Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[CH:10][C:9]([CH:12]([OH:15])[CH2:13]C)=[CH:8][CH:7]=2)=[CH:2]1.[CH:16]1[N:20]=[CH:19][N:18]([C:21](N2C=NC=C2)=[O:22])[CH:17]=1>C(#N)C>[N:18]1([C:21]([O:15][CH:12]([C:9]2[CH:10]=[N:11][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:7][CH:8]=2)[CH3:13])=[O:22])[CH:17]=[CH:16][N:20]=[CH:19]1
Reactant: CCC(O)c1ccc(-c2ccoc2)nc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(OC(=O)n1ccnc1)c1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 48a (73.0 mg, 0.36 mmol), CDI (291 mg, 1.80 mmol) and acetonitrile (4 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:1) as eluent. Green oil. Yield: 62 mg, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.00 (t, J=7.4 Hz, 3H), 1.96-2.08 (m, 1H), 2.12-2.24 (m, 1H), 5.85 (t, J=7.1 Hz, 1H), 6.88 (dd, J=1.9, 0.6 Hz, 1H), 7.04-7.09 (m, 1H), 7.42 (t, J=1.4 Hz, 1H), 7.45-7.51 (m, 2H), 7.69 (dd, J=8.2, 2.2 Hz, 1H), 8.01-8.06 (m, 1H), 8.15 (s, 1H), 8.63 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=9.7, 28.6, 79.8, 108.5, 117.0, 119.8, 126.5, 130.7, 131.8, 134.9, 136.9, 141.5, 144.0, 148.0, 148.3, 152.3; MS (ESI): m/z=298.27 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([O:23][CH2:24][O:25][CH:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:27])[C:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[OH:21])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C>[CH2:3]([C:7]1[N:8]([O:23][CH2:24][O:25][CH:26]([Si:28]([CH3:30])([CH3:29])[CH3:31])[CH3:27])[C:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1ncc(C(=O)c2ccc(OC)cc2O)n1OCOC(C)[Si](C)(C)C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(C(=O)c2ccc(OC)cc2OCC(=O)OCC)n1OCOC(C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93750.5 %

Procedure:
To a mixture of NaH (80% oil dispersion, 33 mg, 1.1 mmol, previously washed with hexanes), in DMF (4 ml) was added dropwise a solution of 2-n-butyl-5-(2-Hydroxy-4-methoxybenzoyl)-1-trimethylsilylethyloxymethoxy-1H-imidazole-(404 mg, 1.00 mmol) in DMF (3 ml) at 0° under argon. The cooling bath was removed and the mixture stirred for 10 min. at ambient temperature. Ethyl bromoacetate (125 μl, 1.10 mmol) was added neat and the reaction stirred for 2 h. The mixture was partitioned between water and EtOAc and the layers separated. The aqueous layer was further extracted (EtOAc, 2x) and the combined organic extract was washed with water (5x) and brine. Evaporation under reduced pressure, after drying (MgO4 anhydrous) afforded the title compound as a reddish oil (475 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([CH3:14])=[C:11]([CH:15]=[O:16])[CH:10]=1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O1CCCC1>>[CH:17]1([CH:15]([C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[O:13][C:12]=2[CH3:14])[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1oc(-c2ccc(Cl)cc2Cl)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Cl)cc2Cl)cc1C(O)C1CCCCC1
Yield: 77 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(2,4-dichlorophenyl)-2-methyl-3-furaldehyde (1.3 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (7.5 mL) to give the title compound (1.3 g, 77%) as a white crystal.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].OC1C=CC([C:13]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:14])=CC=1>>[C:1]([CH2:14][C:13]([O:21][C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Product: C=CC(=O)CC(Oc1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 85 %

Procedure:
Acryloyl chloride (45.3 g, 0.5 mole) was dissolved in 50 g (0.63 mole) of pyridine anhydride in a reaction vessel. The exothermic reaction was cooled by placing the reaction vessel in a liquid nitrogen-isopropyl alcohol bath. Thereafter, 193 g (0.63 mole) of 1,1,1-tris(4-hydroxy phenyl)ethane was added dropwise to the reaction mixture and stirred. After the addition of 1,1,1-tris(4-hydroxy phenyl)ethane, the reaction vessel was removed from the cooling bath, and the reaction was stirred at room temperature for over 24 hours. The progress of the reaction was monitored by TLC. The reaction mixture was transferred to a separatory funnel, neutralized using 1 N aqueous sulfuric acid solution, and extracted with dichloromethane. The organic layer was washed with deionized water, concentrated under reduced pressure, and purified by distillation under reduced pressure to yield acryloyl phenoxy bis(-4-hydroxy phenyl)ethane monomer (yield 85%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[N:5]=[C:6]([CH3:10])[N:7](O)[CH:8]=1.C(=O)(O)[O-].[Na+]>CO.[Cl-].[Ti+3].[Cl-].[Cl-]>[CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[N:5]=[C:6]([CH3:10])[NH:7][CH:8]=1
Reactant: Cc1nc(CC(C)(C)C)cn1O
Agent: [Ti+3]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Product: Cc1nc(CC(C)(C)C)c[nH]1
Temperature: 25 °C

Procedure:
Titanium (III) chloride (30% weight solution in 2N HCl) (600 mL, 1.5 mol) was added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-methyl-1H-imidazol-1-ol (ca. 0.56 mmol) in methanol (1200 mL). After stirring at ambient temperature for a few days, the reaction mixture was basified with saturated aqueous sodium bicarbonate until the black solution turned white. The reaction mixture was extracted with ether. The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 10-20% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-methyl-1H-imidazole.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[N:8][C:7]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[Br:19]N1C(=O)CCC1=O>CS(C)=O.O>[Br:19][C:9]1[C:10]([NH2:12])=[N:11][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[C:7]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Nc1cnc(-c2ccncc2)c(-c2ccco2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc(-c2ccco2)c(-c2ccncc2)nc1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.1 %

Procedure:
To a 0° C. stirred solution of 6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5, 195 mg, 0.82 mmol) in dimethylsulfoxide (1.5 mL) and water (40 μL), was added portionwise N-bromosuccinimide (146 mg, 0.82 mmol). The mixture was stirred at room temperature for 40 min, then poured into water, extracted with dichloromethane (×3), the organic layers washed with brine, dried (MgSO4) and evaporated to furnish the title compound (198 mg, 75%) as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[C@@H:6]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:5]([CH3:22])[O:4][C:3]1=[O:23].[OH:24][C:25]1[C:26]([C:33](O)=[O:34])=[N:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:24][C:25]1[C:26]([C:33]([NH:1][C@H:2]2[CH2:10][O:9][CH2:8][C@H:7]([O:11][C:12]([CH2:13][CH3:14])([CH3:15])[CH3:16])[C@@H:6]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:5]([CH3:22])[O:4][C:3]2=[O:23])=[O:34])=[N:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: CCC(C)(C)O[C@H]1COC[C@H](N)C(=O)O[C@@H](C)[C@@H]1OCC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C)(C)O[C@H]1COC[C@H](NC(=O)c2nccc(OC)c2O)C(=O)O[C@@H](C)[C@@H]1OCC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a mixture of (3S,7S,8S,9S)-3-amino-7-(1,1-dimethylpropoxy)-8-isobutoxy-9-methyl-1,5-dioxonan-2-one and 3-hydroxy-4-methoxypicolinic acid (79.0 mg, 0.466 mmol) in DCM (2.0 mL) were added 4-methylmorpholine (0.205 mL, 1.86 mmol) followed by HATU (189 mg, 0.497 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was directly purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a white solid (50.0 mg, 42%): mp 138-140° C.; IR (neat) 3370, 2926, 1750, 1650, 1529, 1243, 1085 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.98 (s, 1H), 8.73 (d, J=8.0 Hz, 1H), 8.01 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.08 (dq, J=9.1, 6.3 Hz, 1H), 5.00 (ddd, J=8.1, 6.1, 3.8 Hz, 1H), 4.00 (dd, J=12.1, 6.1 Hz, 1H), 3.94 (s, 3H), 3.95-3.89 (m, 2H), 3.79 (dd, J=8.6, 5.6 Hz, 1H), 3.56-3.45 (m, 2H), 3.07 (dt, J=12.6, 8.4 Hz, 2H), 1.90-1.78 (m, 1H), 1.56-1.43 (m, 2H), 1.45 (d, J=6.4 Hz, 3H), 1.15 (s, 3H), 1.14 (s, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.91-0.85 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 170.17, 169.09, 155.47, 148.89, 140.79, 130.47, 109.68, 85.26, 81.29, 81.18, 77.82, 75.32, 75.19, 73.37, 56.23, 53.07, 35.01, 29.10, 25.16, 25.08, 19.95, 19.60, 18.97, 9.06; HRMS-ESI (m/z) [M]+ calcd for C24H38N2O8, 482.2628; found, 482.2631.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 335 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)[OH:11])[CH3:3].C(Cl)Cl.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[O:17])[OH:11])[CH3:1]
Reactant: CCNCC
Reactant: CN(C)CC1CCCCC1(O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)c1cccc(C2(O)CCCCC2CN(C)C)c1
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
A sample of 3-[(1-RS,2-RS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzoic acid (0.1 g, 0.36 mmol), CH2Cl2 (5 mL), and diethylamine (0.08 mL, 0.36 mmol) was placed into a flask and stirred for 5 min. To the reaction was added HATU (0.13 g, 0.36 mmol) and stirring was continued for 2 h. Water was added and the organic phase was separated, washed again with water, dried (Na2SO4), and filtered. The filtrate was evaporated in vacuo and the residue passed through a silica gel column (90:10:1, CH2Cl2:MeOH:NH4OH) to give 42 mg (35%) of 3-[(1-RS,2-RS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-N,N-diethyl-benzamide: MS m/z=333 (MH+); 1H NMR (CDCl3) δ 7.7-7.2 (Ar, 4H), 3.6 and 3.2 (bq, 4H), 2.4 (dd, 1H), 2.1 (s, 6H), 2.0-1.5 (m, 10H), 1.1 (bt, 6H).
Reaction SMILES: [CH2:1]([OH:77])[C@H:2]1[O:7][C@@H:6]2[O:8][C@H:9]3[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]4[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]5[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@@H:30]([O:35][C@H:36]6[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]7[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]8[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]1[C@H:4]([OH:76])[C@H:5]2[OH:75])[O:56][C@@H:55]8[CH2:63][OH:64])[O:47][C@@H:46]7[CH2:65][OH:66])[O:38][C@@H:37]6[CH2:67][OH:68])[O:29][C@@H:28]5[CH2:69][OH:70])[O:20][C@@H:19]4[CH2:71][OH:72])[O:11][C@@H:10]3[CH2:73][OH:74].[CH2:78]1[O:81][CH:79]1[CH3:80]>[OH-].[Na+]>[CH3:3][CH:2]([OH:7])[CH2:1][O:70][CH2:69][C@H:28]1[O:29][C@@H:30]2[O:35][C@H:36]3[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]4[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]5[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]6[C@H:4]([OH:76])[C@@H:5]([OH:75])[C@@H:6]([O:8][C@H:9]7[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]8[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]1[C@H:32]([OH:33])[C@H:31]2[OH:34])[O:20][C@@H:19]8[CH2:71][O:72][CH2:41][CH:36]([OH:35])[CH3:37])[O:11][C@@H:10]7[CH2:73][O:74][CH2:14][CH:9]([OH:8])[CH3:10])[O:7][C@@H:2]6[CH2:1][O:77][CH2:28][CH:27]([OH:26])[CH3:32])[O:56][C@@H:55]5[CH2:63][O:64][CH2:46][CH:45]([OH:44])[CH3:50])[O:47][C@@H:46]4[CH2:65][O:66][CH2:19][CH:18]([OH:17])[CH3:23])[O:38][C@@H:37]3[CH2:67][O:68][CH2:78][CH:79]([OH:81])[CH3:80]
Reactant: CC1CO1
Reactant: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Agent: [Na+]
Agent: [OH-]
Product: CC(O)COC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8COCC(C)O)O[C@@H]7COCC(C)O)O[C@@H]6COCC(C)O)O[C@@H]5COCC(C)O)O[C@@H]4COCC(C)O)O[C@@H]3COCC(C)O
Yield: 90 %

Procedure:
In HU 202889, β-cyclodextrin (β-CD) is reacted with propylene oxide in aqueous sodium hydroxide solution to give hydroxypropyl-β-cyclodextrin. The resulting sodium chloride and the propylene glycol are removed by ion exchange and precipitation of the hydroxypropylated β-cyclodextrin in large amounts of acetone, filtration, taking up the filter cake in water, distillation and, finally, spray-drying. The yield is around 90%, and the salt and propylene glycol content is 0.1%.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[NH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1)([CH3:6])([CH3:5])[CH3:4].S(OC)(O[CH3:23])(=O)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl>[C:3]([C:7]1[N:11]([CH3:23])[C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1[nH]c(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c([N+](=O)[O-])cc(C(C)(C)C)n1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
Sodium hydroxide (0.21 g, 2.65 mmol, 50% aqueous, 6 equiv) is added to a cold (0-−10° C.) solution of methyl 5-t-butyl-3-nitropyrrole-2-carboxylate (100 mg, 0.44 mmol), benzyltributyl ammonium bromide (158 mg, 0.44 mmol, 1 equiv), and dimethyl sulfate (46 mL, 0.49 mmol, 1.1 equiv) in dichloromethane (1 mL). After 5 min, the cooling bath is removed and the mixture is stirred for 4 h at rt. The reaction mixture is diluted with dichloromethane, washed with water (1×), 10% ammonium acetate (2×), dried (Na2SO4), and concentrated in vacuo to give a bright yellow oil. The residue is purified by flash chromatography (30% hexane in dichloromethane) to give 61 mg of methyl 5-t-butyl-1-methyl-3-nitropyrrole-2-carboxylate as a pale yellow oil which solidifies upon standing (62%). 1H NMR (CDCl3) d 6.47 (s, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)[CH2:19][N:20]3[C:21](=[O:30])[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]3=[O:29])=[O:15])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (170 mg, 0.68 mmol), 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (256 mg, 0.67 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (387 mg, 0.83 mmol) in chloroform (7 mL). DIEA (600 μL, 3.44 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (311 mg, 0.55 mmol, 80%): LC-MS (ES) m/z=567 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[NH2:12][C:13]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:14]=1[C:15](OCC)=[O:16]>>[NH2:12][C:13]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:14]=1[C:15](=[O:16])[CH2:6][S:3](=[O:5])(=[O:4])[NH:2][CH3:1]
Reactant: CCOC(=O)c1cc(OC)ccc1N
Reactant: CNS(C)(=O)=O
Agent: [Li]CCCC
Product: CNS(=O)(=O)CC(=O)c1cc(OC)ccc1N

Procedure:
In a similar manner to that described in Example 12(a), N-methylmethanesulphonamide was reacted with n-butyl lithium and the product was reacted with ethyl 2-amino-5-methoxybenzoate to give the novel compound 1-(2-amino-5-methoxyphenyl)-2-(N-methylsulphamoyl)ethanone, m.p. 117°-118°.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:19]N1C(=O)CCC1=O>CN(C=O)C>[Br:19][C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[C:13]([OH:18])[CH:14]=1
Reactant: Oc1ccccc1NC1CCC2(CC1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Oc1cc(Br)ccc1NC1CCC2(CC1)OCCO2
Yield: 32.9 %

Procedure:
A solution of intermediate D8 (1 g, 4.011 mmol) and N-bromosuccinimide (0.785 g, 4.412 mmol) in DMF (15 ml) was stirred at r.t. for 1 h. Subsequently, the r.m. was washed with an aqueous saturated NaHCO3 solution. The organic layer was separated, dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc 8:2 as eluent). The desired fractions were collected and evaporated in vacuo to yield D10 (0.433 g, 32.89%) as a reddish solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH2:21][CH2:22][NH:23][CH:24]3[CH3:29])=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:22][CH2:21][C:20]4[C:25](=[CH:26][CH:27]=[CH:28][C:19]=4[C:16]4[CH:17]=[CH:18][O:14][CH:15]=4)[CH:24]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3ccoc3)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(-c3ccoc3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([N:20]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][N:22]=[C:21]2S)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1>O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([N:20]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][N:22]=[CH:21]2)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1
Reactant: CCCC(c1ccc(C)cc1)n1c(C(=O)OC)cnc1S
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCCC(c1ccc(C)cc1)n1cncc1C(=O)OC
Yield: 86 %

Procedure:
0.07 Parts of sodium nitrite and 0.6 parts of nitric acid were solved in 2 parts of deionisized water. 1.0 Part of methyl 1-[1-(4-methylphenyl)butyl]-2-mercapto-1H-imidazole-5-carboxylate was added portionwise at a temperature between 25° C. and 30° C. The precipitate was isolated, yielding 0.94 parts (86% ) of methyl 1-[1-(4-methylphenyl)butyl]-1H-imidazole-5-carboxylate mononitriate. This colourless salt has a melting point of 141°-143° C. (compound 1.15).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=4)[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cn1cncc1Br
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 41.5 %

Procedure:
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.6849 mmol) was reacted with 5-bromo-1-methyl-1H-imidazole (121.3 mg, 0.753 mmol), 1,4-dioxane (5 mL), copper iodide (12.99 mg, 0.0684 mmol), trans N,N′-dimethyl-cyclohexane-1,2-diamine (29.176 mg, 0.205 mmol) and potassium phosphate (435.01 mg, 2.05 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 85 mg of the product (41.64% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:11][C:2]=1[NH:1][C:18](=[O:20])[CH3:19]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(N2CCOCC2)cc1NC(C)=O
Reaction time: 22 h

Procedure:
To a stirred solution of methyl 2-amino-4-morpholin-4-ylbenzoate (55 mg; 0.23 mmol) in dry CH2Cl2 (2 mL) was added acetic anhydride (0.05 mL; 0.53 mmol) and pyridine (0.02 mL; 0.25 mmol) via syringe at room temperature under a nitrogen atmosphere. The resulting solution was allowed to stir for 22 hours, then diluted with EtOAc (15 mL) and washed with 0.5 N aqueous hydrochloric acid, water, and brine, then dried (MgSO4), filtered and concentrated in vacuo to provide the amide as a white solid (56 mg; 88%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([OH:13])=O.[Cl-].[CH2:19]([O:21][C:22](=[O:34])[CH:23]([OH:33])[CH:24]([NH3+:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20]>>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:32][CH:24]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:23]([OH:33])[C:22]([O:21][CH2:19][CH3:20])=[O:34])=[O:13]
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1F
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F

Procedure:
The reaction was carried out in analogy to reaction of step 20.1 by reacting (R)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxylic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+=443.2.