Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[I-].[Na+].C[O:32][CH2:33][CH2:34][O:35][CH3:36]>>[O:35]1[C:36]2([CH2:8][CH2:13][N:12]([CH2:2][CH2:3][O:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([NH:17][C:18]5[CH:26]=[C:25]6[C:21]([CH:22]=[N:23][NH:24]6)=[CH:20][CH:19]=5)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]4)=[CH:7][C:6]=3[O:27][CH3:28])[CH2:11][CH2:10]2)[O:32][CH2:33][CH2:34]1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: COCCOC
Agent: [I-]
Agent: [Na+]
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCC2(CC1)OCCO2
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 716.0 mg (5.0 mmol) of 1,4-dioxa-8-azapiro[4,5]decane and 75.0 mg (0.5 mmol) of sodium iodide in 5 mL of DME was heated at 135° C. for 16 hr. The work up gave 173.1 mg (69.2%) of the product as aoff white solid, m.p. 245° C. (dec.), mass (electrospray, m/e): M+H 501.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(F)cc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3ccc(F)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 69 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.0 mmol), 4-Fluoro-phenylamine (0.27 g, 2.5 mmol), Cs2CO3 (2 M, 3.0 Xantphos (58 mg, 0.1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in dioxane (5 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give (4-Fluoro-phenyl)-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine as brown solid in 69% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18].Cl>C1COCC1.O>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17]([OH:19])=[O:18])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)c1ccc(C(=O)O)cc1
Reaction time: 0.33 h
Yield: 86 %

Procedure:
1-Bromo-4-trimethylsilyl-benzene (0.426 ml, 2.18 mmol) was dissolved in THF (20 ml), and n-butyllithium (1.59 M solution in n-hexane, 1.51 ml, 1.40 mmol) was added dropwise at −78° C. After stirring for 20 minutes, crushed dry ice (excess) was added. The reaction solution was stirred at room temperature for one hour, and 1 M hydrochloric acid and water were then added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 4-trimethylsilanyl-benzoic acid (363 mg, 86%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:42][CH3:43])=[C:39]([OH:41])[CH:40]=1.Cl>C(O)(C)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([O:42][CH3:43])=[C:39]([OH:41])[CH:40]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: COc1ccc(N)cc1O
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1O

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (prepared according to a procedure similar to that described in Example 27, Step C) and 5-amino-2-(methyloxy)phenol were heated in isopropanol with catalytic conc. aq. HCl using conditions similar to those described in Example 27, Step D. HRMS C31H23N6O3F2 (M+H)+ calcd 565.1794, found 565.1795.
Reaction SMILES: CI.[C:3]([C:6]1[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[S:9][CH:10]=1)(=[O:5])[CH3:4].[C:14](=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C)C=O.O>[C:3]([C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1)(=[O:5])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1csc(C(=O)O)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(C(C)=O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyliodide (783 mg, 5.51 mmoles) was added to a stirred suspension of 4-acetyl-2-thiophenecarboxylic acid (prepared according to Satonaka, H., Bull. Chem. Soc. Japan 56:2463 (1983)) (782 mg, 4.59 mmoles) and sodium carbonate (1.70 g, 16.08 mmoles) in 25 ml of N,N-dimethylformamide. After stirring overnight at room temperature the mixture was poured into water (125 ml), saturated with solid sodium chloride and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine, dried (magnesium sulfate) and concentrated in vacuo to an off-white solid (761 mg, 90%), m.p. 94°-6° C. EIMS (m/z): 184 (M+, 74%), 169 (M+ --CH base), 153 (M+ --CH3O, 51%); 1HNMR (DMSO-d6) delta, 8.17 (1H, d, J=1.5 Hz), 8.13 (1H, d, J=1.5 Hz), 3.88 (3H, s), 2.51 (3H, s).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][C:30]=1[CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[O:13][CH2:14][C:15]1[S:16][C:17](/[C:20](/[CH2:26][CH3:27])=[CH:21]/[CH:22]=[C:23](Br)Br)=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][C:30]=1[CH2:31][O:32][Si:33]([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35])[O:13][CH2:14][C:15]1[S:16][C:17](/[C:20](/[CH2:26][CH3:27])=[CH:21]/[C:22]#[CH:23])=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC/C(=C\C=C(Br)Br)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#C/C=C(\CC)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3.9 g (5.4 mmol) of 2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-5-((E)-4,4-dibromo-1-ethylbuta-1,3-dienyl)thiophene are dissolved in 100 mL of THF and the mixture is cooled to −78° C. 4.4 mL (11 mmol) of 2.5 M butyllithium are added slowly and the reaction medium is stirred at the same temperature for 1 hour. After the usual treatment and chromatography on silica gel (eluent: 96 heptane/4 ethyl acetate), the desired product is obtained in the form of a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.C([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)(=O)C.[OH-].[Na+].O>C(O)C>[OH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: CC(=O)OCCCCCBr
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc2nc(SCCCCCO)[nH]c2c1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
2.46 g of 5-methyl-2-mercaptobenzimidazole and 3.4 g of 5-bromopentyl acetate were dissolved in 30 ml of ethanol and the mixture was refluxed with stirring under heating for 7 hours. After cooling to room temperature, the reaction mixture was added with was 22.5 ml of 2 N sodium hydroxide solution and stirred at room temperature for 1 hour, and then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=95:5) to obtain 3.04 g of the title compound as pale yellow oil (yield: 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]#[C:15][Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]#[CH:15])([OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#C[Si](C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
A mixture of the 4-Hydroxy-4-trimethylsilanylethynyl piperidine-1-carboxylic acid tert-butyl ester (7 g, 23.5 mmol, 1 eq) and potassium carbonate (1.0 g, 7.25 mmol, 0.3 eq) in MeOH (30 ml) were stirred for 6 h at room temperature. After this time, the solvent was removed under reduced pressure and the residue suspended in diethyl ether. The suspension was washed with saturated ammonium chloride and water and dried over MgSO4. After filtering, the filtrate was evaporated to give the product (4.5 g, 86%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)[NH2:19])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:12])[CH3:14]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(NC(=O)c2cc(Cl)ccc2O)cc(C(C)(C)C)c1
Yield: 34.1 %

Procedure:
Using 5-chlorosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3](OC(=O)C(C)C)[CH3:4].[CH:14]1(C(O)=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][CH2:4][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C1CCCCC1
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Product: CSC(=O)OCCC1CCCCC1

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing isobutyric acid with cyclohexanecarboxylic acid in Step B affords O-(cyclohexylethyl) S-methyl thiocarbonate (6) as an oil.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH3:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Pt]=O.C(O)(=O)C>[OH:23][CH:16]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[CH3:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN1C=CC=CC1C(=O)c1ccccc1
Agent: O=[Pt]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC(=O)O
Product: CN1CCCCC1C(O)c1ccccc1
Reaction time: 8 h
Yield: 89.3 %

Procedure:
The trifluoromethanesulfonate salt of N-methyl-2-benzoylpyridine (23.2 g, 0.066 mol) was added to a Parr bottle containing platinum oxide (0.20 g) and acetic acid (100 ml). Hydrogenation was stopped after 8 hours and a 299 psi drop in pressure. The reaction mixture was filtered. The filtrate was concentrated using a rotovap and poured onto ice. It was basified using 25% sodium hydroxide to pH 11. This aqueous mixture was extracted with ethyl acetate. The organic layer was washed with a small amount of water and brine. It was dried over potassium carbonate, filtered and stripped. The residue was dissolved in toluene and filtered. The toluene was stripped using the rotovap leaving 12.1 g (88% yield) 2-(α-hydroxybenzyl)-N-methylpiperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH2:29][C:30]1[C:31]([C:37](O)=[O:38])=[N:32][C:33]([Br:36])=[CH:34][N:35]=1>C(#N)C>[NH2:29][C:30]1[C:31]([C:37]([NH:1][C:2]2[CH:7]=[C:6]([C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=[CH:4][C:3]=2[N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:38])=[N:32][C:33]([Br:36])=[CH:34][N:35]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)c3ccccc3)cc2N)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)c3ccccc3)cc2NC(=O)c2nc(Br)cnc2N)CC1
Yield: 50 %

Procedure:
Following method 11, tert-butyl 4-(2-amino-4-benzoylphenyl)piperazine-1-carboxylate was coupled to 3-amino-6-bromopyrazine-2-carboxylic acid with TEA (1.5 eq) in ACN at 55° C. for 48 hours. Concentrated, triturated in cold ACN, filtered, and dried in vacuo yielding tert-butyl 4-(2-(3-amino-6-bromopyrazine-2-carboxamido)-4-benzoylphenyl)piperazine-1-carboxylate (50%). LCMS (m/z): 581.1 (MH+); LC Rt=4.00 min.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@@H:41]3[CH3:50])=[CH:36][N:35]=2)[C:30](=[O:51])[N:29]([CH3:52])[CH:28]=1)(=O)C.O.[Li+].[OH-]>C1COCC1>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH:46]5[CH2:47][O:48][CH2:49]5)[CH2:42][C@@H:41]4[CH3:50])=[CH:36][N:35]=3)[C:30](=[O:51])[N:29]([CH3:52])[CH:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Yield: 40.8 %

Procedure:
At room temperature, to a solution of 106a (153 mg 0.22 mmol) in THF/iPA/H2O (6 mL/6 mL/2 mL) was added LiOH (70 mg, 2.9 mmol) while stirring. This mixture was stirred for 0.5 h. Then, H2O (20 mL) was added and the mixture was extracted with EA (30 mL×3). The combined organic layer was dried with Na2SO4 and concentrated to give a yellow solid, which was further purified by reverse-phase prep-HPLC to afford 106 as a white solid (60 mg, 42% yield). LCMS: [M+H]+ 668. 1H NMR (500 MHz, CDCl3) δ 8.57 (dd, J=2.0, 7.0, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.48 (t, J=2.5, 1H), 7.33 (d, J=7.0, 1H), 7.16 (d, J=8.0, 1H), 6.96 (dd, J=2.5, 9.0, 1H), 6.87 (s, 1H), 6.83 (d, J=9.0, 1H), 4.69-4.72 (m, 4H), 4.55 (d, J=11.5, 1H), 4.29-4.38 (m, 2H), 4.14-4.20 (m, 3H), 3.90-3.93 (m, 1H), 3.71 (s, 3H), 3.57 (s, 1H), 3.48 (s, 1H), 3.09-3.14 (m, 2H), 2.52-2.61 (m, 7H), 2.23 (s, 1H), 1.88-1.91 (m, 2H), 1.79-1.81 (m, 2H), 0.99 (d, J=5.0, 3H)
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[Cl-].[S:9]1[C:13]([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][N:11]2[CH:34]=[N:35][CH:36]=[C:10]12.[CH2:37]([O:40][C:41]([N:43]1[C@H:47]([CH:48]=O)[CH2:46][C@@H:45]([O:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH2:44]1)=[O:42])[CH:38]=[CH2:39].C(OCC)(=O)C>C1COCC1.CS(C)=O>[CH2:37]([O:40][C:41]([N:43]1[C@H:47]([CH:48]=[CH:14][C:13]2[S:9][C:10]3=[CH:36][N:35]=[CH:34][N:11]3[CH:12]=2)[CH2:46][C@@H:45]([O:50][S:51]([CH3:54])(=[O:52])=[O:53])[CH2:44]1)=[O:42])[CH:38]=[CH2:39]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C=O
Reactant: c1ccc([P+](Cc2cn3cncc3s2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C=Cc1cn2cncc2s1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
Potassium t-butoxide (1.06 g) is added to a solution of 2.24 g of (imidazo[5,1-b]thiazol-2-yl)methyltriphenylphosphonium chloride hydrochloride in a mixture of 5 ml of THF and 5 ml of dimethylsulfoxide under ice cooling. The mixture is stirred under ice cooling for 2 hr, a solution of 1.32 g of (3R,5S)-1-allyloxycarbonyl-3-methanesulfonyloxy-5-formylpyrrolidine in 5 ml of THF, and the mixture is stirred under ice cooling for 2 hr. Ethyl acetate is added to the reaction mixture, and the mixture is successively washed with dilute hydrochloric acid and saturated saline and dried over magnesium sulfate. The solvent is removed by evaporation. The residue is purified by column chromatography on silica gel to give 1.07 g of (3R,5S)-1-allyloxycarbonyl-3-methanesulfonyloxy-5-[2-(imidazo[5,1-b]thiazol-2-yl)vinyl]pyrrolidine (a mixture of geometrical isomers).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:18]=O)[CH3:13].Cl>CO>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:13]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CCOc1cc(C=O)ccc1OCc1ccccc1
Agent: Cl
Solvent: CO
Product: CCOc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-ethoxy-4-benzyloxybenzaldehyde 1.80 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.33 g.
Reaction SMILES: O=[C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:10][NH:11][C:3]1=2.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:10][NH:11][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)c2[nH]nc(-c3ccc(Cl)cc3)c2[nH]1
Product: Cc1cc(Cl)c2[nH]nc(-c3ccc(Cl)cc3)c2n1

Procedure:
A mixture of 4,7-dihydro-7-oxo-5-methyl-3-(4-chlorophenyl)-1H-pyrazolo[4,3-b]pyridine (D15) (0.8 g) in phosphoryl chloride (20 ml) was heated under reflux under nitrogen for 20 mins and then evaporated to dryness in vacuo. The residue was basified with 10% sodium carbonate solution and extracted with ethyl acetate (3×200 ml). The organic fraction was washed with water, dried (Na2SO4), and evaporated to dryness in vacuo, and recrystallised from ethyl acetate to afford the title compound (0.4 g), m.p. 243°-245° C.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12](=[O:14])[CH3:13])[CH2:9]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:46]=[C:47]1[NH:56][C:55]2[N:54]=[CH:53][C:52](/[CH:57]=[CH:58]/[C:59](O)=[O:60])=[CH:51][C:50]=2[CH2:49][CH2:48]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[C:12]([CH:10]1[CH2:11][N:8]([C:59](=[O:60])[CH:58]=[CH:57][C:52]2[CH:51]=[C:50]3[C:55](=[N:54][CH:53]=2)[NH:56][C:47](=[O:46])[CH2:48][CH2:49]3)[CH2:9]1)(=[O:14])[CH3:13]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CC(=O)C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1CN(C(=O)C=Cc2cnc3c(c2)CCC(=O)N3)C1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
1-Azetidin-3-yl-ethanone TFA (700 mg, 3.54 mmol), EDCI (676 mg, 3.54 mmol), HOBt (477 mg, 3.54 mmol) and diisopropylethylamine (2.1 mL, 11.8 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (600 mg, 2.36 mmol) in dimethylformamide (15 mL) at room temperature. The reaction mixture was stirred overnight. The reaction mixture was then diluted by addition of ethyl acetate (40 mL) and water (40 mL). The organic layer was discarded and the aqueous layer was gasified with an aqueous solution of saturated sodium carbonate until pH=12 and finally extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (1:0 to 95:5) as eluent to obtain the title compound as a white solid (354 mg, 50%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[N:14]1([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12][CH3:13])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: CCCC(c1ccc(C(=O)OC)cc1)n1ccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(c1ccc(CO)cc1)n1ccnc1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
1.0 g of benzoic acid methyl ester of example 1 is dissolved in 15 ml of tetrahydrofuran and mixed with 0.15 g (3.9 mmol) of lithium aluminum hydride and left at room temperature for 1 hour. The reaction solution is mixed with 50% sodium hydroxide solution and the organic phase is decanted. The organic phase is concentrated by evaporation in a vacuum and distilled on a bulb tube, boiling point 200° C./0.03 mbar. 0.6 g of 4-[1-(1-imidazolyl)-butyl]-benzyl alcohol is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH2:20][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:22][CH3:23])[N:12]2[N:11]=1)[CH3:2].[S:28]([Cl:32])(=O)(=[O:30])[OH:29].S(Cl)(Cl)(=O)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:28]([Cl:32])(=[O:30])=[O:29])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH2:20][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:22][CH3:23])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Solvent: O=S(=O)(Cl)Cl
Product: CCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 300 mg (0.81 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-(2-n-propylbutyl)-3H-imidazo[5,1-f][1,2,4]-triazin-4-one (Example 25A) and 950 mg. (8.1 mmol) of chlorosulphuric acid. This gives 300 g (78.9%) of sulphonyl chloride which is directly reacted further.