Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)CC)C.[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:15]([S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(C(C)c2nccn2S(=O)(=O)N(C)C)c1C
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To a solution of the compound of Example 1 (100 mg, 0.5 mmol) and triethylamine (77 μl, 0.55 mmol) in anhydrous tetrahydrofuran (4 ml), was added dimethylsulphamoyl chloride (59 μl, 0.55 mmol). The reaction mixture was stirred at 60° C., under nitrogen, for 36 h and then concentrated in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (10 ml) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:11]([NH:18][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: Brc1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: c1ccc(CNc2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), benzylamine (128 mg; 0.127 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.150 g (67.3%); MS m/z: 224.5 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.33 (s, 2H); 6.64 (d, 1H, 4J=2.1 Hz); 6.98 (dd, 1H; 4J=2.1 Hz, 3J=8.9 Hz); 7.23-7.38 (m, 5H); 7.51 (d, 1H, 3J=8.9 Hz); 8.07 (s, 1H); HPLC (METHOD [A]): rt 22.19 min (80.6%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[C:18]1([CH2:17][O:9][C:5]2[C:6]([F:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:10])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(F)c1OCc1ccccc1

Procedure:
4-bromo-2,6-difluorophenol (2 g, 9.57 mmol) was dissolved in DMF (19 mL) and to this was added Cs2CO3 (4.37 g, 13.34 mmol) and the solution was stirred for 15 minutes before benzyl bromide (1.64 g, 9.57 mmol) was added. After 2 hours at room temperature the mixture was partitioned between ethyl acetate (100 mL)/water (100 mL), the layers were separated and the aqueous extracted with ethyl acetate (100 mL). The combined organics were washed with brine (2×50 mL) and water (2×50 mL) and dried over MgSO4. The crude material (2.67 g) was filtered through a pad of silica and eluted with hexane to afford 4-bromo-2,6-difluorophenyl phenylmethyl ether after evaporation of the solvent (2.38 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[Cl:9][CH2:10][C:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12].CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:9][CH2:10][C:11]([NH:14][C:15]([NH:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)(CCl)N=C=O
Reactant: Cc1ccncc1N
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1NC(=O)NC(C)(C)CCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.1 %

Procedure:
4-Methyl-pyridin-3-ylamine (1.98 g, 18.33 mmol) was added to solution of 1-chloro-2-isocyanato-2-methyl-propane (I-200c: 3 g, 20.40 mmol) in toluene (30 mL). The resulting mixture was stirred at room temperature for 3 days. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was filtered and the residue was dried to afford 4.3 g of the product (87.75% yield).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[N:17]3[CH:18]=[CH:19][N:20]=[C:21]([CH3:22])[C:16]3=[C:15]([Br:23])[N:14]=2)[CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:23][C:15]1[N:14]=[C:13]([C@@H:10]2[CH2:11][CH2:12][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:9]2)[N:17]2[CH:18]=[CH:19][N:20]=[C:21]([CH3:22])[C:16]=12
Reactant: CC(=O)OCC(=O)N1CC[C@@H](c2nc(Br)c3c(C)nccn23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nccn2c([C@@H]3CCN(C(=O)CO)C3)nc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To (R)-2-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-2-oxoethyl acetate (0.105 mmol, 40 mg) in methanol (4 ml) was added potassium carbonate (0.126 mmol, 17.40 mg). After stirring the reaction mixture at room temperature for one hour, the solids were removed by filtration and the filtrate concentrated in vacuo to give (R)-1-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-2-hydroxyethanone (35.6 mg). Reaction of the latter compound (35.6 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (50 mg) according to the procedure described in example 4 step 4c and purification using prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid) gave ((R)—N-(4-(3-(1-(2-hydroxyacetyl)pyrrolidin-3-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (25.8 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH2:6][CH3:7])=[O:4].O1CCCC1.[H-].[Na+].C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH2:6]([N:5]1[CH2:8][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:22][CH2:2][C:3]1=[O:4])[CH3:7]
Reactant: CCN(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)C(=O)CCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To a 250 mL round bottom flask containing tert-butyl 4-((2-chloro-N-ethylacetamido)methyl)-4-hydroxypiperidine-1-carboxylate (3.14 g) was added tetrahydrofuran (50 mL). The entire vessel was placed under nitrogen and stirred at room temperature. To this was portionwise added NaH (60% in mineral oil, 2 g, 50.0 mmol). After complete addition, the reaction mixture was stirred at room temperature. After 3 hours, saturated aq sodium bicarbonate (70 mL) was added to the flask (slowly dropwise via pipette at first, then the final 60 mL can be added directly). The solution was transferred to a reparatory funnel containing ethyl acetate (150 mL) and water (50 mL). The organic layer was washed with the aqueous solution, separated, and set aside. The aqueous layer was washed with ethyl acetate (1×50 mL). The combined organic extracts were washed with brine (2×50 mL), separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (50-100% ethyl acetate:hexanes) afforded the title compound (1.7 g, 61%). MS(ES)+ m/e 299.5 [M+H]+.
Reaction SMILES: CO.[F:3][C:4]1[CH:36]=[CH:35][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[C:25]([C:27]([O:29]C)=[O:28])[N:26]=4)=[CH:18][C:17]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:14])=[O:13])=[C:10]([CH3:11])[C:6]=2[CH:5]=1.[OH-].[Na+]>O>[F:3][C:4]1[CH:36]=[CH:35][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=4)=[CH:18][C:17]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:13])=[O:14])=[C:10]([CH3:11])[C:6]=2[CH:5]=1
Reactant: COC(=O)c1coc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(C(=O)O)co3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
Into 150 mL of methanol was dissolved 7.85 g of Compound 23, and 15 mL of 10% aqueous sodium hydroxide solution and 15 mL of water were added thereto at room temperature, followed by 15 minutes of stirring. The precipitated crystals were dissolved by adding 90 mL of water, and the solution was stirred at the same temperature for 17 hours. After the solvent was removed by evaporation, 45 mL of 1 mol/L hydrochloric acid was added to the residue, the precipitated crystals were collected by filtration and washed with water, and 100 mL of DMF was added to the resulting crude crystals, followed by heating under refluxing. After filtration at a hot state, 70 mL of ethanol was added and recrystallization was carried out. The resulting crystals were collected by filtration, washed several times with ethanol and water alternatively, and dried over diphosphorus pentoxide under reduced pressure to obtain 5.78 g of the title compound as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[C:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=2)=O)[C:4]=1[NH:27]C(=O)OC(C)(C)C.[I-:35].[Na+]>C(O)(=O)C.C(O)=O>[I:35][C:9]1[C:5]2[C:4](=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=2)[N:27]=[C:11]([C:13]2[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=2)[CH:10]=1
Reactant: COCCOc1ccn2c(C(=O)C#Cc3cccc(OC)c3NC(=O)OC(C)(C)C)cnc2c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=CO
Product: COCCOc1ccn2c(-c3cc(I)c4cccc(OC)c4n3)cnc2c1
Temperature: 60 °C
Yield: 92 %

Procedure:
To tert-butyl 2-methoxy-6-(3-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)-3-oxoprop-1-ynyl)phenylcarbamate (2.51 g, 5.39 mmol) and sodium iodide (16.2 g, 108 mmol) was added acetic acid/formic acid (5 mL/5 mL). The reaction vessel was purged with N2 and heated to 60° C. for 3 hours. The reaction was then cooled to ambient temperature and diluted with H2O/DCM (50 mL/100 mL), followed by extraction with DCM. The combined organics were washed with saturated NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/MeOH 10:1) provided the desired product (92%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)(=O)C.[H][H]>[Pt].C(O)(C)C>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)CNc1c(N)c(Cl)nc2ccccc12
Yield: 73 %

Procedure:
A solution of 2-chloro-N-(2-methylpropyl)-3-nitro-4-quinolinamine (120 g), acetic acid (300 mL), isopropyl alcohol (300 mL), and 5% platinum on carbon (7.2 g) was allowed to stand at room temperature for 30 h under 2 bars of hydrogen pressure. The resulting solution was filtered, and the solvent was removed from the filtrate at reduced pressure. The residue was dissolved in aqueous hydrochloric acid (1 L, 4N). The product was precipitated by adding this solution to a solution of sodium hydroxide. The precipitate was filtered and washed with water to afford the product 2-chloro-N4 -(2-methylpropyl)-3,4-quinolinediamine in 73% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](=[CH:28]/[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])/[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2.CC1(C)CCC(C)(C)C2C=C(/C(=C/CCCCCCCCCCCCC)/C(NC3C=CC(C(O)=O)=CC=3)=O)C=CC1=2>>[CH3:1][C:2]1([CH3:42])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])/[C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCCCCCCCCC/C=C(\C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CCCCCCCCCCCCC/C=C(\C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCCCCCCCCCCCC/C=C(/C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
Following the basic procedure of Example 19 (d), beginning with 503 mg (0.9 mmol) of methyl (Z)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido]benzoate, 435 mg (89%) of (Z)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido]benzoic acid of melting point 164°-5° C. were obtained.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]=[CH:24]/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>>[CH2:5]([C@H:2]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][N:23]([S:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)(=[O:22])=[O:21])[C:3]1=[O:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N=C/C=C/c2ccccc2)cc1
Reactant: O=CC(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2C=C[C@H](c3ccccc3)[C@H](Cc3ccccc3)C2=O)cc1
Yield: 40 %

Procedure:
The title compound was prepared according to the general procedure from 2-chloro-3-phenylpropanal and trans-N-(4-methoxybenzenesulfonyl)-3-phenyprop-2-ene-1-imine using 10 mol % 7 and 1.5 equiv DIPEA in 40% yield. 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, 2H, J=7.0, 2.1 Hz), 7.24-7.10 (m, 4H), 7.09-6.94 (m, 7H), 6.47 (dd, 2H, J=8.0, 1.0 Hz), 5.48 (dd, 1H, J=8.0, 6.3 Hz), 3.90 (s, 3H), 3.33-3.30 (m, 1H), 3.27-3.21 (m, 1H), 3.15 (dd, 1H, J=14.6, 4.3 Hz), 2.10 (dd, 1H, J=14.6, 9.0 Hz); 13C NMR (100 MHz, CDCl3) δ 170.2, 164.3, 138.8, 137.4, 131.5, 129.2, 129.1, 128.8, 128.7, 128.2, 127.7, 126.6, 124.1, 114.4, 114.3, 56.0, 48.9, 41.1, 31.5; IR (thin film) ν 3062, 3029, 2926, 1721, 1594, 1496, 1362, 1263, 1167, 1091, 1027 cm−1; HRMS (ESI) calcd for C25H23NO4S [M+Na]+ XX, found XX.
Reaction SMILES: CCOCCO[CH2:7][CH2:8][O:9][C:10]([CH:12]=[CH2:13])=[O:11].[CH3:14][C:15](N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH3:14][CH2:15][CH2:7][CH2:8][O:9][C:10]([CH:12]=[CH2:13])=[O:11]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: C=CC(=O)OCCOCCOCC
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCC
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A solution of 39.2 g (0.208 mol) of di(ethylene glycol) ethyl ether acrylate and 916 mg (0.0056 mol) of AIBN in 100 ml of dry toluene is degassed by purging with argon for 3 hours. This solution was added to the above solution [Example 3a] by syringe. The mixture is stirred at 60° C. under argon for 48 hours. The solvent is removed by evaporation under vacuum. (viscous yellow oil; 1H NMR: total conversion ˜100%; GPC: not available due to incomplete solubility in THF).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)=[CH:9][C:8]([N:18]2[C:22]([CH:23]([CH3:25])[CH3:24])=[N:21][N:20]=[N:19]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][NH2:34])=[N:31][CH:32]=1>>[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)=[CH:9][C:8]([N:18]2[C:22]([CH:23]([CH3:25])[CH3:24])=[N:21][N:20]=[N:19]2)=[CH:7][C:3]=1[C:4]([NH:34][CH2:33][C:30]1[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][N:31]=1)=[O:6]
Reactant: Cc1ccc(-c2cc(-n3nnnc3C(C)C)cc(C(=O)O)c2F)nc1
Reactant: Cc1cnc(CN)cn1
Product: Cc1ccc(-c2cc(-n3nnnc3C(C)C)cc(C(=O)NCc3cnc(C)cn3)c2F)nc1

Procedure:
2-Fluoro-5-(5-isopropyl-tetrazol-1-yl)-3-(5-methyl-pyridin-2-yl)-benzoic acid was reacted with C-(5-methyl-pyrazin-2-yl)-methylamine using the procedure of step 4 of Example 7 to provide 2-fluoro-5-(5-isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-3-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=447.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:19].[Na+]>CO.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:19]
Reactant: COC(=O)CCCCCSc1ccc(Cl)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCCCCS(=O)c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To a solution of 6-(4-chlorophenylsulfanyl)-hexanoic acid methyl ester (2.5 g, 9.2 mmol) in methanol (100 mL) was added dropwise at 0° C. a solution of sodium metaperiodate (2.6 g, 12 mmol) in distilled water (30 mL). The mixture was heated at 60° C. for 1 hour. The solution was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL), then with brine (50 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (1:1 to 8:2 ethyl acetate:40-60° C. petroleum ether). The title compound was obtained as a colourless oil (2.0 g, 76%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1.CCOCC>[ClH:28].[C:22]1([S:19]([C:16]2[S:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:18][CH:17]=2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccc3)s2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)c1cnc(N2CCNCC2)s1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
To a solution of 0.73 mmol 4-(5-benzenesulfonyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml dioxane was added dropwise 7.32 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 80° C. for 2.5 h. The reaction mixture was then cooled to 0° C. and diluted with ether. The resulting crystals were collected by filtration and washed with ether to afford the title compound as a light brown crystalline solid (yield 81%). MS (m/e): 309.9 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[C:27]([O:28]CC5C=CC=CC=5)[C:22]4=[N:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[C:27]([OH:28])[C:22]4=[N:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(OCc5ccccc5)cccn34)n2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(O)cccn34)n2)CC1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A mixture of 4-[4-(8-benzyloxy-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (0.215 g) and Pd/C (10%, 600 mg) in EtOH (200 mL) was stirred under H2 overnight. The reaction mixture was heated and filtered hot through silica. The product was washed with DCM, and the filtrate concentrated and dried to provide 4-[4-(8-hydroxy-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (128 mg), which was used without further purification.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:15]([O:17][C:18](=[O:23])[CH2:19][C:20](=[NH:22])[NH2:21])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18]([C:19]1[CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:23])=[C:20]([NH2:21])[NH:22][C:20]=1[NH2:21])=[O:23])[CH3:16]
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1-c1ccccc1
Yield: 33 %

Procedure:
Upon heating a solution of 9.1 g biphenyl-2-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 200 ml ethanol for 2 hours, 2,6-diamino-4-(biphenyl-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 215° (ethanol) is obtained.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]>C(O)C>[C:9]([C:8]1[CH:17]=[CH:18][C:5]([NH:2][NH2:3])=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 75 %

Procedure:
20 ml of hydrazine hydrate were added to the suspension of 52.33 g of 4-chloro-3-nitrobenzophenone in 200 ml of abs. ethanol under stirring. The reaction mixture was stirred at room temperature for 75 minutes, then slowly heated to the boiling point. After completion of the violent reaction, the mixture was refluxed for an additional 1 hour. After cooling down, the crystals were filtered by suction, thoroughly washed with water and dried at 80° C. Thus, 38.62 g (75%) of 4-benzoyl-2-nitrophenylhydrazine were obtained as orange-red crystals, m.p.: 163°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:14]2[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=2)[C:17]([O:19]C(C)(C)C)=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.II.O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[C:14]2[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=2)[C:17]([OH:19])=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2cccc(C(=O)OC(C)(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: II
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2cccc(C(=O)O)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A solution of 253B (100 mg, 0.20 mmol) in acetonitrile (5 mL) was treated with iodine (15.54 mg, 0.061 mmol) and water (50 μL, 2.78 mmol). The reaction mixture was stirred at 80° C. for 8 hours. The reaction mixture was diluted with ethyl acetate, and washed with water. The aqueous layer was extracted with ethyl acetate (4×20 mL). The pooled organic phase was dried over Na2SO4 and concentrated. The residue was triturated with DCM and filtered. The filtrate was concentrated, dissolved in DCM, and purified by flash chromatography, silica column (12 g, gradient elution from hexanes-ethyl acetate in 15 min.). The appropriate fraction was concentrated under reduced pressure and dried in vacuo to yield 253C (57.5 mg, 64.9% yield) as a yellow solid. HPLC: Rt=4.23 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=434.0 [M+H]+.