH2:26][CH2:25]OCC1>>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:25]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[C:26]([OH:21])=[O:19])[CH:4]=[CH:5][N:6]=1
Reactant: C1COCCO1
Reactant: Cc1nccn1-c1cc(C#N)cc(C(F)(F)F)c1
Reactant: [OH-]
Agent: [Na+]
Product: Cc1nccn1-c1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 95 °C

Procedure:
A solution of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile (Example 91a; 16.7 g, 66 mmol) in dioxane (300 mL) is added to an aqueous solution of sodium hydroxide (275 mL of 1 M) and the mixture is heated at 95° C. for 18 h. The solvent is evaporated off under reduced pressure and the residue is neutralised with hydrochloric acid (1 M) and extracted with butanol (2×250 mL). The solvent is evaporated of under reduced pressure to give the title compound. 1H-NMR (400 MHz, DMSO-d6, δ): 7.17 (s, 1H); 8.03 (s, 1H); 8.12 (s, 1H); 8.35 (s, 1H); 8.41 (s, 1H); 8.53 (s, 1H); 13.90 (br., 1H).
Reaction SMILES: C12OC3CC([O:9]1)C(C=C3)C2.C(=O)(O)[O-].[K+].[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OO>CO.C(Cl)Cl>[C:16]([NH2:23])(=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccccc1
Reactant: C1=CC2CC3OC1CC2O3
Agent: O=C([O-])O
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Reaction time: 10 h

Procedure:
To a solution of 165 mg of racemic 9,10-dioxatricyclo[4,3,1,03,8 ]dec-4-ene in 4 ml of methanol are added, with stirring and at room temperature 865 mg of potassium bicarbonate and 740 mg of benzonitrile. To this mixture are added at intervals of 8 hours 5 portions each of 0.3 ml of 30% hydrogen peroxide and stirring is continued for 10 hours. Methylene chloride (25 ml) is then added to the reaction mixture, which is washed with 2% sodium hydrogen carbonate solution, dried over sodium sulphate and concentrated. Benzamide which has formed is removed by crystallisation from methylene chloride/pentane. The residual oil can be used directly in the next reaction, or chromatographed on 22 g of basic aluminium oxide (activity level IV). Elution with petroleum ether/benzene (7:3) yields the racemic mixture of 4β,5β-epoxy-9,10-dioxatricyclo[4,3,1,03,8 ]decane of the formula ##SPC18##
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3](C(OCC)=O)[CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>>[C:2]([C:3]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:25]2[C:21](=[N:22][NH:23][CH:24]=2)[NH:20][C:9]=1[CH:9]1[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)#[N:1]
Reactant: CCOC(=O)C1CCCNC1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1ccccc1

Procedure:
The title compound was prepared from ethyl nipecotate, benzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[N:6]3[C:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)=[CH:9][C:8]([C:14]([OH:16])=O)=[N:7]3.[CH:19]([NH:22][CH2:23][CH2:24][OH:25])([CH3:21])[CH3:20].C(N(CC)CC)C>[Pd]>[OH:25][CH2:24][CH2:23][N:22]([CH:19]([CH3:21])[CH3:20])[C:14]([C:8]1[CH:9]=[C:10]2[N:6]([C:5]3[CH:17]=[CH:18][CH:2]=[CH:3][C:4]=3[O:13][CH2:12][CH2:11]2)[N:7]=1)=[O:16]
Reactant: CC(C)NCCO
Reactant: O=C(O)c1cc2n(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CC(C)N(CCO)C(=O)c1cc2n(n1)-c1ccccc1OCC2
Reaction time: 2.75 h
Yield: 68 %

Procedure:
Following the procedure for 116, 8-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid was reacted with 2-isopropylamino-ethanol. The intermediate formed (145 mg, 0.37 mmol) was dissolved in IMS (10 mL) and triethylamine (50 μL, 0.37 mmol) then 10% Pd/C (20 mg) added before the reaction mixture stirred under hydrogen (1 atmosphere) for 2.75 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resultant residue was partitioned between DCM and water, the aqueous layer was isolated and extracted with DCM. The combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was dissolved in diethyl ether and the solution washed with water, dried (Na2SO4), filtered and then concentrated in vacuo to give 140 (79 mg, 68%). 1H NMR (DMSO-d6, 400 MHz): δ 7.83 (dd, J=8.0, 1.6 Hz, 1H); 7.30 (td, J=7.6, 1.8 Hz, 1H); 7.26-7.16 (m, 2H); 6.54 (s, 1H); 4.67-4.53 (m, 1H); 4.46 (t, J=6.0 Hz, 2H); 4.35-4.27 (m, 1H); 3.64-3.56 (m, 2H); 3.55-3.46 (m, 2H); 3.13 (t, J=6.0 Hz, 2H); 1.22 (d, J=6.8 Hz, 6H). LCMS: RT=9.00 min, M+H+=316
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10]2)[N:5]=[CH:4]1.[N:33]1([C:39]([Cl:41])=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[ClH:41].[ClH:1].[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH:20][C:39]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:40])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10]2)[N:5]=[CH:4]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Agent: Cl
Product: O=C(Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2)N1CCOCC1

Procedure:
Example 91 was prepared as a light yellow solid from Example 26 and morpholine N-carbonyl chloride as described for Example 27.