Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[N:12]([C:21]2[N:22]=[C:23]([NH2:29])[NH:24][C:25](=[O:28])[C:26]=2[N:27]=1)[C@@H:13]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:14]1.C(O)(=O)C>CS(C)=O>[CH2:2]([O:9][C:11]1[N:12]([C:21]2[N:22]=[C:23]([NH2:29])[NH:24][C:25](=[O:28])[C:26]=2[N:27]=1)[C@@H:13]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc2c(nc(Br)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Nc1nc2c(nc(OCc3ccccc3)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Temperature: 65 °C

Procedure:
Two hundred mL of dimethyl sulfoxide (DMSO) are added to a freshly prepared solution of sodium benzoylate (made from benzyl alcohol (75 mL) and sodium (2.14 g)) under an atmosphere of argon. 8-Bromodeoxyguanosine (10 g, 29 mmol) in DMSO (80 mL) is added to the resulting mixture and the reaction is heated to 65° C. for 24 hours. After cooling to room temperature, the reaction mixture is neutralized with glacial acetic acid and the DMSO is removed by vacuum distillation at 65° C. The remaining solution is poured into ether with stirring. The oily residue that remains after decanting off the ether is added to acetone and the resulting white precipitate is removed by filtration. After stirring with water, the slurry is filtered and the collected white solid recrystallized from methanol to give 8-(benzyloxy)-2'-deoxyguanosine.
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:12]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH3:30])=[N:11]2)=O)(C)(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>ClCCl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([N:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:30])=[N:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:6]#[N:5])[CH:9]=3)[N:14]=2)=[CH:19][CH:20]=1
Reactant: C[C@H]1CCCN1c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1ccc(F)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CCCN1c1nc2cc(C#N)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)—N-tert-butyl-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxamide (160 mg, crude) in dichloromethane (30 mL) was added TFAA (4 mL). The resulting solution was stirred overnight at room temperature and then quenched by the addition water (100 mL), adjusted to pH 7 with sodium bicarbonate, and extracted with dichloromethane (3×30 mL). The organic layers combined and dried over anhydrous sodium sulfate and concentrated in vacuo to (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carbonitrile as a yellow solid (100 mg, 53%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[OH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=1
Reactant: OCCOCCCl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCOCCO)cc1
Yield: 56 %

Procedure:
2-(2-Chloroethoxy)ethanol (1, 0.18 mol), ethyl 4-hydroxybenzoate (2, 0.12 mol) and potassium carbonate (0.24 mol) were stirred in N,N-dimethylformamide (DMF) at 120° C. for 10 hours to obtain ethyl 4-(2-(2-hydroxyethoxy)-ethoxy)benzoate 3, followed by tosylation according to usual process to obtain a compound 4 in a yield of 56%.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].[C:8]([OH:17])(=[O:16])[C@H:9]([C@@H:11]([C:13]([OH:15])=[O:14])[OH:12])[OH:10].C(O)C>O>[NH:1]1[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:13]([C@H:11]([C@@H:9]([C:8]([O-:17])=[O:16])[OH:10])[OH:12])([O-:15])=[O:14]
Reactant: O=C(O)C1CCN1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CCN1
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]

Procedure:
The method described in Example 1 above was followed using DL-AzeOH (3.7 g; 37 mmol), D-tartaric acid (3.0 g; 20.0 mmol), ethanol (4.5 g) and water (5.5 g) to yield 3.8 g (83%) of L- AzeOH-D-tartrate with a d.e. of 95%.
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].Cl[CH2:13][CH2:14][OH:15].Cl>CO>[C:3]1([CH2:2][CH2:1][S:9][CH2:13][CH2:14][OH:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCCc1ccccc1
Reactant: OCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCCSCCc1ccccc1
Reaction time: 6 h
Yield: 68.2 %

Procedure:
Phenethylmercaptan (2.0 g) and potassium hydroxide (0.81 g) in methanol (15 ml) were stirred together under nitrogen for 15 min. 2-Chloroethanol (2.33 g) was added and the solution stirred under nitrogen for 6 h. 2N hydrochloric acid was added to acidify the mixture to pH5, and the methanol evaporated in vacuo. The residue was partitioned between water (100 ml) and diethyl ether (100 ml) and separated. The aqueous phase was re-extracted with diethyl ether (100 ml) and the combined ethereal layers dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System F (3:1) gave the title compound (1.80 g) as a colourless oil. T.l.c. (diethyl ether) Rf 0.70
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([CH3:28])=[C:10]([C:25]([OH:27])=[O:26])[S:11][C:12]=1[NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:15])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[CH3:28][C:9]1[C:8]([C:6]([OH:7])=[O:5])=[C:12]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:15])[S:11][C:10]=1[C:25]([OH:27])=[O:26]
Reactant: CCCCCCCCNC(=O)Nc1sc(C(=O)O)c(C)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCCCCCCNC(=O)Nc1sc(C(=O)O)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.6 %

Procedure:
(7.1) To a stirring solution of 3-methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester (50.0 mg, 0.13 mmol) in CH2Cl2 (1 mL) was added TFA (1 mL). The reaction was stirred at RT for 2 h, and then solvent was removed under reduced pressure to give a solid. The product was dissolved in EtOAc, washed with sat. NaHCO3 (aq.), and brine. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure to give 10.0 mg of a solid (22%): 1H NMR (CDCl3) δ 10.45 (bs, 1H), 6.27 (bs, 1H), 5.00 (bs, 1H), 3.50-3.20 (m, 2H), 2.37 (s, 3H), 1.70-1.40 (m, 2H), 1.26 (bs, 10H), 0.88 (t, 3H, J=6.2 Hz). MS (EI): 312.9 (m+—COOH).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[OH:19][NH3+:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:11]([CH:12]=[N:20][OH:19])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
55.23 g (0.199 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate are suspended in 400 ml of methanol/100 ml of water and treated with 15.27 g (0.219 mol) of hydroxylammonium chloride. 11.56 g (0.11 mol) of sodium carbonate—dissolved in 100 ml of water—are then slowly added dropwise at room temperature. After stirring at room temperature for 4 hours, the methanol is removed in a rotary evaporator, the residue is diluted with water and the mixture is extracted three times with dichlormethane. 56.05 g (96% of theory) of methyl 2-chloro-3 hydroximinomethyl-4-methylsulfonylbenzoate having a melting point of 126-130° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:12])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23](Cl)=O>O1CCCC1>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]1[O:11][CH2:10][CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]=1
Reactant: NC(CCO)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1cccc(F)c1C1=NC(c2ccc(Cl)cc2)CCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.9 %

Procedure:
To a solution of 0.9 g of 3-(4-chlorophenyl)-3-amino-1-propanol, 0.5 g of triethylamine in 10 ml of tetrahydrofuran at 0° C., was added dropwise 0.8 g of 2,6-difluorobenzoyl chloride. The reaction mixture was stirred at room temperature for 5 hours. The precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. To the residue, there was added 20 ml of tetrahydrofuran and 2.4 g of triphenylphosphine and further added 2.0 g of diisopropyl azodicarboxylate. The reaction mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.5 g of 2-(2,6-difluorophenyl)-4-(4-chlorophenyl)-5,6-dihydro-4H-1,3-oxazine. ND23.2 1.5532
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:14]1[O:24][C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[O:17][CH:15]1[CH3:16]>C1COCC1.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:14]1[O:24][C:18]2([CH2:23][CH2:22][N:21]([C:2]3[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=3[C:4]#[N:5])[CH2:20][CH2:19]2)[O:17][CH:15]1[CH3:16]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: CC1COC2(CCNCC2)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1COC2(CCN(c3ccc(C(F)(F)F)cc3C#N)CC2)O1

Procedure:
A solution of 2-fluoro-5-trifluoromethylbenzonitrile (2.01 g, 10.61 mmol) and 4-piperidone propylene ketal (1.71 g, 10.9 mmol) in THF (10 mL) was stirred at room temperature (1 h). The resulting mixture was diluted with ether and sodium carbonate solution. The aqueous layer was extracted with two portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (24).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([C:14]1[CH:19]=[C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:27][N:26]=3)[O:22][N:21]=2)[CH:17]=[C:16]([CH3:36])[C:15]=1[CH2:37][CH2:38][C:39](O)=[O:40])[CH3:13]>>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][C:39](=[O:40])[CH2:38][CH2:37][C:15]1[C:16]([CH3:36])=[CH:17][C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][CH:33]([CH3:34])[CH3:35])=[CH:27][N:26]=3)[O:22][N:21]=2)=[CH:19][C:14]=1[CH2:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)NCCNC(=O)OC(C)(C)C

Procedure:
[2-(3-{2-Ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionylamino)-ethyl]-carbamic acid tert-butyl ester is prepared in analogy to Example 37 by coupling (2-amino-ethyl)-carbamic acid tert-butyl ester with 3-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid; LC-MS: tR=1.14 min, [M+H]+=550.33.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C[O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.B(O)O.Br>C(O)(=O)C>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([OH:29])=[N:31][CH:32]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: Br
Agent: OBO
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(O)nc4)nc(N4CCOCC4)c3s2)CC1
Temperature: 125 °C

Procedure:
2-Chloro-6-((4-methanesulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine, prepared via General Procedure B-3, (100 mg) was used in General Procedure A using 2-methoxypyridine-5-boronic acid as the boronic acid. The resulting crude (60 mg) was treated with 1 mL of 48% HBr in acetic acid and heated to 125° C. for 6 min in the microwave. The 2-hydroxy pyridine was extracted into ethylacetate and washed with water. After evaporation of the organic layer the crude was purified by reversed phase HPLC purification to yield 17 mg of 189. NMR (CDCl3): 2.67 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.30 (m, 4H, 2×CH2), 3.87-3.89 (m, 6H, 3×CH2), 3.98-4.00 (m, 4H, 2×CH2), 6.65 (d, H, ArH, J=10.27 Hz), 7.25 (s, H, ArH) 8.50-8.53 (m, 2H, 2×ArH), 11.6 (sbr, H, OH). MS: (ESI+): MH+491.22
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C:8]([CH3:10])=[O:9]>>[CH3:6][O:5][C:1]([CH2:2][CH2:3][CH2:7][C:8](=[O:9])[CH3:10])=[O:4]
Reactant: CC(C)=O
Reactant: C=CC(=O)OC
Product: COC(=O)CCCC(C)=O

Procedure:
41.5% of the total quantity of methyl acrylate has been converted and calculated in relation to the amount of converted acetone, the efficiency amounts to 81%, and to 72% referred to the quantity of converted methyl acrylate.
Reaction SMILES: C([O:8][C:9](=[O:29])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:18]2)=[C:13]([F:28])[CH:12]=1)C1C=CC=CC=1.[CH3:30][C:31](C)([O-:33])C.[Li+]>C(OCC)(=O)C>[F:28][C:13]1[CH:12]=[C:11]([N:10]2[CH2:13][C@H:12]([CH2:11][NH:10][C:31](=[O:33])[CH3:30])[O:8][C:9]2=[O:29])[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:18]1
Reactant: CC(C)(C)[O-]
Reactant: O=C(Nc1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1)OCc1ccccc1
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3ccc(-c4ccccn4)n3)c(F)c2)C(=O)O1
Yield: 91.5 %

Procedure:
The above-described product 20a (1.235 g, 3.18 mmol) and lithium tert-butoxide (0.762 g) were mixed in a reaction vessel. After the air in the vessel was purged with nitrogen, tetrahydrofuran (5 mL) was added into the vessel and the mixture was cooled in an ice-water bath for 5 minutes. Then, methanol (0.204 g, 0.258 mL) was added. Two minutes later, a solution of Compound (11) (1.237 g) in tetrahydrofuran (5 mL) was added. Then, the water-ice bath was removed and the resultant mixture was reacted for 14 hours at room temperature. After completion of the reaction, ethyl acetate was added to the reactant mixture, resulting in a substantial amount of precipitate. Thus obtained mixture was suction-filtered, and the filter cake was recrystallized with a solvent mixture of ethyl acetate/petroleum ether to afford the product 12a (575 mg) as a white powder, with a yield of 45.7%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1Br.[S-:15][C:16]#[N:17].[K+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[S:15][C:16]#[N:17]
Reactant: O=[N+]([O-])c1cc(Br)c(Br)c([N+](=O)[O-])c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CO
Product: N#CSc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a stirred solution of 1,2-dibromo-3,5-dinitrobenzene (723 g, 2.22 mol) in MeOH (7.5 L) at rt was added potassium thiocyanate (431 g, 4.44 mol) and the resulting reaction mixture stirred under a nitrogen atmosphere for 16 h. The reaction mixture was then filtered and washed with methanol. The filtrate was concentrated at 30-33° C. under reduced pressure. The residue thus obtained was purified over silica gel (2-6% EtOAc-hexane) to obtain the desired product (549 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[NH2:10][C@H:11]([CH2:16][OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14].[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C@@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:16][OH:17])[C:5]([C:20]2[CH:21]=[CH:22][S:18][CH:19]=2)=[CH:4][N:3]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: OB(O)c1ccsc1
Reactant: Clc1ncc(I)c(Cl)n1
Product: CC(C)C[C@@H](CO)Nc1nc(Cl)ncc1-c1ccsc1

Procedure:
Preparation according to procedures 2 and 3 with the use of 2,4-dichloro-5-iodopyrimidine, L-leucinol (Aldrich) and thiophen-3-boronic acid (Aldrich).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]([OH:5])=[O:4].CO.[N+](=C)=[N-].[CH3:23][CH2:24]OCC>>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:3]([O:5][CH2:23][CH3:24])=[O:4]
Reactant: O=C(O)C(Br)CCCCCc1ccc(Cl)cc1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: CO
Product: CCOC(=O)C(Br)CCCCCc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 31.0 g (0.097 mol) of 2-bromo-7-(4-chlorophenyl)heptanoic acid in 250 ml of absolute ether which contains 0.5 ml of methanol, a solution of about 0.16 mol of diazomethane in 300 ml of absolute ether is added drop by drop, with stirring, at room temperature, until the evolution of nitrogen ceases. Then the reaction mixture is concentrated by evaporation and the concentrate is chromatographed with toluene on silica gel. 18.1 g (56% of theory) is obtained of ethyl 2-bromo-7-(4-chlorophenyl)heptanoate, a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=1[NH2:13]>O>[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=1[N:13]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: Nc1c(F)cccc1F
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Temperature: 170 °C
Yield: 37.5 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (10.0 g, 0.079 mol) and 2,6 difluoroaniline (9.5 g, 0.073 mol) was heated at 170° C. under argon atmosphere for 20 min. The water formed was removed using a Dean-stark apparatus. The melt was cooled, the dark solid was tritutrated with EtOAc., and filtered. This material was washed thoroughly with EtOAc to afford the desired product 1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one 6.5 g (35%) as a light brown solid: 1H NMR (CD3OD/400 MHz) δ 7.56 (m, 1H), 7.19 (m, 2H), 6.09 (m, 1H), 5.77 (d, 1H, J=2.4 Hz), and 1.99 (s, 3H); ES-HRMS m/z 238.0679 (M+H C12H10NO2F2 requires 238.0674).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:11][C:12]1[S:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[C:15]([CH3:17])[N:16]=1)(=[O:10])[CH3:9].C([N:24](CC)CC)C>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:24][S:18]([C:14]2[S:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[N:16][C:15]=2[CH3:17])(=[O:20])=[O:19])[CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NN2CCN(C)CC2)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 70.7 %

Procedure:
To a stirred solution of 1-methylpiperazine (1.18 g, 11.8 mmol) in THF (24 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (2.0 g, 7.85 mmol) and triethylamine (1.2 ml, 8.6 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (dichloromethane/MeOH 9:1) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (4-methylpiperazinyl)-amide (1.85 g, 74%) as a white solid. MS (ISP) 319.0 [(M+H)+]; mp 245° C.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].C([Li])(C)(C)C.CCCCC.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CCOCC>[C:19]([C:3]1[CH:4]=[C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:12])[CH3:13])[CH:8]([CH3:9])[CH3:10])[CH:17]=[CH:18][C:2]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)[Si](Oc1ccc(Br)c(C(C)(C)C)c1)(C(C)C)C(C)C
Reactant: CCOC(=O)Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CCOC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1C(C)(C)C
Temperature: 25 °C
Yield: 124.9 %

Procedure:
To a solution of (4-bromo-3-tert-butyl-phenoxy)-triisopropyl-silane (Intermediate 105, 1.00 g, 2.60 mmols) in 15 mL Et2O cooled to −78° C. was added 3.6 mL of tert-butyllithium, 1.7 M in pentane (395.0 mg, 6.2 mmols). After stirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6 mmols) was added. The resulting solution was warmed to room temperature and quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic layers dried (MgSO4) concentrated under reduced pressure The residue was chromatographed (2-5% EtOAc-hexanes) to give 1.23 g (88%) of the title compound as a colorless oil.
Reaction SMILES: [NH:1]1C=C[N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[Cl:19]N1C(=O)CCC1=O.Cl[CH:28]([Cl:30])[CH3:29]>>[Cl:19][C:29]1[N:1]=[C:2]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[NH:3][C:28]=1[Cl:30]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc[nH]2)CC1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Cl)c(Cl)[nH]2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 29 %

Procedure:
Add tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (6.00 g, 23.87 mmol) in dichloroethane (200 mL). Add N-chlorosuccinimide (3.19 g, 1.0 eq). Stir at room temperature under nitrogen for 14 hours. Concentrate the reaction mixture in vacuo. Purify by silica gel chromatography, eluting with hexanes to 9:1 hexanes:ethyl acetate to 4:1 hexanes:ethyl acetate to 2:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate, to give two major spots. Concentrate fractions containing the higher Rf spot in vacuo to give tert-butyl 4-(4,5-dichloro-1H-imidazol-2-yl)piperidine-1-carboxylate (2.25 g, 29%). MS (ES) m/z=321 [M]+. Concentrate fractions containing the lower spot in vacuo. Slurry the resulting solid into diethyl ether/chloroform, then filter. Concentrate the filtrate in vacuo to give tert-butyl 4-(4-chloro-1H-imidazol-2-yl)piperidine-1-carboxylate (1.16 g, 17%). MS (ES) m/z=286 [M]+.
Reaction SMILES: C=O.[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][CH2:9][NH2:10].[CH3:11]N(C)C=O.Cl>>[O:3]1[C:4]2[CH2:8][CH2:9][NH:10][CH2:11][C:5]=2[CH:6]=[CH:7]1
Reactant: CN(C)C=O
Reactant: NCCc1ccco1
Agent: C=O
Agent: Cl
Product: c1cc2c(o1)CCNC2
Reaction time: 0.25 h
Yield: 27 %

Procedure:
3.7 g (46 mmole) of a 37% aqueous formaldehyde solution were added dropwise at room temperature to 5.1 g (46 mmole) of 2-furylethylamine [the compound described, for example, in Brit., J. Pharmacol., 9, 376 (1954)], and the resulting mixture was stirred for about 15 minutes, after which it was extracted with diethyl ether. The organic extract was washed with water and dried over anhydrous sodium sulfate, and then the diethyl ether was removed by distillation under reduced pressure. 5 ml of dimethylformamide were added to the residue, and the resulting solution was added dropwise to 15 ml of dimethylformamide containing 3.6 g (100 mmole) of dry hydrogen chloride at room temperature. The resulting mixture was then stirred for 3 hours. At the end of this time, the greater part of the dimethylformamide was removed by distillation under reduced pressure, and then water and a 0.1N aqueous solution of sodium hydroxide were added to the residue so as to adjust its pH to a value of about 11; the mixture was then extracted with chloroform. The organic extract was washed with water and dried over anhydrous sodium sulfate. The chloroform was then removed by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 50:1 by volume mixture of chloroform and methanol as the eluent, to give the title compound as a brown oil in a yield of 27%.