Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:29])=[C:10]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:19][CH2:18]3)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:30])[C:5]([C:31]([OH:33])=[O:32])=[CH:4]1)[CH3:2].O[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH3:3].[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:29])=[C:10]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:21][CH2:22]3)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:30])[C:5]([C:31]([O:33][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:32])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(c4ncccn4)CC3)c(OC(F)F)c21
Reactant: OCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCn1cc(C(=O)OCCN2CCOCC2)c(=O)c2cc(F)c(N3CCN(c4ncccn4)CC3)c(OC(F)F)c21
Product: N
Temperature: 25 °C
Reaction time: 96 h
Yield: 28 %
Yield: 137.2 %

Procedure:
In 3 l of methylene chloride were added 58.94 g (0.127 mole) of 1-ethyl-6-fluoro-8-difluoromethoxy-7-[4-(2-pyrimidinyl)piperazin-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 25.05 g (0.191 mole) of 4-(2-hydroxyethyl)morpholine, 23.3 g (0.191 mole) of 4-dimethylaminopyridine and 48.8 g (0.254 mole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and the mixture was stirred at room temperature for 4 days. Then, the solvent was removed under reduced pressure. The residue was dissolved in chloroform, washed with a 1N hydrochloric acid aqueous solution, washed with water and dried. The solvent was removed under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of chloroform: methanol: 28% aqueous ammonia=40:9:1) to obtain 50.25 g of the title compound as slightly yellowish white powder.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([Cl:14])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1Cl)([O-:3])=[O:2].[OH-:16].[K+].[CH2:18]([OH:22])[CH2:19][CH2:20][OH:21]>>[N+:1]([C:4]1[C:5]([O:16][CH2:18][CH2:19][CH2:20][OH:21])=[C:6]([Cl:14])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[O:21][CH2:20][CH2:19][CH2:18][OH:22])([O-:3])=[O:2]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: OCCCO
Agent: [K+]
Product: O=[N+]([O-])c1cc(Cl)c(OCCCO)c([N+](=O)[O-])c1OCCCO
Temperature: 85 °C

Procedure:
1 mole (271.5 g) of 3,5-dinitro-1,2,4-trichlorobenzene in 700 ml of 1,3-propanediol was heated to 85° C. 2 moles of powdered potassium hydroxide dissolved in 280 ml of 1,3-propanediol were added over 30 minutes. The reaction mixture was heated for 1 hour at 85° C. upon completion of the additions. After cooling, the expected product was filtered off, washed with water and then dissolved in 1.5 litres of ethyl acetate which, after washing with water, was dried over sodium sulphate. Upon concentration to dryness, a precipitate was obtained which, after having recrystallized from isopropyl ether, melted at 90° C.
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12](=O)[CH3:13])[CH:8]=[CH:9][C:10]=1[CH3:11].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:13])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: CC(=O)c1ccc(C)c(OCC(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1ccc(C(C)N[S@](=O)C(C)(C)C)cc1OCC(F)F
Yield: 66 %

Procedure:
The title compound is prepared in 66% yield (860 mg, clear colorless oil) from 1-(3-(2,2-difluoroethoxy)-4-methylphenyl)ethanone (880 mg, 4.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1>C(O)(=O)C>[C:24]([C:23]1[CH:27]=[C:19]([N:18]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[CH:7]=[C:6]2[C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[CH:20]=[CH:21][C:22]=1[OH:28])([OH:26])=[O:25]
Reactant: O=C(CC1CCCCC1=O)c1ccc(F)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc(F)cc3)cc3c2CCCC3)ccc1O

Procedure:
A solution of 17.9 g. (0.077 mole) of 2-(p-fluorophenacyl)cyclohexanone, 11.8 g. (0.077 mole) of 5-aminosalicylic acid, and 90 ml. of glacial acetic acid was heated under reflux under nitrogen for 43/4 hours, cooled and filtered. The collected solid was washed with water and recrystallized from acetic acid to provide 10.0 g. (37%) of yellow crystals, m.p. 239°-240°.
Reaction SMILES: N1[CH2:6][CH2:5][O:4][CH2:3]C1.Cl[CH:8](Cl)[C:9]([OH:11])=[O:10].[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>OS(O)(=O)=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:15][C:14]([CH:8]([C:16]2[CH:17]=[CH:18][C:13]([O:19][CH3:20])=[CH:14][CH:15]=2)[C:9]([OH:11])=[O:10])=[CH:13][CH:18]=1
Reactant: COc1ccccc1
Reactant: O=C(O)C(Cl)Cl
Reactant: C1COCCN1
Agent: O=S(=O)(O)O
Product: COc1ccc(C(C(=O)O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
To neat morpholine (43.56 g, 0.5 mol) was added dichloroacetic acid (12.89 g, 0.1 mol) portionwise under argon, with ice bath. When the addition was finished, the ice bath was removed and the reaction was allowed to stand at ambient temperature for 16 hours. The reaction mixture was dissolved in a mixed solvent of 120 mL acetic acid and 12 mL H2O and was stirred at room temperature until it was clear. To the reaction was then added anisole (43.2 g, 0.4 mol) followed by 100 mL concentrated H2SO4 with ice bath keeping temperature less then 25° C. The reaction was stirred at room temperature for 16 hours and warmed to 60° C. for 3 hours. The reaction mixture was poured over the ice and was extracted with CHCl3. The CHCl3 layer was then washed with 1N NaOH then filtered. The aqueous solution was acidified with HCl to give a cloudy solution which crystallized upon standing at room temperature for 64 hours. The crystalline solid was filtered and rinsed with H2O to give the acid (15.2 g, 55%).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:20][C@@:19]2([CH3:21])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[OH:22])[CH2:5][C:4]1=O.[NH2:24][OH:25].Cl.[CH3:27][C:28]([O-:30])=O.[Na+].O>O>[C:28]([O:22][C@H:13]1[CH2:12][CH2:11][C@H:10]2[C@H:9]3[C@H:18]([CH2:17][CH2:16][C@:14]12[CH3:15])[C@:19]1([CH3:21])[C@H:6]([CH2:5][C:4](=[N:24][OH:25])[C:3](=[N:2][OH:1])[CH2:20]1)[CH2:7][CH2:8]3)(=[O:30])[CH3:27]
Reactant: NO
Reactant: C[C@]12CC(=NO)C(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=NO)C(=NO)C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C

Procedure:
A suspension of steroid 7, NH2OH.HCl and NaOAc/H2O was refluxed for 20 minutes. The reaction was cooled to room temperature and poured into H2O. The precipitate was collected by filtration. The resulting solid 8 was washed with H2O and air and dried; wt. 23.4 g.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(N(CC)CC)C>[ClH:31].[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[CH:20]1[C:19]2[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=2[C:17]2[N:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:9][CH:10]=3)[N:24]=[CH:23][C:22]=2[CH2:21]1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)cc2Cl)C3)cc1
Solvent: CCN(CC)CC
Product: Cl
Product: Clc1ccc(C2Cc3cnc(Nc4ccc(CCN5CCCCC5)cc4)nc3-c3ccccc32)c(Cl)c1

Procedure:
This was synthesized by using 4-(6-(2,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, piperidine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=225-230° C. 1H NMR (DMSO) 400 MHz δ 10.05 (bs, 1H), 9.66 (s, 1H), 8.36 (d, J=6.4 Hz, 1H), 8.32 (s, 1H), 7.83-7.80 (m, 2H), 7.72-7.70 (m, 1H), 7.57-7.46 (m, 2H), 7.30-7.22 (m, 3H), 7.05 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 4.80-4.75 (m, 1H), 3.53-3.48 (m, 2H), 3.27-3.07 (m, 4H), 3.03-2.86 (m, 4H), 1.86-1.69 (m, 5H), 1.42-1.38 (m, 1H). LCMS 529 [M+H]. Calc. for C31H30Cl2N4.2.1 Hydrochloric acid: C, 61.44; H, 5.34; N, 9.24. Found C, 61.45; H, 5.32; N, 9.31.
Reaction SMILES: [H-].[K+].[CH3:3][C:4]1[C:5]([CH2:16][Si](C)(C)C)(O)[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]2[C:12]=1[O:11][CH2:10][O:9]2.O>O1CCCC1>[CH3:3][C:4]1[C:5](=[CH2:16])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]2[C:12]=1[O:11][CH2:10][O:9]2
Reactant: CC1=C2OCOC2CC(C)(C)C1(O)C[Si](C)(C)C
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1C(C)=C2OCOC2CC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
23 ml (about 1 eq.) of potassium hydride (20% in oil) were placed in a 750 four-necked sulphonation flask provided with a magnetic stirrer, dropping funnel and argon gasification, washed three times with hexane and 120 ml of tetrahydrofuran were added. A solution of 30.4 g (0.11 mol) of 4,6,6-trimethyl-5,6,7,7a-tetrahydro-5-trimethylsilylmethyl-1,3-benzodioxol-5-ol in 200 ml of tetrahydrofuran was added dropwise thereto at 0° C. Subsequently, the suspension was stirred at 20-30° C. for 2 hours. It was again cooled to 0° C. and 200 ml of water were cautiously added dropwise. Subsequent three-fold extraction with 100 ml of hexane each time, washing with saturated sodium chloride solution and drying over anhydrous sodium sulphate gave, after removal of the solvent under reduced pressure, 18.7 g of yellow oil which was subjected to short path distillation under reduced pressure. At 77-85° C./0.75 mbar (7.5 kPa) there were obtained 15.6 g (74% yield) of 4,6,6-trimethyl-5,6,7,7a-tetrahydro-5-methylidene-1,3-benzodioxol as a colorless oil. The content of desired product was 96% according to GC (area %). IR (film, cm−1): 1697, 1600; mass spectrum: 180 (M+, 50), 107 (100); 1H-NMR (C6D6, 400 MHz): inter alia 0.83 and 0.95 (2s, in each case 3H), 1.78 (bs, 3H), 3.9 (m, 1H), 4.59 (s, 1H), 4.79 (s, 1H), 4.75 (s, 1H), 4.91 (s 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].CC1C=CC(S(O[CH2:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Temperature: 70 °C
Yield: 98.7 %

Procedure:
4-Bromo-3,5-dimethylphenol (40.00 g), 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (72.71 g) and potassium carbonate (35.75 g) were added to N,N-dimethylformamide (400 mL), and the mixture was stirred. The mixture was heated to 70° C., stirred for 46 hr, and cooled to 5° C. Water (200 mL) was added dropwise at 10° C. or below, seed crystal (60 mg) was added, and water (400 mL) was continuously added. After stirring for 2 hr, the precipitated crystals were collected by filtration, washed with water (400 mL) and dried to give the title compound (63.08 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:23])[NH:13][C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH:28]([CH3:30])[CH3:29]>CN(C=O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:23])[N:13]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[NH2:22])[CH:28]([CH3:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)Nc1cc(C#N)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CCCCNC(=O)OC(C)(C)C)c1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (242 mg) obtained in Example 45-3 was dissolved in DMF (5.0 ml). The solution was added with 60% sodium hydride (29.1 mg) and then 2-iodopropane (79.6 μl) in an ice bath. The whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with distilled water and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (44.1 mg) as a pale-yellow oily substance.
Reaction SMILES: C([O:5][C:6]([C:8](NC(=O)OC(C)(C)C)=[CH:9][C:10]1[N:11]=[CH:12][O:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])(C)(C)C.Cl.[O:28]1CCOCC1>>[C:15]([C:14]1[O:13][CH:12]=[N:11][C:10]=1[CH:9]=[C:8]([OH:28])[C:6]([OH:5])=[O:7])([CH3:18])([CH3:17])[CH3:16]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NC(=Cc1ncoc1C(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)(C)c1ocnc1C=C(O)C(=O)O

Procedure:
Compound 2 (6.0 g, 16.3 mmol) was treated with 4N HCl-dioxane (64 ml) for 1 h at room temperature. After the solvent was removed, the residue was extracted with EtOAc, washed with 5% citric acid and saturated NaCl. Then, the organic layer was dried over Na2SO4 and evaporated in vacuo to obtain compound 3. yield 2.6 g (76%); m.p. 150-155° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 6.55 (s, 1H), 1.36 (s, 1H); m/z 211.0841 (M+) (calcd for C10H13NO4: 211.0844).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([Br:19])[C:6]2[O:10][C:9]([Br:11])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:18]=1.[CH3:20][N:21](C)C=O.[C-]#N.[Na+]>O>[C:20]([CH2:2][C:3]1[CH:4]=[C:5]([Br:19])[C:6]2[O:10][C:9]([Br:11])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:18]=1)#[N:21]
Reactant: BrCc1cc(Br)c2oc(Br)c(-c3ccccc3)c2c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1cc(Br)c2oc(Br)c(-c3ccccc3)c2c1
Reaction time: 16 h

Procedure:
A solution of 17.8 g. (0.040 mole) of 5-bromomethyl-2,7-dibromo-3-phenylbenzofuran in 150 ml. of N,N-dimethylformamide, 2.0 g. (0.04 mole) of sodium cyanide and 15 ml. of water is heated on a steam bath for 1.5 hours. The mixture is poured into one liter of water and stirred for about 16 hours. The mixture is extracted with 500 ml. of ethyl acetate, the extracts washed with water, then dried. Evaporation followed by trituration with hexane-ethyl acetate gives 5-cyanomethyl-2,7-dibromo-3-phenylbenzofuran as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:40]=[CH:41][C:42]([OH:50])=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:44]=1)[OH:38]>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][CH:31]([NH:35][CH2:36][CH:37]([C:39]5[CH:40]=[CH:41][C:42]([OH:50])=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:44]=5)[OH:38])[CH2:32][CH2:33]4)=[CH:26][CH:27]=3)[C:18](=[O:20])[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(NC5CCN(Cc6ccccc6)CC5)=NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 21) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 9) according to the procedure of Example 1 as a pale yellowish solid; mp >210° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.8 Hz, 2 H), 2.50-3.50 (m, 6 H), 2.92 (s, 3 H), 3.47 (s, 2 H), 3.70-4.00 (m, 2 H), 4.47 (dd, J=7.9, 4.3 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.95-7.05 (m, 2 H), 7.17 (d, J=1.9 Hz, 1 H), 7.20-7.55 (m, 8H); MS (ES) m/z:353.1 ((M+2 H)2+, 100%); 705.1 (MH+, 5%); HRMS Calcd. for C36H45N6O5S2 (MH+): 705.2893. Found: 705.2921.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH3:22].[CH2:24](O)[CH3:25]>>[CH2:24]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:2]=1[O:1][CH2:21][CH3:22])[CH3:25]
Reactant: CCI
Reactant: CCO
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1OCC
Yield: 74 %

Procedure:
To a solution of 2-hydroxy-4-trifluoromethyl-benzoic acid (5 g, 24.258 mmol, Matrix Scientific) in ethanol (50 mL) were added potassium carbonate (8.38 g, 60.645 mmol) and ethyl iodide (7.68 mL, 97.032 mmol). The reaction mixture was heated at gentle reflux for 4 h then concentrated in vacuo. The residue was taken in petroleum ether and water, and the layers were separated. The product was extracted with petroleum ether (1×). The organic layers were washed with brine (1×), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the crude residue by flash chromatography (40 g of silica gel, eluting with 10% ethyl acetate in hexane) gave 2-ethoxy-4-trifluoromethyl-benzoic acid ethyl ester as colorless oil (4.68 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19](O)=[O:20].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19]([NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=1)=[O:20]
Reactant: O=C(O)Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (2,6-dichloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)acetic acid (Step 56.1) and 3-(trifluoromethyl)aniline. Title compound: ES-MS: 462.9/464.9 [M-H]−; tR=5.08 min (System 1); Rf=0.37 (CH2Cl2/(2N NH3 in MeOH), 95:5).
Reaction SMILES: [C:1](OC(N1CCCC1CNC1C(N)=NC=C(Br)N=1)=O)(C)(C)[CH3:2].Br[C:24]1[N:29]=[C:28]2[N:30]([CH2:34][CH:35]3[CH2:39][CH2:38][CH2:37][N:36]3C(OC(C)(C)C)=O)[C:31](=[O:33])[NH:32][C:27]2=[N:26][CH:25]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[O:59]1[CH2:63][CH2:62][CH2:61][CH2:60]1>>[OH:59][C:63]1[CH:62]=[CH:61][C:60]([C:24]2[N:29]=[C:28]3[N:30]([CH2:34][CH:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)[C:31](=[O:33])[NH:32][C:27]3=[N:26][CH:25]=2)=[CH:2][CH:1]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCC1Cn1c(=O)[nH]c2ncc(Br)nc21
Reactant: CC(C)(C)OC(=O)N1CCCC1CNc1nc(Br)cnc1N
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=c1[nH]c2ncc(-c3ccc(O)cc3)nc2n1CC1CCCN1
Temperature: 120 °C
Yield: 80 %

Procedure:
tert-Butyl 2-((6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)pyrrolidine-1-carboxylate tert-Butyl 2-((3-amino-6-bromopyrazin-2-ylamino)methyl)pyrrolidine-1-carboxylate (2.0 g., 5.4 mmol), 1,1′-carbonyldiimidazole (1.75 g., 10.80 mmol), and tetrahydrofuran (7 mL) were combined in a sealed tube and heated to 120° C. overnight. The solvent was removed and the crude purified using silica gel chromatography (20% hexane in ethyl acetate) to yield the title compound (1.73 g., 80% yield). MS (ESI) m/z 398 [M]+, 400 [M+2]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:8]=1)=[O:5]
Reactant: BrCc1ccccc1Cc1ccccc1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2ccccc2Cc2ccccc2)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2,6-Difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(45 mg, 0.202 mmol), potassium carbonate (42 mg, 0.304 mmol) and 1-(bromomethyl)-2-(phenylmethyl)benzene (for a preparation see Intermediate 3)(64 mg, 0.245 mmol) were weighed into a vial with a stirrer. DMF (1 ml) was added, the vial was capped and the mixture was stirred at room temperature for 17 h. The reaction mixture was filtered, washing with MeOH to give a total volume of 2 ml. This solution was purified by MDAP (Sunfire column, formic acid buffer) (Method B). The solvent was removed to give the title compound as a colourless solid (10 mg); LCMS: (System 4) MH+=404, tRET=3.23 min.
Reaction SMILES: [CH:1](=[N:8][C@@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:10]([O:12]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([NH2:33])(=[O:32])[CH:30]=[CH2:31].CC(C)([O-])C.[K+]>C1COCC1>[CH:1](=[N:8][C:9]1([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:30][C:29](=[O:32])[NH:33][C:10]1=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(N)=O
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)N=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N=Cc2ccccc2)C(=O)N1
Reaction time: 3.5 h
Yield: 82.1 %

Procedure:
To a solution of 2 (4 g, 10.4 mmol) and acrylamide (1.11 g, 15.7 mmol) in THF (40 mL) was added portionwise potassium tert-butoxide (1.23 g, 11.0 mmol) over a period of 15 min at 0° C. After 3.5 h, the mixture was quenched with aqueous NH4Cl and extracted into EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to afford 3 (3.6 g, 82%) without further purification. Rf=0.33 (95:5 DCM:MeOH).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)(Cl)Cl>[C:32]([N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)(=[O:34])[CH3:33]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)n1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of 6.5 g of the compound of Example 1 in 50 ml of chloroform and 2.4 g of triethylamine is added dropwise 1.9 g of acetyl chloride over 15 minutes under cooling and stirring. After addition, the resulting mixture is stirred under cooling for 2 hours and then at room temperature for 3 hours. The reaction solution is washed with water, dried and then concentrated. The obtained residue is recrystallized from ethanol to give 5.7 g of 1-acetyl-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine as oale yellow crvstals. melting at 169°-171° C.