Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:74])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[O:62][N:61]=[C:60]([C:63]5[CH:68]=[CH:67][C:66]([C:69]([F:72])([F:71])[F:70])=[CH:65][CH:64]=5)[CH:59]=4)=[O:57])=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:73])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:74])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56]([C:58]4[O:62][N:61]=[C:60]([C:63]5[CH:64]=[CH:65][C:66]([C:69]([F:72])([F:71])[F:70])=[CH:67][CH:68]=5)[CH:59]=4)=[O:57])=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:73])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(C(F)(F)F)cc5)no4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(C(F)(F)F)cc5)no4)cc3)cc2C1=O
Yield: 82 %

Procedure:
The compound of example 620 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 619.
Reaction SMILES: OC1([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)CC2(CCN(C(OCC)=O)CC2)OC1.[O:25]=[C:26]1[CH2:31][C:30]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[O:29][CH2:28][CH2:27]1>>[OH:25][C:26]1([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:31][C:30]2([CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]2)[O:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)CCO2
Reactant: CCOC(=O)N1CCC2(CC1)CC(O)(C#Cc1ccccc1)CO2
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)(C#Cc1ccccc1)CCO2

Procedure:
The title compound was prepared following the method reported here for Compound 26a, substituting ethyl 2-oxo-4-oxa-8-azaspiro[4.5]decane-8-carboxylate with Compound 29b. After the usual work-up procedure the oily residue was purified by means of automated flash chromatography (SP1®TM-Biotage; Petroleum Ether-EtOAc gradient 9:1 to 6:4) to give 0.96 g of the title compound as a grey solid. Yield: 57.3%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][NH:11][CH2:10][C@@:9]2([N:14]([CH3:25])[C:15](=[O:24])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:13])=[CH:4][CH:3]=1.[C:26]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)(=[O:30])[CH:27]([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:15](=[O:24])[N:14]([C@:9]2([CH3:13])[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][N:11]([C:37]([CH:34]3[CH2:33][CH2:32][N:31]([C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH2:36][CH2:35]3)=[O:38])[CH2:10]2)[CH3:25])=[CH:22][CH:21]=1
Reactant: CC(C)C(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@]1(C)CNC[C@@H]1c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C(=O)N1CCC(C(=O)N2C[C@H](c3ccc(Cl)cc3)[C@@](C)(N(C)C(=O)Oc3ccc(F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 34 mg (0.093 mmol) rac-4-fluorophenyl (3R,4S)-4-(4-chlorophenyl)-3-methylpyrrolidin-3-yl(methyl)carbamate, 14.9 mg (0.075)mmol 1-isobutyrylpiperidine-4-carboxylic acid, 34.2 (0.09 mmol) HATU and 58 mg (0.45 mmol) DIPEA in 2 mL DMF was shaken for 3 h at room temperature. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 26.8 (66%) of the title compound as light yellow viscous oil. MS m/e: 544.2 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[C:9](=[O:25])[NH:10][C:11]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:12][C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.CO>C(OCC)(=O)C.O1CCOCC1>[CH:1]([N:4]1[C:8]2[C:9](=[O:25])[NH:10][C:11]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:12][C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c1C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)C2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl 1′-isopropyl-7′-oxo-1′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (100 mg, 0.29 mmol) in 4 mL ethyl acetate was added 4 N HCl in dioxane (2 mL). After stirring 30 minutes at room temperature, methanol (1 mL) was added and the resultant solution was stirred for 5 hours at room temperature. The volatiles were removed under reduced pressure and the resultant colorless solid triturated with 1:1 acetonitrile/dichloromethane to yield 71 mg of the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6, δ): 8.72 (br. s., 2H), 8.05 (s, 1H), 7.37 (s, 1H), 5.36 (m, 1H), 3.15 (m, 2H), 3.05 (m, 2H), 2.78 (s, 2H), 1.78 (m, 4H), 1.33 (d, J=6.6 Hz, 6H).
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:14])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[F:13])C.[NH3:15]>>[ClH:1].[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH2:14])=[NH:15])=[C:7]([F:13])[CH:8]=1
Reactant: N
Reactant: CCOC(=N)c1ccc(Br)cc1F
Agent: Cl
Product: N=C(N)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-2-fluoro-benzimidic acid ethyl ester hydrochloride (20.3 g, 72 mmol) in IMS (250 mL) at 0-5° C. was saturated with NH3 (gas), and the flask sealed before allowing to warm to RT and stirring for 18 h. Solvent was removed in vacuo and the residue triturated in diethyl ether to give 4-Bromo-2-fluoro-benzamidine hydrochloride as a white solid (18.1 g, 100%). 1H NMR δ (ppm) (DMSO-d6): 9.26 (4H, s), 7.92-7.87 (1H, m), 7.71-7.62 (2H, m).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[S:17][C:16]([NH2:18])=[N:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:29][NH:30][C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:32][OH:33]>CN1C(=O)CCC1>[NH2:18][C:16]1[S:17][C:12]2[C:11]([N:30]([CH3:29])[C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:32][OH:33])=[N:10][C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:14][C:13]=2[N:15]=1
Reactant: CCC[C@H](CO)NC
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](CO)N(C)c1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 120 °C
Yield: 76 %

Procedure:
5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidin-2-amine (6.0 g, 19.4 mmol) was dissolved in NMP (25 mL). DIPEA (6.8 mL, 38.8 mmol) and (2R)-2-(methylamino)pentan-1-ol (3.4 g, 29.1 mmol) were added and the mixture was heated to 120° C. for 3 days. Additional (2R)-2-(methylamino)pentan-1-ol (350 mg, 2.99 mmol) and DIPEA (1 mL, 5.74 mmol) was added and the reaction mixture was heated for 6 h at 120° C. After cooling to room temperature, the mixture was poured into ice. The precipitated product was collected by filtration and purified by flash column chromatography (eluent DCM: ethyl acetate gradient) to yield the title compound (5.74 g, 76% yield).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=[O:22])[C:8]([F:23])=[CH:7][C:6]=1[Cl:24].S(OC)(O[CH3:31])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[N:13]([CH3:31])[C:12]2=[O:22])[C:8]([F:23])=[CH:7][C:6]=1[Cl:24]
Reactant: COS(=O)(=O)OC
Reactant: CON(C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CON(C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 19.8 g of N-methoxy-N-methyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, 5.7 ml of dimethyl sulphate as well as 14.0 g of sodium carbonate in 80 ml of acetonitrile is stirred at 50° C. for 1 hour. The mixture is then treated with 150 ml of ice-water and the aqueous mixture is extracted three times with 150 ml of ethyl acetate each time. The combined organic phases are washed to neutrality, dried over anhydrous sodium sulphate and the solvent is evaporated. The crude product is recrystallized from diethyl ether/n-hexane and gives N-methoxy-N-methyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, m.p. 158° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][C:13]3=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:8][CH:9]=2)[C:13]1=[O:16])[CH:18]=[CH:19][CH3:20]
Reactant: O=C1CCc2ccc(OC3CCCC3)cc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(OC3CCCC3)cc2C1=O
Yield: 69 %

Procedure:
A solution of 9.45 g of 6-cyclopentoxy-1-indanone, 9.0 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxy-propane was boiled under reflux for 63 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). There were obtained 8.1 g (69%) of (RS)-2-(2-buten-1-yl)-6-cyclopentoxy-1-indanone as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:23][C:24]3[C:33]4[C:28](=[C:29]([F:34])[CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CN(C=O)C.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:23][C:24]3[C:33]4[C:28](=[C:29]([F:34])[CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[O:22])[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(NC(=O)Nc3ccnc4c(F)cccc34)n2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)Nc3ccnc4c(F)cccc34)n2)CC1
Reaction time: 24 h
Yield: 87.8 %

Procedure:
0.340 g of tert-butyl-6-[3-(8-fluoro-quinolin-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylate (0.734 mmol) were dissolved in a mixture of 220 ml of DMF and 125 ml of methanol. After addition of 0.078 g of Pd/C (0.734 mmol) and 0.5 ml of acetic acid (8.73 mmol) hydrogenation was performed for 24 h at room temperature, which led to complete double bond hydrogenation according to HPLC/MSD analysis. The catalyst was filtered off, the solvent removed under reduced pressure and the residue extracted three times with ethyl acetate after adding water and a small amount of NaOH (pH 9). The combined organic phases were washed with a small amount of brine, dried over sodium sulfate and the solvent was removed under reduced pressure. 300 mg of the desired product were obtained as a powder (yield: 88%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[C:17]([NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=[N:72][O:73][CH3:74])[C:43]([NH:45][CH:46]2[C:53](=[O:54])[N:52]3[CH:47]2[CH2:48][S:49][C:50]([SH:71])=[C:51]3[C:55]([O:57][CH:58]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])=[O:44])[N:41]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)Cl>[C:17]([NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=[N:72][O:73][CH3:74])[C:43]([NH:45][C@H:46]2[C:53](=[O:54])[N:52]3[C@@H:47]2[CH2:48][S:49][C:50]([S:71][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:51]3[C:55]([O:57][CH:58]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[O:56])=[O:44])[N:41]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: ClCCN1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON=C(C(=O)N[C@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCCN3CCCC3)SC[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
85 mg of N-chloroethyl pyrrolidine hydrochloride, 2 ml of methylene chloride and 210 μl of triethylamine were mixed together and 412 mg of diphenylmethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-3-mercapto-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate in 3 ml of methylene choride was added. The mixture was refluxed for 3 hours and after cooling to 20° C., the reaction mixture was poured into 10 ml of iced water. The mixture was stirred for 5 minutes, decanted and re-extracted with methylene chloride. The combined organic phases were dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of methylene chloride and acetone (1-1). After taking up again in isopropyl ether, 157 mg of syn isomer of racemic cis diphenylmethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-3-[(2-(1-pyrrolidinyl)-ethyl)-thio]-8-oxo-4-thia-1-azabicyclo [4,2,0]oct-2-en-2-carboxylate were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][CH:9]=1)=[O:7])([O-])=O>C1COCC1>[NH2:1][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:20])[CH3:18])[N:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: C[Si](C)(C)CCOCn1nccc1C(=O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nccc1C(=O)c1ccccc1N
Reaction time: 2 h
Yield: 48.8 %

Procedure:
The mixture of pyrazoles of examples 13C and 13D (2.35 g, 6.772 mmol) was taken up in dry THF (100 ml) and degassed. 5% Pd.-on-carbon (1.2 g) was added and the mixture hydrogenated at 30 psi and ambient temperature for 2 h. The mixture was filtered (celite filter aid) and evaporated and then chromatographed (eluant 30% EtOAc in hexanes) to provide the two tide compounds as an equimolar mixture (1.05 g, 49%).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[OH-].[K+].[F:8][C:9]([F:22])([F:21])[C:10]1([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[N:12]=[N:11]1.O>C(#N)C>[O:18]1[CH2:2][CH:17]1[C:16]1[CH:19]=[CH:20][C:13]([C:10]2([C:9]([F:8])([F:21])[F:22])[N:11]=[N:12]2)=[CH:14][CH:15]=1
Reactant: C[S+](C)C
Reactant: O=Cc1ccc(C2(C(F)(F)F)N=N2)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)C1(c2ccc(C3CO3)cc2)N=N1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 52.7 %

Procedure:
0.95 g of trimethylsulfonium iodide and 0.52 g of potassium hydroxide were dissolved in 4 ml of acetonitrile, and agitated for 10 minutes at 60° C. in a nitrogen gas atmosphere. 1.00 g of 4-(3-trifluoromethyl-3H-diazirine-3-yl)benzaldehyde were added together with 5.3 ml of acetonitrile, then 0.02 g of water were added. This was agitated for one hour at 60° C. in a nitrogen gas atmosphere. After extracting with ethyl ether, the resulting substance was washed twice with water and once with saturated saline solution, then dried with anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the resulting substance was purified by silica gel chromatography (hexane:chloroform=1:2, V/V) to obtain 0.56 g of 3-(4-oxiranylphenyl)-3-trifluoromethyl-3H-diazirine (52% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:27][C@@H:28](O)[CH2:29][C@H:30]([OH:32])[CH3:31].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[O:7]([C@@H:28]([CH3:27])[CH2:29][C@H:30]([OH:32])[CH3:31])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](O)C[C@H](C)Oc1ccccc1
Reaction time: 21 h

Procedure:
After phenol (300 mg, 3.19 mmol), triphenylphosphine (1006 mg, 3.83 mmol), (2R,4R)-2,4-pentanediol (399 mg, 3.83 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (2.01 ml, 3.83 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 21 hours. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-phenoxypentane-2-ol as a colorless oily substance (461 mg, yield: 80%/phenol).
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.[BH4-].[Na+]>CO>[F:1][CH:2]([F:18])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([OH:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1
Reactant: O=C(c1ccccc1)c1ccc(OC(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccccc1)c1ccc(OC(F)F)cc1

Procedure:
60 g of 4-difluoromethoxybenzophenone are reduced using sodium borohydride in 400 ml of methanol at 40° C. After an hour, the mixture is concentrated to dryness, 1.2 l of water is added to the contents of the flask and the mixture is extracted with chloroform. The organic phase is then dried and concentrated.
Reaction SMILES: B#B.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH2:18][C:19]#[N:20])[C:8]=2[CH:21]=1.Cl>O1CCCC1>[ClH:3].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH2:18][CH2:19][NH2:20])[C:8]=2[CH:21]=1
Reactant: N#CCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: NCCc1c(-c2ccccc2)sc2ccc(Cl)cc12

Procedure:
3 eq. of diborane in tetrahydrofuran and 1 eq. of the nitrile obtained in Step D are introduced into a 100 ml round-bottomed flask, and the mixture is then heated at reflux for 2 hours. After cooling, 15 eq. of 6M HCl are added and the tetrahydrofuran is evaporated off under reduced pressure. The precipitate formed is filtered off and recrystallised.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:5]=12.[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]=[C:27]1S(C)(=O)=O.O>CN(C=O)C>[CH3:22][O:23][CH2:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]=[C:27]1[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:4]3[CH:3]=[CH:2][N:1]=[C:5]23)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2cccnc21
Reaction time: 0.17 h

Procedure:
To a solution of 4-(9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (175 mg) obtained in Example 9, step C) in DMF (2 ml) was added sodium hydride (60% in oil, 30 mg) at room temperature by small portions. After stirring for 10 min, a solution of 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine[191 mg) in DMF (2 ml) was added, and the obtained mixture was stirred under microwave irradiation at 180° C. for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF) and recrystallized from ethanol to give the title compound (198 mg).
Reaction SMILES: [C:1]([CH:6]1[CH2:15][C:14](=[O:16])[C:13]2[C:8](=[C:9]([CH2:37][CH2:38][CH3:39])[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([OH:33])[C:25]=3[CH2:34][CH2:35][CH3:36])=[CH:11][CH:12]=2)[O:7]1)([O:3]CC)=[O:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:34]([C:25]1[C:26]([OH:33])=[C:27]([C:30](=[O:32])[CH3:31])[CH:28]=[CH:29][C:24]=1[O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:10]1[C:9]([CH2:37][CH2:38][CH3:39])=[C:8]2[C:13]([C:14](=[O:16])[CH2:15][CH:6]([C:1]([OH:3])=[O:2])[O:7]2)=[CH:12][CH:11]=1)[CH2:35][CH3:36]
Reactant: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OCC)CC3=O)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)O)CC3=O)ccc(C(C)=O)c1O
Temperature: 5 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
1.35 g (2.5 mmole) of the compound of Example 3 was dissolved in 50 ml of 50% ethanol-tetrahydrofuran in a 250 ml single neck round bottom flask equipped with a magnetic stirring bar. The contents of the flask were cooled to 5° C. in an ice bath and 25 ml of 0.2N sodium hydroxide solution was added. The reaction mixture was stirred at room temperature for eight hours. Most of the solvent was removed by rotoevaporation, 50 ml of water was added and the aqueous mixture acidified with dilute hydrochloric acid. The acidified solution was extracted three times with 150 ml portions of ethyl acetate and the combined extract washed once with brine. The ethyl acetate extract was dried over anhydrous magnesium sulfate, filtered, and the ethyl acetate removed by rotoevaporation to give 1.19 g (93%) of the title compound as a white solid, mp. 166°-168° C. Calc: C, 67.95; H, 7.08, Found: C, 67.79; H, 7.04.
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:8]=[CH:7][C:6](I)=[C:5]([CH2:10][CH3:11])[CH:4]=1.II.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[O:20]>O1CCCC1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:19]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[OH:20])=[C:5]([CH2:10][CH3:11])[CH:4]=1
Reactant: O=Cc1ccco1
Reactant: CCc1cc(Br)ccc1I
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1C(O)c1ccco1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Magnesium turnings (1.16 g, 0.048 mol) are stirred under a nitrogen atmosphere for 30 minutes, followed by dropwise addition of 4-bromo-2-ethyl-1-iodobenzene (15.0 g, 0.048 mol) as a solution in anhydrous tetrahydrofuran (40 ml), until the magnesium is just covered. A crystal of iodine is added and the reaction heated to reflux. After initiation begins external heating is stopped and the remaining aryl halide solution is added at such a rate as to maintain a controlled reflux. Once addition is complete the reaction is heated at reflux for 1 hour and the mixture is then cooled to room temperature. A solution of furan-2-carbaldehyde (4.0 ml, 0.048 mol) in anhydrous tetrahydrofuran (10 ml) is then added dropwise, and the suspension is then stirred at room temperature for 20 hours. The reaction is quenched with saturated ammonium chloride (200 ml) and extracted with ethyl acetate (200 ml). The organic phase is separated, dried over anhydrous magnesium sulfate then evaporated under reduced pressure. The crude product is purified by flash column chromatography (1:4 ethyl acetate/hexane eluant) to afford (4-bromo-2-ethyl-phenyl)furan-2-yl methanol as a brown oil.