Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=N1.C[N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][NH2:11].[C:13]([N:21]1[C:25]2[N:26]=[CH:27][C:28]3C(OC4C=CC=CC=4)=[N:30][C:31]4[N:32]([N:34]=[CH:35][N:36]=4)[C:33]=3[C:24]=2[CH:23]=[N:22]1)(=O)[C:14]1C=CC=CC=1>>[CH2:13]([N:21]1[C:25]2[N:26]=[CH:27][C:28]3[C:12]([N:7]4[CH:8]=[CH:9][CH:10]=[N:11]4)=[N:30][C:31]4[N:32]([N:34]=[CH:35][N:36]=4)[C:33]=3[C:24]=2[CH:23]=[N:22]1)[CH3:14]
Reactant: CN(C)CCCN
Reactant: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12
Agent: c1cn[nH]c1
Product: CCn1ncc2c1ncc1c(-n3cccn3)nc3ncnn3c12

Procedure:
By substituting pyrazole for the 3-(dimethylamino)propylamine in the procedure of Example 1 (c), 8-ethyl-5-(1-pyrazolyl)-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[1,5-a]pyrimidine is obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1O)[CH:27]=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:20][C@H:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[N:14]=1)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:27]=[O:28]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CCCC[C@@H](O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Product: CCCC[C@H](Oc1ccc(C=O)cc1Cl)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 19.7 %

Procedure:
Prepared according to the procedure used to prepare Intermediate 103 from (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (208 mg, 0.67 mmol) and 3-chloro-4-hydroxybenzaldehyde (141, 0.90 mmol) to afford the title compound (59 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)([OH:3])=O.C1CCN2C(=NCCC2)CC1.ClC(OCC(C)C)=O.[OH:39][CH2:40][CH2:41][CH2:42][NH:43][CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>CO.C(Cl)(Cl)Cl>[CH:45]1([CH2:44][N:43]([CH2:42][CH2:41][CH2:40][OH:39])[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:3])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: OCCCNCC1CCCCC1
Reactant: O=C(O)CCCCOc1ccc2c(c1)CCC(=O)N2
Agent: CC(C)COC(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1CCc2cc(OCCCCC(=O)N(CCCO)CC3CCCCC3)ccc2N1
Reaction time: 0.5 h

Procedure:
Into 400 ml of chloroform, were added 5 g of 6-(4-carboxybutoxy)-3,4-dihydrocarbostyril and 3.2 g of DBU. The outside of the reaction vessel containing the above mentioned mixture was ice-cooled and 2.8 g of isobutyl chloroformate was added dropwise to the mixture under stirring condition. After the addition operation, stirring was continued at a room temperature for 30 minutes and 3.9 g of N-(3-hydroxypropyl)-N-cyclohexylmethylamine was added to the reaction mixture and the reaction was continued for 3 hours. After the reaction was completed, the reaction mixture was washed with 1 N-NaOH aqueous solution, 10% HCl and water in this order and was dried with anhydrous Na2SO4. The drying agent was removed by filtration and the thus obtained dried product was concentrated to obtain a residue. The residue was treated by a silica-gel column chromatography (solvent used was a mixture of chloroform:methanol=40:1). The elute obtained was concentrated and was recrystallized from ethyl acetate-petroleum ether. 4.0 Grams of 6-{4-[N-cyclohexylmethyl-N-(3-hydroxypropyl)aminocarbonyl]butoxy}-3,4-dihydrocarbostyril was obtained in the form of colorless needle-like crystals. Melting point: 95°-97° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][N:8]1[CH:7]=[C:6]2[C:10]([CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)=[N:9]1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc2cc([N+](=O)[O-])ccc2n1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
5-Nitroindazole (1.00 g, 6.13 mmol) was dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (2.50 g, 18.1 mmol) was added. The mixture was stirred for 30 minutes and then (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.32 g 9.16 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated in vacuo and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) ppm 2.18 (s, 6H), 2.81 (t, 2H, J=6.44), 4.60 (t, 2H, J=6.44), 7.78 (m, 1H), 8.00 (m, 1H), 8.82 (s, 1H), 8.89 (m, 1H); MS (DCI/NH3) m/z 235 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([CH:21]=3)[N:19]=[CH:18][N:17]=[C:16]4O)[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:25]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:25][C:16]1[C:15]2=[CH:14][C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:12]=3)=[CH:21][N:20]2[N:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnn2cc(-c3ccnc(N4CCOCC4)c3)cc12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Clc1ncnn2cc(-c3ccnc(N4CCOCC4)c3)cc12
Temperature: 100 °C

Procedure:
To a suspension of 6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (110 mg, 0.37 mmol) in toluene (100 mL) were added one drop of DMF and POCl3 (30 mL). The flask was sealed and heated at 100° C. for 3 d. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was then dissolved in DCM, neutralized with saturated aq. NaHCO3 solution and the organic layer was separated. The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product, which was used directly in the next step. MS(ESI) m/z 316.2/318.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14]1)[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1.[NH4+].[Cl-].[N:37]([O-])=O.[Na+].N.O>C(O)C.O.[Fe]>[CH3:1][N:2]([C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14]1)[C:3]1[CH:8]=[C:7]2[CH:9]=[N:37][NH:10][C:6]2=[CH:5][N:4]=1
Reactant: O=N[O-]
Reactant: Cc1cc(N(C)[C@@H]2CCN(c3ncnc4c3ccn4COCC[Si](C)(C)C)C2)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CN(c1cc2cn[nH]c2cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Yield: 33 %

Procedure:
To a solution of (R)—N,4-dimethyl-5-nitro-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyridin-2-amine (0.248 mmol) in ethanol (20 mL) and water (5 mL), was added iron powder (0.752 mmol) and NH4Cl (1.495 mmol). The mixture was stirred at refluxing temperature for 2 hours, cooled, and filtered. The filtrate was concentrated, and dissolved in CH3COOH (1.5 mL) and water (2.5 mL). NaNO2 (0.304 mmol) was then slowly added, and the mixture was stirred at room temperature overnight, which was subsequently treated with NH3.H2O and extracted with EtOAc (3×20 mL). The combined extracts were concentrated and the residue was purified by column chromatography to give the title compound in 33.0% yield.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:27]=[CH:26][C:9]=1[C:10](=[O:25])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[C:4]([CH2:6][O:7][C:8]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([CH3:34])[CH3:35])[CH:27]=[CH:26][C:9]=1[C:10](=[O:25])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=1)([OH:5])=[O:3]
Reactant: CCCCCCc1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2OCC(=O)OCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCc1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2OCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 77.3 %

Procedure:
To a solution of 4.30 g of 2'-ethoxycarbonylmethoxy-4-n-hexyl-4'-(3-methyl-2-butenyloxy)chalcone in 43 ml of ethanol was added a solution of 6.2 g of potassium carbonate in 11 ml of water, and the mixture was stirred at 50° C. for 5 hours. After completion of the reaction, the mixture was neutralized with dilute hydrochloric acid, and the precipitated solid was collected by filtration, washed with water, dried and recrystallized from ethyl acetate-n-hexane to give 3.13 g of 2'-carboxymethoxy-4-n-hexyl-4'-(3-methyl-2-butenyloxy)chalcone.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH2:12][NH2:13])[CH2:7][CH2:6][CH2:5]2.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br>C(O)(C)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH2:12][N:13]1[CH2:17][CH:16]([OH:18])[CH2:14]1)[CH2:7][CH2:6][CH2:5]2
Reactant: NC[C@@H]1CCCc2cc(I)ccc21
Reactant: BrCC1CO1
Solvent: CC(C)O
Product: OC1CN(C[C@@H]2CCCc3cc(I)ccc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of C—((R)-6-iodo-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine (0.79 g, 2.75 mmol) in isopropanol (6 mL) at ice bath temperature and under nitrogen atmosphere, was added dropwise epibromohydrin ((0.38 g, 2.8 mmol). The ice bath was removed and the reaction mixture was stirred for 18 hours at room temperature. Triethylamine ((0.39 mL, 2.8 mmol) was added, and the reaction mixture was stirred at room temperature for two hours, then at 60° C. for three hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was taken up in EtOAc. The EtOAc solution was washed with water and 0.5 M aqueous sodium carbonate, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting oil was chromatographed by HPLC (hexanes/EtOAc 1:1 to 50% hexanes/27% EtOA/15% MeOH/8% con. NH4OH) to 0.5 g (53%) of 1-((R)-6-Iodo-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-azetidin-3-ol, MS M+H=344
Reaction SMILES: NC1C=CC=CC=1.[C:8]1([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)C#N)[N:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:27]1([NH:26][C:22]2[N:21]=[C:20]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]3[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:25]=[CH:24][N:23]=2)[CH:28]=[CH:29][CH:32]=[CH:33][CH:34]=1
Reactant: N#Cc1cccc(Nc2nccc(N3CCCCC3c3ccccc3)n2)c1
Solvent: Nc1ccccc1
Product: c1ccc(Nc2nccc(N3CCCCC3c3ccccc3)n2)cc1
Yield: 82 %

Procedure:
Intermediate 16, (0.20 g, 0.73 mmol) and aniline (0.08 g, 0.80 mmol) were reacted together following the procedure detailed for the compound of Example 6, which gave the title compound as a white solid (0.22 g, 82%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]=[CH:5][O:4]1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>N1C=CC=CC=1>[S:9]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]=[CH:5][O:4]1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC=CO1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Whilst cooling a solution of 14.2 g of 2-hydroxymethyl-3,4-dihydro-2H-pyran in 120 ml of pyridine on an ice-water bath at 0°-5° C., 28.4 g of crystals of tosyl chloride were added and the mixture was then stirred at room temperature overnight. The salt which precipitated with the aid of a Celite (Trademark) filter aid was separated by filtration and the filtrate was concentrated under reduced pressure. Water was added to the residue and the resulting mixture was extracted with diethyl ether. The ethereal extract was washed with a saturated aqueous solution of sodium bicarbonate and then with aqueous sodium chloride, after which the solvent was evaporated off under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 7:1 by volume mixture of hexane and ethyl acetate, to give 31.5 g of the title compound, in the form of colourless crystals melting at 47°-48° C.
Reaction SMILES: [CH:1]([C:3]([CH2:5][CH3:6])=[O:4])=[CH2:2].[CH2:7]=[CH:8][C:9](=[CH2:11])[CH3:10].Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>>[CH3:11][C:9]1[CH2:8][CH2:7][C@@H:1]([C:3](=[O:4])[CH2:5][CH3:6])[CH2:2][CH:10]=1
Reactant: C=CC(=O)CC
Reactant: C=CC(=C)C
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCC(=O)[C@H]1CC=C(C)CC1
Reaction time: 72 h
Yield: 79 %

Procedure:
Prepared according to general procedure B from ethyl vinyl ketone (70 μL, 0.70 mmol), isoprene (140 μL, 1.40 mmol), 70% aqueous perchloric acid (12.1 μL, 0.14 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (38 mg, 0.14 mmol) neat for 3 days at −20° C. Then, another portion of isoprene (100 μL, 1.00 mmol) was added and the solution was allowed to stir for an additional 3 days. Purification by silica gel chromatography (10:1 pentane:ether) provided the title compound as a single regioisomer (as judged by GLC analysis) in 79% yield (84 mg, 0.55 mmol) and 85% ee. IR (film) 2967, 2928, 2836, 1710, 1452, 1413, 1377, 1343, 1217, 1149, 1126, 952.6, 915.1, 871.9, 800.0 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.34 (m, 1H, C═CH), 2.46 (m, 3H, CH2CO and CHCO), 2.09 (m, 2H, CH2CH═C(CH3)), 1.94 (m, 2H, CH2C(CH3)═CH), 1.86 (m, 1H, one of CH2CH2CH), 1.54 (m, 1H, one of CH2CH2CH), 0.99 (dd, J=7.5, 7.5 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 214.4, 133.8, 119.6, 46.6, 34.1, 29.9, 27.6, 25.4, 23.7, 8.1; HRMS (CI) exact mass calc'd for (C10H16O) requires m/z 152.1201, found m/z 152.1201. [α]D=+37.8 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (100° C., 23 psi); (R) isomer tr=16.1 min, and (S) isomer tr=15.4 min.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][CH:17]([CH3:21])[C:18](=O)[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CN(C=O)C.ClCCl.C(O)(=O)C>[CH:17]([C:18]1([CH3:19])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)([CH3:21])[CH3:16]
Reactant: CC(=O)C(C)C
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 3-methyl-2-butanone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred overnight at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate-tetrahydrofuran (3:1, 2×100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave a solid. This solid was dissolved with DMF-dichloromethane (2:5, 7 mL) and purified by column chromatography (Combiflash, 12 g silica gel, ethyl acetate to 90:10 ethyl acetate/methanol), then recrystallized from methanol-ethyl acetate to afford the title compound (0.0125 g, 8.7%) as a yellow solid:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:37])[CH:4]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]([N:20]3[CH2:23][C@H:22]([NH:24]C(=O)OCC4C=CC=CC=4)[C:21]3=[O:35])=[O:19])(=[O:16])=[O:15])[C:10]2=[O:36])[NH:6][CH:7]=1.C1(SC)C=CC=CC=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[NH2:24][C@H:22]1[CH2:23][N:20]([C:18]([NH:17][S:14]([N:11]2[CH2:12][CH2:13][N:9]([CH2:8][C:5]3[NH:6][CH:7]=[C:2]([OH:1])[C:3](=[O:37])[CH:4]=3)[C:10]2=[O:36])(=[O:16])=[O:15])=[O:19])[C:21]1=[O:35]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(Cc3cc(=O)c(O)c[nH]3)C2=O)C1=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(Cc3cc(=O)c(O)c[nH]3)C2=O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-[1-[[[[3-[(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (0.50 g, 0.93 mmol) was added to a mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid . The solution was stirred overnight at room temperature and evaporated in vacuo. The residue was triturated with ether, filtered off by suction, and dried in vacuo, yielding 0.49 g of the title compound, melting point 155° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:4]=1.[H-].[Na+].Br[CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C>CN(C=O)C>[CH3:1][N:2]([CH3:23])[C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:27][CH2:28][OH:29])=[CH:12][CH:13]=2)[N:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:4]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1ccc(-n2nc(N(C)C)cc2-c2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(N(C)C)cc2-c2ccc(OCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenol (98.7 mg) in DMF (2 ml) was added sodium hydride 60% dispersion in mineral oil (15.3 mg). The mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added (2-bromoethoxy)-tert-butyldimethylsilane (153 mg) in DMF (1 ml) dropwise and the mixture was stirred at ambient temperature overnight. The mixture was poured into ice water, extracted with AcOEt, washed with H2O and saturated aqueous sodium chloride solution. The aqueous layer was reextracted with AcOEt. The combined organic layers were dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in EtOH (2 ml) . To this solution was added concentrated hydrochloric acid (100 μl) and the mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated invacuo, and the residue was partitioned between AcOEt and saturated aqueous sodium bicarbonate solution, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=60%. The residual crystals were collected and washed with IPE to give 2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethanol (97 mg) as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]C1CC(C(C)C)CCC1=O>>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([Br:16])[C:10](=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: O=C1CCCCN(Cc2ccccc2)C1
Product: O=C1CN(Cc2ccccc2)CCCC1Br

Procedure:
The bromination of 1-benzyl-azepan-3-one takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([O:24]C)[CH:19]=2)=[N:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([C:18]2[CH:23]=[CH:22][NH:21][C:20](=[O:24])[CH:19]=2)=[O:26])=[N:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)Nc2nc(C)c(C(=O)NCc3ccccc3)s2)ccn1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc(NC(=O)c2cc[nH]c(=O)c2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of N-benzyl-2-(2-methoxyisonicotinamido)-4-methylthiazole-5-carboxamide (0.26 g, 0.68 mmol) in anhydrous chloroform (15 mL) was added iodotrimethylsilane (1.37 g, 6.80 mmol) at 0° C. The mixture was refluxed for 16 hours and cooled down to ambient temperature. Methanol (3 mL) was added dropwise to quench the reaction. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated sodium bicarbonate solution (2×100 mL), and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrate in vacuo. The residue was recrystallized from ethyl acetate and methanol to yield a colorless solid in 55% yield (0.13 g); m.p. 290-292° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.74 (s, br, 2H), 8.63 (t, J=5.9 Hz, 1H), 7.48 (d, J=6.8 Hz, 1H), 7.35-7.17 (m, 5H), 6.95 (d, J=1.6 Hz, 1H), 6.66 (dd, J=1.6, 6.8 Hz, 1H), 4.37 (d, J=5.9 Hz, 2H), 2.49 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 165.5, 162.6, 163.1, 162.0, 144.1, 140.0, 136.8, 128.7, 127.6, 127.1, 120.3, 119.2, 103.3, 43.0, 17.0; MS (ES+) m/z 369.2 (M+1).
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][CH2:12][CH2:13][C:14](=[O:39])[NH:15][C@@H:16]2[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]2[O:18][C:19](=[O:21])[CH3:20])C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:15][C@@H:16]1[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]1[O:18][C:19](=[O:21])[CH3:20])=[O:39]
Reactant: CC(=O)OC[C@H]1O[C@@H](NC(=O)CCCNC(=O)OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](NC(=O)CCCN)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Pd/C (10%) is added to a solution of N-[4-oxo-4-[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)amino]butyl]-carbamic phenylmethyl ester (1.02 g) in 30 mL methanol/THF (1:1). The reaction mixture is stirred under hydrogen at room temperature for 5 h. The mixture is filtered through diatomite and is concentrated to give the product (760 mg; 98%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[CH:24]([NH:27][CH3:28])([CH3:26])[CH3:25]>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:27]([CH:24]([CH3:26])[CH3:25])[CH3:28])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Reactant: CNC(C)C
Product: CC(C)N(C)c1nc2c(Cl)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and isopropyl-methyl-amine. Light brown foam. MS (ESI): 389.2 (M+H)+.