Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6](=[O:24])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:34]1([N:40]([CH3:49])[C@H:41]([C:46](O)=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH:7]([NH:8][C:46](=[O:47])[CH:41]([N:40]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH3:49])[CH2:42][CH:43]([CH3:45])[CH3:44])[C:6](=[O:24])[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:15][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N(C)C1CCCCC1
Reaction time: 2 h
Yield: 13.4 %

Procedure:
O-Benzyl-L-tyrosine-t-butyl-amide (Ia, 0.5 g, 1.53 mmol) was dissolved in DMF (8 mL) and treated with diisopropylethylamine (0.8 mL, 4.6 mmol), N-cyclohexyl-N-methyl-leucine (Iid, 0.34 g, 1.53 mmol), and HBTU (0.58 g, 1.53 mmol). The reaction was stirred for 2 hours, then diluted with EtOAc (100 mL), washed with saturated bicarbonate solution (2×100 mL), brine (100 mL), dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 50% EtOAC/hexane. The resulting material was chromatographed again on silica gel eluting with 8% acetone/CH2Cl2 to give 0.11 g (14%) of the title compound. MS: 537 (M+1 for C33H49N3O3); TLC: SiO2, Rf 0.57 (10% MeOH/CH2Cl2).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.Cl.N([O-])=O.[Na+].[I-:20].[Na+]>O>[I:20][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: [I-]
Reactant: COC(=O)c1cc(N)c2cc[nH]c2c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(I)c2cc[nH]c2c1
Yield: 16.2 %

Procedure:
To a mixture of methyl 4-amino-1H-indole-6-carboxylate (EXAMPLE SP-216, step 3) (3.2 g) in water (50 mL) was added concentrated hydrochloric acid (5 mL). The mixture was chilled to below 5° C. with the addition of ice. To this was added sodium nitrite (1.16 g) dissolved in water (10 mL). The mixture was stirred chilled for 1 h followed by addition of sodium iodide (3 g) in water (20 mL). The mixture was stirred for 30 minutes, filtered and the solids collected by filtration were washed with water and dried at 50° C. The solids turned black and gas evolved rapidly upon drying. Column chromatography on silica gel (200 mL) using 20% hexanes in CH2Cl2 as eluent to give 0.82 g of the title compound: 1H NMR (CDCl3) δ 3.94, 6.55, 7.43, 8.14, 8.22, 8.62.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[SH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: Cc1cccnc1S
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Sc1ncccc1C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
1.21 ml (13.9 mmole) of propionyl chloride were added dropwise, whilst ice-cooling and under an atmosphere of nitrogen, to a solution of 1.46 g (11.7 mmole) of 2-mercapto-3-methylpyridine (prepared as described in Preparation7) and 1.94 ml (13.9 mmole) of triethylamine in 15 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was mixed with 50 ml of methylene chloride, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by medium pressure column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.89 g (yield 89%) of the title compound as a light yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH2:8][OH:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(Cl)Cl.N1C=CC=CC=1.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:20]1([C:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:9][CH2:8][CH:2]([OH:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 26.8 %

Procedure:
To 25 g of methyl 3,4-dihydroxybutanoate was added 250 mL of DCM and stirred to dissolve. 19.8 g of pyridine was added and cooled to 0° C. 41.4 g of trityl chloride was dissolved in 50 mL of DMC and was added at 0-5° C. for 15 minutes. The temperature was allowed to rise to room temperature and was stirred at room temperature for 17 hours. Water was added and the layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was triturated with 25 mL of cyclohexane and the product was purified to give 15 g of the pure product. 1H NMR (CDCl3): 4.25 (m, 1H), 3.6 (s, 3H), 3.15 (d, 2H), 2.5 (m, 2H), 7.2-7.4 (m, 15H).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:10])=O>C1C=CC=CC=1>[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:7]=1)=[O:10]
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(N)c1C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
Thionyl chloride (14.5 mL, 198 mmol) was added to a solution of 2-amino-6-methylbenzoic acid (10.0 g, 66.1 mmol) in benzene (250 mL). The resulting suspension was heated to reflux and stirred overnight. After cooling, the reaction was concentrated in vacuo, and the resulting residue was dissolved in chloroform (300 mL). Aniline (15, mL, 165 mmol) was added, and the mixture heated to reflux. After three hours, the reaction was allowed to cool and the resulting suspension was filtered. The filtrate was subjected to flash chromatography, and the Crude product recrystallized from isopropanol to provide compound 15 as a yellow crystalline solid. MS (ES): m/z 227 (M+H), 134. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.75 (d, 2H, J=7.9 Hz), 7.32 (t, 2H, J=7.8 Hz), 7.07 (t, 1H, J=7.3 Hz), 7.00 (t, 1H, J=7.8 Hz), 6.58 (d, 1H, J=8.1 Hz); 6.46 (d, 1H, J=7.4 Hz), 4.98 (br. s, 2H), 2.21 (s, 3H). The reaction described above and compound 15 are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([CH2:24][NH2:25])[CH2:12]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:26]([S:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)(=[O:30])=[O:29])[CH3:27]>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([CH2:24][NH:25][S:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:37][CH:36]=3)(=[O:40])=[O:39])[CH2:12]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(N2CCN(Cc3ccccc3)C(CN)C2)c1
Reactant: CCS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CCS(=O)(=O)Nc1ccc(S(=O)(=O)NCC2CN(c3cc(OC)cc(OC)c3)CCN2Cc2ccccc2)cc1

Procedure:
In a manner similar to Preparation 3, react 4-(3,5-dimethoxyphenyl)-1-(phenylmethyl)-2-piperazinemethanamine with 4-[(ethylsulfonyl)amino]benzenesulfonyl chloride to obtain the title compound.
Reaction SMILES: C1(S)C=CC=CC=1.[Cl:8][C:9]1[CH:46]=[CH:45][CH:44]=[CH:43][C:10]=1[CH2:11][CH2:12][N:13]([CH2:26][C@H:27]([NH:29][S:30]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[CH:39]=[N:38][CH:37]=[CH:36]2)(=[O:32])=[O:31])[CH3:28])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:8][C:9]1[CH:46]=[CH:45][CH:44]=[CH:43][C:10]=1[CH2:11][CH2:12][NH:13][CH2:26][C@H:27]([NH:29][S:30]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[CH:39]=[N:38][CH:37]=[CH:36]2)(=[O:32])=[O:31])[CH3:28]
Reactant: C[C@H](CN(CCc1ccccc1Cl)S(=O)(=O)c1ccccc1[N+](=O)[O-])NS(=O)(=O)c1ccc2cnccc2c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@H](CNCCc1ccccc1Cl)NS(=O)(=O)c1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
0.1 mL of thiophenol was added to a suspension of 300 mg of (R)—N-[1-{N-(2-chlorophenethyl)-2-nitrophenylsulfonamido}propan-2-yl]isoquinoline-6-sulfonamide and 360 mg of potassium carbonate in 20 mL of acetonitrile, and the mixture was stirred at room temperature for 16 hours. 50 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 179 mg of the title compound as a white solid (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]3[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][N:21]([S:51]([CH3:50])(=[O:53])=[O:52])[CH2:20][C@H:19]3[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:30])[CH3:31])[CH:26]([CH3:28])[CH3:27])=[CH:15][CH:16]=2)(=[O:9])=[O:10])=[CH:39][CH:40]=1
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCNC[C@H]2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(S(C)(=O)=O)C[C@H]2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of N-(4-chloro-benzyl)-N-isobutyl-4-((+/−)trans-3-triisopropylsilanyloxy-piperidin-4-yloxy)-benzenesulfonamide (185 mg, 304 μmol) in DCM (5 mL) was added DIPEA (106 μL, 609 μmol) followed by methanesulfonyl chloride (1 mL of a 231 μL, 3 mmol solution in 10 mL of DCM) and the reaction stirred at room temperature for 1 hour. Saturated aqueous NaHCO3 was then added, extracted with DCM, filtered through a phase separator and concentrated to give N-(4-Chloro-benzyl)-N-isobutyl-4-((+/−)trans-1-methanesulfonyl-3-triisopropylsilanyloxy-piperidin-4-yloxy)-benzenesulfonamide (271 mg, 100%). LCMS (m/z, Method A) ES+ 709 [M+23]+.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:11]=[N:10][C:9]([C:12]([OH:14])=O)=[CH:8][CH:7]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][NH2:28].C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl.ClCCl>[Cl:5][C:6]1[N:11]=[N:10][C:9]([C:12]([NH:28][CH2:27][CH2:26][C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[C:17]([Cl:16])[CH:18]=3)[NH:22][CH:21]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.7 %

Procedure:
Thionyl chloride (0.092 mL; 0.150 mmol) was added to a suspension of 6-chloropyridazine-3-carboxylic acid (0.100 g; 0.630 mmol) in chloroform (1 mL); the resulting mixture was refluxed for 18 hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.160 g; 0.693 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.271 mL; 1.58 mmol) were added. The resulting green solution was stirred at room temperature for 2 hours, diluted with dichloromethane and successively washed with sodium hydrogen sulphate (1M), sodium carbonate (1M) and brine, dried over magnesium sulphate and the crude material was purified by flash chromatography on silica gel (eluent 10 to 60% ethyl acetate in dichloromethane) to yield 0.048 g (23%) of 6-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyridazine-3-carboxamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@H:18]4[C@H:22]5[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]5[O:20][CH2:19]4)=[N:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[N:36]1([C:42]([O:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[N:36]1([C:42]([O:44][CH:45]2[CH2:50][CH2:49][N:48]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[N:13]=[C:12]5[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@@H:18]6[CH2:19][O:20][C@@H:21]7[C@H:25]([OH:26])[CH2:24][O:23][C@H:22]67)=[N:16][C:11]5=[CH:10][C:9]=4[Cl:35])=[CH:4][CH:3]=3)[CH2:47][CH2:46]2)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O=C(OC1CCNCC1)N1CCOCC1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(N4CCC(OC(=O)N5CCOCC5)CC4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(5-(4-bromophenyl)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and piperidin-4-yl morpholine-4-carboxylate following a procedure analogous to that described for Intermediate 23. LC (method 1): tR=1.03 min; Mass spectrum (ESI+): m/z=716 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[C:6]([F:10])[C:7]=1[O:8]C.CC(O)=O.O>I>[F:10][C:6]1[CH:5]=[C:4]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=[C:2]([F:1])[C:7]=1[OH:8]
Reactant: COc1c(F)cc(-c2cc(=O)c3ccccc3o2)cc1F
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2cc(F)c(O)c(F)c2)oc2ccccc12
Temperature: 110 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of 2′-hydroxyacetophenone (0.68 g, 5 mmol) in 10 mL anhydrous pyridine was added 3,5-difluoro-4-methoxybenzoyl chloride (1.03 g, 5 mmol) and the reaction mixture was stirred at rt for 15 h under nitrogen atmosphere. The reaction mixture was poured into 100 mL 2N HCl. The solid was filtered off, washed with water and dried under vacuum to give a white solid (1.44 g, 94%). The compound (1.42 g, 4.63 mmol) was dissolved in 10 mL anhydrous pyridine. Powdered KOH (0.78 g, 13.9 mmol) was added and the reaction mixture was stirred at rt overnight under nitrogen. Water (50 mL) was added and the solid was isolated by filtration, and washed with water to give yellow solid (1.05 g, 74%). To a suspension of the yellow solid (0.82 g, 2.67 mmol) in 6 mL glacial AcOH was added 3 drops of conc. HCl and the reaction mixture was stirred at 110° C. for 2 h. The mixture was cooled to rt and 50 mL water was added. The solid was isolated by filtration, washed with water and dried under vacuum to give 2-(3,5-difluoro-4-methoxyphenyl)chromen-4-one as a white solid (0.61 g, 79%). 2-(3,5-Difluoro-4-methoxyphenyl)chromen-4-one was suspended in 15 mL hydroiodic acid. Glacial AcOH (6 mL) was added and the reaction mixture was stirred at 110° C. for 4 h. The mixture was cooled to rt. Water (100 mL) was added and the solid was isolated by filtration, washed with water and dried under vacuum. The crude compound was washed with 1:1 dichloromethane and MeOH (15 mL) to give 2-(3,5-difluoro-4-hydroxyphenyl)-4H-chromen-4-one (0.416 g, 73%) as a pale yellow solid. MS (ES) m/z: 275.04 (M+1); Mp. 275-276° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[S-:10][C:11]#[N:12].[K+]>C(O)=O>[Cl:1][C:2]1[N:7]=[C:6]([S:10][C:11]#[N:12])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: N#C[S-]
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [K+]
Solvent: O=CO
Product: N#CSc1nc(Cl)ncc1F
Yield: 68 %

Procedure:
In 50 ml of formic acid, a reaction of 10.0 g of 2,4-dichloro-5-fluoropyrimidine and 5.8 g of potassium thiocyanate was conducted at room temperature (20° C.) for 5 hours in a similar manner as Synthesis Example 1. Then, the reaction mixture was treated in a similar procedure as Synthesis Example 1, there was obtained a 68.0% yield of 2-chloro-5-fluoro-4-thiocyanopyrimidine, m.p. 103°-104° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:49][C:50]1[CH:62]=[CH:61][C:53]2[NH:54][C:55]([C@@H:57]([NH2:60])[CH2:58][OH:59])=[N:56][C:52]=2[CH:51]=1.BrBr>O1CCCC1.ClCCl.C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([NH:60][C@H:57]([C:55]1[NH:54][C:53]2[CH:61]=[CH:62][C:50]([Br:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][OH:59])=[O:7]
Reactant: N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: BrBr
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CO)c2nc3cc(Br)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 43 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxyethylamine in tetrahydrofuran. Yield: 43%; Rf value: 0.23 (silica gel: dichloromethane/ethanol=95:5); C22H23BrN4O3 (471.36); mass spectrum: (M+H)+=471/473 (bromine isotope). The Examples that follow describe the preparation of pharmaceutical formulations which contain as active substance any desired compound of general formula (1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[N:27]([CH3:28])[C:18]2=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=[C:17]2[N:16]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH3:28][N:27]1[C:18]2=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=[C:17]2[N:16]=[C:15]1[C:14]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[OH:8]
Reactant: Cn1c(-c2ccncc2OCc2ccccc2)nc2cc(C(F)(F)F)cnc21
Agent: [Pd]
Solvent: CCO
Product: Cn1c(-c2ccncc2O)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A mixture of 1.16 g of 2-(3-benzyloxypyridin-4-yl-)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine, 60 ml of ethanol and 0.12 g of 5% palladium charcoal was stirred for 3 hours at room temperature under a hydrogen atmosphere of about 1 atm. The mixture was filtrated through Celite (registered trademark), and the filtrate was concentrated under reduced pressure, to obtain 0.27 g of 4-(3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine-2-yl]-pyridin-3-ol (hereinafter, referred to as present active compound 215).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[C:4]([N+:20]([O-])=O)[CH:3]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:20][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccccc1CSc1ccc(C)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COC(=O)c1ccccc1CSc1ccc(C)cc1N
Yield: 84.3 %

Procedure:
Following General Procedure L, the title compound (567 mg, 85%) was prepared from methyl 2-(((4-methyl-2-nitrophenyl)thio)methyl)benzoate (741 mg, 2.34 mmol), Zn (3.7 g, 58.44 mmol) and saturated aqueous NH4Cl (1 ml) in MeOH (20 ml).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6]>[Pd].CC#N>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][CH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH3:5])[CH:3]=1
Reactant: Cc1cccc(CN)c1
Agent: [Pd]
Solvent: CC#N
Product: Cc1cccc(CNCc2cccc(C)c2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
3-Methylbenzylamine (0.5 mmol) was heated with catalyst Pd@ba-GO (10 mg) and solvent CH3CN (0.2 mL) at 90° C. in a flask open to air for 6 hours, and then stirred also at 90° C. under H2 gas (1 atm) for 8 hours to obtain di-(3-methylbenzyl)amine. An unexpectedly high yield of 90% was observed.
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9]
Reactant: CC(=O)CCCCCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CCCCCC(=O)OCc1ccccc1

Procedure:
Benzyl 7-oxooctanoate was prepared by benzylation of 7-oxooctanoic acid with benzyl bromide and potassium carbonate in dimethyl formamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1>>[C:5]1([C:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:13])[S:1][CH:2]=[CH:3][CH:4]=1
Reactant: c1ccsc1
Reactant: O=C1CCCC(=O)O1
Product: O=C(O)CCCC(=O)c1cccs1
Temperature: 60 °C

Procedure:
Thiophene (19.5 ml) and glutaric anhydride (27.5 g) were mixed and heated to 60° C. under a nitrogen atmosphere until all solid dissolved. The heat was removed and 2.4 grams of 85% orthophosphoric acid was added. The reaction mixture was then heated to 100° C. for four hours, cooled, and 46 ml of water added. The mixture was extracted with ether then the ether phase was extracted with aqueous sodium hydroxide solution (2.5N). The aqueous phase was cooled and made acidic by addition of 6N hydrochloric acid. Solid which precipitated out was collected on a filter, washed with water and dried under vacuum at 60° C. Yield 9.2 g N.M.R. (CDCl3)δ2.1 (m, 2H), 2.54 (t, 2H), 3.04 (t, 2H), 7.14 (t, 1H), 7.64 (dd, 1H), 7.74 (d, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[C:13]([F:19])[C:9]=1[C:10](O)=[O:11].C(O)C.O>CCOCC>[F:7][C:8]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[C:13]([F:19])[C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1c(F)c(F)cc(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: OCc1c(F)c(F)cc(F)c1F
Reaction time: 3 h
Yield: 46.7 %

Procedure:
Lithium aluminium hydride (4.6 g) was added in small portions to a stirred solution of 2,3,5,6-tetrafluorobenzoic acid (30.0 g) in dry ether (600 ml) at the ambient temperature, and stirring continued for a period of 3 hours. After decomposition of the excess lithium aluminium hydride with ethyl alcohol, water was added in excess and the ethereal phase separated, washed with water, and concentrated to yield crude 2,3,5,6-tetrafluorobenzyl alcohol (13.0 g) as a colourless oil.