Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1.[CH3:27][S:28][C:29]1[N:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1>>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[N:12]=[CH:11][C:10]([C:8]([C:6]2[CH:7]=[C:2]([C:31]3[CH:32]=[CH:33][N:34]=[C:29]([S:28][CH3:27])[N:30]=3)[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Product: COc1ccc(-c2ccnc(SC)n2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1
Yield: 45 %

Procedure:
[6-(2,4-Difluoro-phenylamino)-pyridin-3-yl]-[2-methoxy-5-(2-methylsulfanyl-pyrimidin-4-yl)-phenyl]-methanone is prepared in analogy to example 11 from (5-bromo-2-methoxy-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanone and 2-methylsulfanyl-4-tributylstannanyl-pyrimidine in 45% yield:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:26]([F:27])=[C:25]([CH3:28])[C:24]([F:29])=[CH:23][C:9]=1[C:10]([C:12](=[CH:18][NH:19][CH:20]1[CH2:22][CH2:21]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11]>CN(C)C=O>[CH:20]1([N:19]2[C:23]3[C:9](=[CH:8][C:26]([F:27])=[C:25]([CH3:28])[C:24]=3[F:29])[C:10](=[O:11])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18]2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C)c(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(C)c(F)cc2c1=O
Yield: 90.2 %

Procedure:
16.5 g of potassium carbonate are added to a solution of 37.7 g of ethyl 2-(2-chloro-3,5-difluoro-4-methylbenzoyl)-3-cyclopropylamino-acrylate in 100 ml of anhydrous dimethylformamide. The reaction mixture is then stirred under reflux for 2 hours and poured hot onto ice. The precipitate is filtered off with suction, washed thoroughly with water and dried in vacuo over calcium chloride at 100° C. 30.4 g of ethyl 1-cyclopropyl-6,8-difluoro-7-methyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 177°-179° C. are obtained.
Reaction SMILES: C([O:4][C@H:5]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=O)C.[H][H]>C(O)(=O)C.[Pd]>[OH:4][C@H:5]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CC(=O)O[C@H](CC(=O)c1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)[C@H](O)CCc1ccccc1

Procedure:
(R)-2-acetoxy-4-oxo-4-phenylbutyric acid (2.36 g) was dissolved in 15 ml of acetic acid, and 0.21 g of 5% by weight palladium on carbon (water content 50%) were added thereto. The mixture was stirred in a hydrogen atmosphere at 60° C. for 24 hours. Palladium on carbon was separated by filtration, and the solvent was then distilled off. Thirty milliliters of 1−N hydrochloric acid were added to the resulting (R)-2-acetoxy-4-phenylbutyric acid, and the mixture was heat-refluxed for 3 hours while being stirred.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][C:36]2=[N:39][N:40]([CH3:43])[C:41]([CH3:42])=[C:35]2[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][C:36]5=[N:39][N:40]([CH3:43])[C:41]([CH3:42])=[C:35]5[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1c2c(nn1C)CCN(CCCCl)C2
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCc2nn(C)c(C)c2C1
Temperature: 80 °C
Yield: 207.9 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.50 g, 0.16 mmol, 1.0 eq) and K2CO3 (0.05 g, 0.32 mmol, 2.0 eq) in 20 mL of DMF was added 5-(3-chloropropyl)-2,3-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (0.05 g, 0.19 mmol, 1.2 eq). The reaction mixture was heated at 80° C. for 8.0 h and concentrated in vacuo. The residue was poured into a mixture of water (100 mL) and CH2Cl2 (150 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a yellow solid (0.17 g, 21.23%), HPLC: 96.27%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 513.02 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.93-2.18 (m, J=4.0 Hz 2H), 2.41 (s, 3H), 2.88 (s, 3H), 2.90-2.95 (m, 6H), 2.97-3.01 (m, 2H), 3.89 (s, 3H), 4.19-4.25 (m, 2H), 7.35 (s, 1H), 7.49 (t, J=8.42 Hz, 1H), 7.57-7.61 (m, 2H), 8.17 (t, J=5.66 Hz, 1H), 8.61 (s, 1H) ppm.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([N:27](C)[C:28](=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[CH3:36][C:37]1[N:42]=[CH:41][C:40]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([NH:27][CH3:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)=[O:21])[CH:7]=2)=[CH:39][CH:38]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: CN[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccc(C)nc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 99.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.81 min, m/z=472.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([O:18]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:13][CH:12]([C:28]([O:30][CH3:31])=[O:29])[CH2:11]2)=[CH:6][CH:5]=1.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[N:34]1([C:16]([N:14]2[CH2:15][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:32])([F:33])[F:1])=[CH:5][CH:6]=3)[CH2:11][CH:12]([C:28]([O:30][CH3:31])=[O:29])[CH2:13]2)=[O:18])[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1
Reactant: C1CSCCN1
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
A solution of 10.3 g (17.9 mmol, purity 81%) of the compound from Example 43A in 1-methyl-2-pyrrolidone (65 ml) was admixed with 12.6 ml (13.7 g, 132 mmol) of thiomorpholine and 11.5 ml (8.56 g, 66.2 mmol) of N,N-diisopropylethylamine and then heated in 5 portions in a single-mode microwave (Emrys Optimizer) at 150° C. for 1 h. For workup, the reaction solutions were combined and purified directly by means of preparative HPLC. Yield: 5.63 g (71% of theory)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH2:14][CH:15]2[CH:19]([CH2:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16]2.CO.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[OH:22][CH:18]1[CH2:17][CH2:16][CH:15]2[CH:19]1[CH2:20][CH:21]=[C:13]([O:12][CH3:11])[CH2:14]2
Reactant: COC1=CCC2C(=O)CCC2C1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CO
Solvent: CCOCC
Product: COC1=CCC2C(O)CCC2C1
Temperature: -10 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Diisobutylaluminium hydride (28.5 ml) was added dropwise to a stirred solution of 3-methoxybicyclo[4,3,0]non-3-en-7-one (20 g; prepared as described in Reference Example 1) in diethyl ether (600 ml), with cooling to -10° C. The resulting solution was stirred at 0° C. for 3 hours and then it was treated with methanol (20 ml). A gelatinous precipitate was formed, and the mixture was then treated with anhydrous sodium sulphate (200 g) and filtered with the aid of diatomaceous earth. The filtrate was concentrated at reduced pressure, to give 7-hydroxy-3-methoxybicyclo[4,3,0]non-3-ene (16 g).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:3]1.O[N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[N:31]1([O:26][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:17][CH2:16][N:15]([C:12]4[CH:11]=[CH:10][C:9]([N:4]5[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]5)=[CH:14][CH:13]=4)[CH2:20][CH2:19]3)=[CH:22][CH:23]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1
Reactant: C[C@@H]1CN(c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2)C[C@H](C)O1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(N3CCN(c4ccc(C(=O)On5nnc6ccccc65)cc4)CC3)cc2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A mixture of 4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoic acid (1.01 g), 1-hydroxybenzotriazole (370 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (986 mg) in methylene chloride (100 ml) was stirred for 4 hours at room temperature then evaporated under reduced pressure. Water was added to the residue and the resulting precipitate collected by filtration, washed with water, then dried under hi-vacuum to give 4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoic acid benzotriazol-1-yl ester (1.197 g).
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH4+].[Cl-]>CCOCC.C1COCC1>[Cl:1][C:2]([F:8])([F:9])[C:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)C(F)(F)Cl
Reaction time: 2 h

Procedure:
A solution of 20 g of ethyl chlorodifluoroacetate in 150 ml ether was treated with one equivalent of benzyl magnesium chloride in 63 ml THF at -40° C. under nitrogen. After 2 hours, the reaction was poured into aqueous NH4Cl and extracted with ether. Evaporation and distillation (0.1 mm Hg) of the residue gave 24.8 g of an oil which was used directly.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=2)[N:30]=[C:29]([C:41]#[N:42])[N:28]=1>ClCCl>[O:23]=[CH:24][CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=2)[N:30]=[C:29]([C:41]#[N:42])[N:28]=1
Reactant: Cc1ccc(-c2cc(CCCO)nc(C#N)n2)cc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccc(-c2cc(CCC=O)nc(C#N)n2)cc1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.7 %

Procedure:
Dess-Martin periodinane (4.2 g) was added to a solution of 4-(3-hydroxy-propyl)-6-(3,4-dimethylphenyl)-pyrimidine-2-carbonitrile (2.0 g) in dichloromethane (100 mL), and the resulting suspension stirred at room temperature for 45 min. The mixture was then washed with water (3×100 mL), dried over sodium sulphate, and evaporated at reduced pressure. The residue was flashed on silica gel using Petrol/EtOAc (2:1) to afford 4-(3-oxo-propyl)-6-(3,4-dimethylphenyl)-pyrimidine-2-carbonitrile as a white solid (1.9 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[C:12]([C:13]([O:15]C)=[O:14])[C:6]=2[N:5]=1.O.[OH-].[Li+].O.Cl>CO>[CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:6]=2[N:5]=1
Reactant: COCc1nc2c(C(=O)OC)cc([N+](=O)[O-])cc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1nc2c(C(=O)O)cc([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
To a suspension of methyl 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylate (Example 11, Step 3) (4.8 g) in MeOH (120 mL), were added lithium hydroxide hydrate (4.56 g) and water (54 mL). The mixture was stirred at room temperature for 16 hours. Under ice-cooling, 1N hydrochloric acid was added slowly to the reaction mixture to adjust the pH to about 2. The precipitate was collected by filtration and dried to obtain 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g). To the solution of 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g) in DMF (90 mL), HBTU (8.23 g), triethylamine (2.19 g) and 3-chloro-2-methylaniline (3.07 g) were added sequentially, and the solution was stirred for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and stirred for 1 hour. The precipitate was collected by filtration and washed sequentially with water and ethyl acetate to obtain N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) as pale yellow powder. To the solution of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) in MeOH-THF (1:1, 120 mL), were added 1% platinum+0.1% copper-activated carbon (Degussa type CF105 R/W) (1.4 g). The mixture was stirred under hydrogen atmosphere (3 atm) for 4 hours. The catalyst was filtered off, and the mother liquid was concentrated. The residual solid was washed with ethyl acetate to obtain 6-amino-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (5.1 g) as pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:7][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:51])[NH:40][C:41]3[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:50])[CH3:49])=[CH:43][CH:42]=3)=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O.CCO>[CH3:23][C:20]1[O:19][C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:32]4[CH:33]=[CH:34][C:35]([NH:38][C:39](=[O:51])[NH:40][C:41]5[CH:42]=[CH:43][C:44]([NH:47][C:48](=[O:50])[CH3:49])=[CH:45][CH:46]=5)=[CH:36][CH:37]=4)=[N:3]3)=[CH:8][CH:7]=2)=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5ccc(C)o5)cc4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazoline (0.15 g, 0.00045 mol; prepared as described in Example 2; Scheme 6B), N-(4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)phenyl)acetamide (0.23 g, 0.00059 mol; prepared according to the methods described in Scheme 9), cesium carbonate (0.44 g, 0.00135 mol), toluene (10 mL), EtOH (4 mL) and water (2 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd (PPh3)2Cl2 (0.022 g, 0.0000315 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 3 h. The reaction mixture was cooled to room temperature to get the precipitate. The precipitate was collected by filtration to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 3% MeOH in chloroform). The compound was further purified by flash column chromatography using 230-400 silica gel and 1.5% MeOH in chloroform to yield the title compound [0.0252 g, 10%]. 1H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 8.92 (s, 1H), 8.67 (s, 1H), 8.42 (d, J=8.8 Hz, 2H), 8.01 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 7.17 (d, J=3.2 Hz, 1H), 6.32 (d, J=2.8 Hz, 1H), 3.83 (s, 4H), 3.80 (s, 4H), 2.41 (s, 3H), 2.02 (s, 3H). LC-MS (ESI): Calculated mass: 562.2; Observed mass: 563.1 (RT: 0.64 min).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[CH2:16]([NH:19][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1)[C:17]#[CH:18].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[O:25]=[C:22]1[N:21]=[C:20]([NH:19][CH2:16][C:17]#[CH:18])/[C:24](=[CH:1]/[CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)/[S:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (11.2 g) in 2-propanol (230 mL) were added 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (16.3 g) and piperidinium acetate (3.90 g). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, the precipitate was removed, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (14.0 g).
Reaction SMILES: C(I)(I)(I)I.[Br:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([N+:18]([O-])=O)[C:16]=1[Cl:17])[C:10]([O:12][CH3:13])=[O:11]>CC(O)=O.[Fe]>[NH2:18][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([Br:6])[C:16]=1[Cl:17])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(Br)c(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: IC(I)(I)I
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(Cl)c(Br)c1
Temperature: 60 °C
Yield: 93.3 %

Procedure:
(I4C): Fe powder (2.84 g, 50.9 mmol) was added to a solution of methyl 3-bromo-4-chloro-5-nitrobenzoate (5 g, 16.98 mmol) in AcOH (29.3 ml). The suspension was heated to 60° C. 1 h. The vessel was cooled to rt and then AcOH was removed via rotovap. The residue was placed in a 1 L beaker and was carefully neutralized with saturated sodium bicarbonate. The precipitate was removed via filtration through Celite and the filtrate was extracted with EtOAc. The organics were combined, washed with water and brine, then dried over sodium sulfate. Filtration and concentration afforded methyl 3-amino-5-bromo-4-chlorobenzoate (4.19 g)) as a yellow solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1Br)(=[O:3])[CH3:2].[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH:24]=[CH:23][N:22]=[CH:21]1.C1(C)C=CC=CC=1>[Cl-].[Zn+2].[Cl-].[O-2].[Zn+2].C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:31][C:28]1[CH:27]=[CH:26][C:25]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:30][CH:29]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Br
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: [Cl-]
Agent: [O-2]
Agent: [Zn+2]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-n2ccnc2)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A mixture of 3 g (22 mmol) of zinc chloride, 5 g of 4 Å molecular sieve, 6.5 g of zinc oxide, 9 g (25 mmol) of 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranosyl bromide, 3.2 g (20 mmol) of 4-(1H-imidazol-1-yl)phenol, 70 ml of toluene and 70 ml of acetonitrile is prepared. The mixture is kept stirred at 55° C. for 24 hours and then cooled and filtered. The residual solid is rinsed on the filter with ethyl acetate and the combined filtrates are successively washed with water, with an N sodium hydroxide solution and again with water to neutral pH. The organic phase is subsequently dried over magnesium sulfate and concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel, elution being carried out using an ethyl acetate/ethyl ether mixture (8/5; v/v). The expected compound is thus obtained in the form of a pulverulent solid which is reacted further in order to obtain the nonacetylated xyloside.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].Br[C:8]1[C:12](Br)=[CH:11][S:10][CH:9]=1.O>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:8]1[C:12]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][S:10][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Brc1cscc1Br
Reactant: CCCC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCCc1cscc1CCCC
Yield: 64 %

Procedure:
Butylmagnesium bromide (140 mmol) was added dropwise at 0° C. to a mixture solution of 3,4-dibromothiophene (50 mmol) and [1,3-bis (diphenylphosphino)propane]dichloronickel(II) (0.3 mmol) in 100 mL of dry diethyl ether. The resulting mixture was heated and refluxed for 6 hours. The reaction mixture was combined with water, and extracted with diethyl ether. The extract solution was derived over magnesium sulfate, and the solvent was evaporated therefrom to obtain a crude product. The crude product was purified by silica gel column chromatography and by distillation to obtain the intended product (32 mmol) in a 64% yield.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1.[Br:13]Br>O.[K+].[Br-]>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]([O:4][CH3:3])=[N:6][CH:7]=1
Reactant: BrBr
Reactant: COc1ccnc(OC)c1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)c(Br)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
According to Scheme 23 Step 2: To a solution of KOH (0.5 eq, 0.8 mmol, 40 mg) in water (75 mL) was added 2,4-dimethoxypyridine (1 eq, 2.00 mmol, 0.21 g) followed by the dropwise addition of Br2 (1 eq, 2.00 mmol, 0.20 g) in 1M aqueous KBr solution (75 mL). The reaction was stirred at room temperature for 5 hours and then poured onto water (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated under reduced pressure to afford 5-bromo-2,4-dimethoxypyridine (1.40 mmol, 0.30 g, 70%) as a colorless oil. The crude product was reacted on.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N

Procedure:
The title compound was prepared from (2-nitro-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example A2) by hydrogenation with 5% Pd/C according to the general procedure J (method a). Obtained as a white solid (9.06 g).