Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[Br:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Br:10][C:11]1[CH:12]=[N:13][C:14]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[N:15][CH:16]=1
Reactant: CN(C)CCCO
Reactant: Clc1ncc(Br)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCCOc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.6 %

Procedure:
To a solution of 3-(dimethylamino)-1-propanol (47, 3.45 mL, 2.84 mmol) in 10 mL of dry tetrahydrofuran, sodium hydride (0.0784 g, 3.10 mmol) was added at room temperature. After 15 minutes, 5-bromo-2-chloro-pyrimidine (46, 0.500 g, 2.58 mmol) was added and the mixture was stirred at room temperature for 16 hours. To this, ˜500 μL of saturated ammonium chloride was added and the reaction was treated with ethyl acetate and filtered. The solvents were removed from the filtrate under vacuum, then added diethyl ether, removed solvent under vacuum and repeated twice. The resulting residue was taken up with tetrahydrofuran/acetonitrile and filtered. Silica gel was added to the filtrate and solvents removed under vacuum, then purified by silica gel chromatography eluting with 1 to 6% methanol in dichloromethane, followed with 20% methanol in dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (48, 259 mg). MS (ESI) [M+H+]+=261.9.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3=[C:15]([OH:32])[C:16]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][C:26]=5[O:30][CH3:31])[C:20](=[O:21])[C:17]=4[C:18]([OH:19])=[C:13]3[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:38])[C@@H:3]1[OH:39].C(N([CH2:45][CH3:46])CC)C.C[C@@H]1O[C@@H]([O:54][C@@H:55]2[C:60]3=[C:61]([OH:78])[C:62]4[C:74](=O)[C:73]5C(=CC=C[C:72]=5[O:76]C)C(=O)[C:63]=4C(O)=[C:59]3[CH2:58][C@@:57](O)([C:79](CO)=[O:80])[CH2:56]2)C[C@H](N)[C@@H]1O.Cl.[C:87](O)(C(F)(F)F)=O>CN(C=O)C.C(#N)C.O>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3=[C:15]([OH:32])[C:16]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][C:26]=5[O:30][CH3:31])[C:20](=[O:21])[C:17]=4[C:18]([OH:19])=[C:13]3[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:38])[C@@H:3]1[OH:39].[CH3:87][C@@:23]12[C@H:74]3[CH2:73][C@@H:72]([OH:76])[C@:45]4([CH3:46])[C@@H:58]([C:57]5[CH2:79][O:80][C:55](=[O:54])[CH:56]=5)[CH2:59][CH2:60][C@:61]4([OH:78])[C@@H:62]3[CH2:63][CH2:20][C@@H:22]1[CH2:27][C@@H:26]([OH:30])[CH2:25][CH2:24]2
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(CC)CC
Agent: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@@H](O)[C@]2(C)[C@@H](C3=CC(=O)OC3)CC[C@]12O
Reaction time: 2 h

Procedure:
Doxorubicin was obtained from Sigma-Aldrich. To couple digoxygenin to doxorubicin, we performed the following procedure: To a solution of Digoxigenin-3-O-methylcarbonyl-epsilon-aminocaproic acid-N-hydroxysuccinimide ester (20 mg, 30.4 μmol) in DMF (500 μL) was added triethylamine (8.4 μL, 60.8 μmol) and the resulting mixture was transferred immediately to a solution of Doxorubicin-HCl (16.6 mg, 30.4 μmol) in DMF (500 μL). The reaction mixture was tumbled for 2 h at ambient temperature, filtered, and the target compound was isolated by preparative reversed phase HPLC employing an acetonitrile/water gradient containing 0.1% TFA (Merck Cromolith prep RP-18e column, 100×25 mm). After lyophilization the Doxorubicin-Digoxigenin conjugate was obtained as a colorless solid (25.2 mg, 76%). Analytical HPLC: tR=13.9 min (Merck Chromolith Performance RP-18e, 100×4.6 mm, water+0.1% TFA acetonitrile/water+0.1% TFA 80:20, 25 min); ESI-MS (positive ion mode): m/z: calcd for C58H75N2O18: 1087.5; found: 1087.6 [M+H]+. The molecular weight of doxorubicin is 579.98 Da. The molecular weight of the resulting Doxorubicin-Dig conjugate is 1087.24 Da. Until the point of complexation to the antibody, we stored the conjugate in aliquots in DMSO at −20° C. FIG. 18 shows the structure of Doxorubicin-digoxygenin conjugate.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Brc1ccc(C(=C(c2ccccc2)c2ccc(Br)cc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
In a suspension of 4-bromobenzophenone (5 g, 19.2 mmol) in 50 mL of THF were added TiCl4 (2.14 mL, 19.2 mmol) and Zn dust (2.48 g, 38.4 mmol). After reflux for 20 h, the reaction mixture was cooled to room temperature and filtered. The solvent was evaporated under vacuum and the crude product was purified by a silica gel column using hexane as eluent. 1,2-Bis(4-bromophenyl)-1,2-diphenylethene (5) was obtained as white solid in 95% yield (4.3 g). 1H NMR (CDCl3, 300 MHz), δ (ppm): 7.27 7.19 (m, 4H), 7.15 7.09 (m, 6H), 6.98 (m, 4H), 6.90 6.86 (m, 4H). 13C NMR (CDCl3, 75 MHz), δ (TMS, ppm): 133.0, 131.3, 131.2, 131.0, 128.1, 127.9, 127.8, 127.0, 126.9. MS (TOF): m/e 489.9 (M+, calcd. 490.0).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:18]([O-])=O)[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]=2[CH3:27])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[C:10]([CH3:27])[N:11]2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c([N+](=O)[O-])cccc21
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(N)cccc21

Procedure:
A solution of [3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-1H-indol-1-yl]acetic acid, ethyl ester (1.99 kg, 4.92 mol) in ethyl acetate (24.2 kg) was hydrogenated in the presence of a 1% Pt/C catalyst paste (1.39 kg 44% w/w) under 4 bar A hydrogen pressure. After 2 hours hydrogen uptake had ceased so the reaction mixture was inerted then filtered through Celite (2.60 kg). The solids were washed with ethyl acetate (3×8 kg) and the combined filtrates distilled until a volume of 26 L remained to leave a solution of [4-amino-3-(4-chlorophenylsulfanyl)-2-methylindol-1-yl]acetic acid, ethyl ester in ethyl acetate. This solution was cooled to 4° C. then triethylamine (0.50 kg, 4.94 mol) added, followed by an ethyl acetate line wash (0.82 kg). A solution of acetyl chloride (0.39 kg, 4.97 mol) in ethyl acetate (3 kg) was added followed by an ethyl acetate line wash (0.76 kg). The reaction mixture was heated at 40° C. for 17 hours then water (16.9 kg) added. The reaction mixture was distilled down until 24.6 kg of distillate had been removed then cooled to 20° C. The solid product was collected by filtration, washed with water (1.9 kg) followed by acetonitrile (1.6 kg) then dried in a vacuum oven at 40° C. to afford [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetic acid, ethyl ester, 1.69 kg (82%) as an off white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]([CH3:27])[CH2:25][C:24](=[O:28])[NH:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:27][CH:26]1[C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][CH:19]=2)=[N:22][NH:23][C:24](=[O:28])[CH2:25]1
Reactant: CC1CC(=O)NN=C1c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC(=O)NN=C1c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
A solution of 4-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (1 g, 2.5 mmol) in methylene chloride at RT was treated with trifluoroacetic acid (3 mL, 38.9 mmol) and stirred at RT for 3 h. TFA was evaporated at reduced pressure to obtain 5-methyl-6-[4-(piperidin-4-yloxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one (0.35 g, 47%), MS m/z 288 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C1C=CC([N+]([O-])=O)=CC=1)=O.[N+](C1C=CC([C@H](O)C)=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([OH:12])[CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: C[C@@H](O)c1ccc([N+](=O)[O-])cc1
Product: C[C@H](O)c1ccc([N+](=O)[O-])cc1
Reaction time: 408 h
Yield: 25 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized buckwheat protein for the substrate (±)-1-(4-nitrophenyl)ethanol (200 mg) requires 17 days by going through bioconversion to 4-nitroacetophenone accompanying sterically selective oxidation of (R)-1-(4-nitrophenyl)ethanol to obtain 50 mg of (S)-1-(4-nitrophenyl)ethanol at a yield of 25%. Optical purity was obtained at 99% e.e.
Reaction SMILES: [F:1][C:2]1([F:46])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:44][CH2:43][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=4)[C:32]([O:34]C(C)(C)C)=[O:33])[C:18]3=[O:42])[CH2:16][CH2:15]2)[C:3]1=[O:45]>Cl.O1CCOCC1>[F:46][C:2]1([F:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][C:17]3([N:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=4)[C:32]([OH:34])=[O:33])[C:18]3=[O:42])[CH2:43][CH2:44]2)[C:3]1=[O:45]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C(F)(F)c5ccccc54)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C(F)(F)c5ccccc54)CC3)C2=O)c1
Yield: 41.8 %

Procedure:
A solution of tert-butyl 3-((8-(3-(3,3-difluoro-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (210 mg, 0.333 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo and the crude residue was purified using preparatory high performance liquid chromatography to afford the acetate salt of the title compound as a white solid (80 mg, 42%); 1H NMR (400 MHz, DMSO-d6): δ 1.64 (d, 2H, J=12.8 Hz); 1.87 (d, 2H, J=6 Hz); 2.40 (t, 2H, J=6.4 Hz); 2.51 (bs, 2H); 2.81 (bs, 4H); 3.80 (t, 2H, J=6.8 Hz); 4.59 (s, 2H); 4.61 (s, 2H); 6.78 (t, 1H, J=7.2 and 7.6 Hz); 6.85 (d, 2H, J=8 Hz); 7.20-7.24 (m, 3H); 7.36 (d, 1H, J=8 Hz); 7.48-7.53 (m, 2H); 7.59 (t, 1H, J=8 and 7.6 Hz); 7.71 (d, 1H, J=7.6 Hz); 7.87 (d, 1H, J=2 Hz); 7.88 (d, 2H, J=2 Hz); 12.45 (bs, 1H); MS for C32H32F2N4O4 m/z 575.03 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:21])[C@H:11]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:12].CN1CCOCC1.[Br:29][CH:30]([CH2:34][CH2:35][CH3:36])[C:31](O)=[O:32].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CCCCCC.C(OCC)(=O)C.ClCCl>[CH3:8][O:9][C:10](=[O:21])[C@H:11]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:12][C:31](=[O:32])[CH:30]([Br:29])[CH2:34][CH2:35][CH3:36]
Reactant: COC(=O)[C@@H](N)CCc1ccccc1
Reactant: CCCC(Br)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCC(Br)C(=O)N[C@@H](CCc1ccccc1)C(=O)OC
Reaction time: 1 h

Procedure:
Combine (L)-homophenylalanine methyl ester trifluoroacetic acid salt (3.6 g, 10 mmol), N-methylmorpholine (3.3 mL, 30 mmol), and dichloromethane (20 mL). Add 2-bromovaleric acid (2.0 mL, 15.3 mmol), hydroxybenzotriazole (2.07 g, 15.3 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.93 g, 15.3 mmol). After 1 hour, partition the reaction mixture between methyl t-butyl ether and an aqueous 5% sulfuric acid solution. Separate the layers, extract the organic layer with a saturated sodium bicarbonate solution and then brine. Dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 3/1 hexane/ethyl acetate and then 2.5/1 hexane/ethyl acetate to give the title compound: Rf=0.55 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [S:1]([O:5]S([O-])(=O)=O)([O-:4])(=[O:3])=[O:2].[NH4+:10].[NH4+].[S:12](=[O:16])(=[O:15])([OH:14])[O-:13].[NH4+].S(OS([O-])(=O)=O)([O-])(=O)=O.S(=O)(=O)(O)[O-]>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+:10].[NH4+:10].[S:12](=[O:14])(=[O:13])([OH:16])[OH:15]
Reactant: O=S(=O)([O-])OS(=O)(=O)[O-]
Reactant: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: O=S(=O)(O)O

Procedure:
At the conclusion of the thermal decomposition reaction, solids or molten liquid comprising the decomposition product are removed from the reactor or allowed to cool in the reactor. In either case, water is added to the decomposition product to produce a second stream. With ammonium sulfate as the primary compound in the ammonium sulfate (first) stream, the addition of water converts preferably all or most of the ammonium pyrosulfate which may be present to ammonium bisulfate. With other sulfate salts present in the ammonium sulfate stream, the corresponding pyrosulfate salts, if present, are converted into bisulfate salts. Without wishing to be bound by theory, when water is added to the decomposition product, salts may be formed in equilibrium with ammonium sulfate and sulfuric acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH:6]([CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)=O)[CH3:2].BrC1C=C(C(=O)CC)C=CC=1.C(OCC)(=O)C(OCC)=O.O.[NH2:41][NH2:42]>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH3:16])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[NH:42][N:41]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)C(C)C(=O)c1cccc(Br)c1
Reactant: NN
Agent: CCC(=O)c1cccc(Br)c1
Solvent: CCOC(=O)C(=O)OCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c(-c2cccc(Br)c2)c1C
Yield: 46 %

Procedure:
In analogy to the procedure described in example 16A], 4-(3-bromo-phenyl)-3-methyl-2,4-dioxo-butyric acid ethyl ester (synthesized from 3′-bromopropiophenone and diethyl oxalate, following a procedure described in Ksander, Gary M.; McMurry, John E.; Johnson, Mark. A method for the synthesis of unsaturated carbonyl compounds. Journal of Organic Chemistry (1977), 42(7), 1180-5) and hydrazine monohydrate were heated at 90° C. in EtOH for 1 h to give after crystallization (Et2O/n-penatane) the title compound in 46% yield as off-white powder. MS: 308.1 (M+, 1 Br).
Reaction SMILES: CS(C(CC#C[C@@H](O)CCCCC)CCCCCCC(O)=O)(=O)=O.[CH3:25][S:26]([CH:29]([CH2:39][C:40]#[C:41][CH:42]([OH:50])[C:43]([CH3:49])([CH3:48])[CH2:44][CH2:45][CH2:46][CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:28])=[O:27]>>[CH3:25][S:26]([CH:29]([CH2:39][CH2:40][CH2:41][CH:42]([OH:50])[C:43]([CH3:49])([CH3:48])[CH2:44][CH2:45][CH2:46][CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:27])=[O:28]
Reactant: CCCCC(C)(C)C(O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O
Agent: CCCCC[C@H](O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O
Product: CCCCC(C)(C)C(O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out by hydrogenation exactly as described in Example 15 except that 8-methylsulfonyl-12(S)-hydroxy-10-heptadecynoic acid is replaced by an equivalent quantity of 8-methylsulfonyl-12-hydroxy-13,13-dimethyl-10-heptadecynoic acid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[N:16]([CH:19]([CH:25]([CH3:27])[CH3:26])[C:20](OCC)=[O:21])=[C:17]=[O:18]>>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([N:14]3[C:20](=[O:21])[CH:19]([CH:25]([CH3:27])[CH3:26])[NH:16][C:17]3=[O:18])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: CCOC(=O)C(N=C=O)C(C)C
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C(C)C)C2=O)cn1
Yield: 30 %

Procedure:
Prepared as in Example 10-41 from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 10-41a) and ethyl 2-isocyanato-3-methylbutanoate. Yield: 30%. 1H NMR (CDCl3, 400 MHz): δ 0.96-0.94 (d, 3H, J=7.2 Hz), 1.09-1.07 (d, 3H, J=8 Hz), 2.19 (s, 3H), 2.26-2.22 (m, 1H), 2.40 (s, 3H), 4.02 (s, 1H), 5.05 (s, 2H), 5.53 (bs, 1H), 7.90 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.1 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](COC)[C:11]3[C:16]([CH:23]=[O:24])=[C:17]([C:19]([O:21][CH3:22])=[O:20])[S:18][C:10]=3[C:9]=2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:4][CH:3]=1.CCOC(C)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]3[C:16]([CH:23]=[O:24])=[C:17]([C:19]([O:21][CH3:22])=[O:20])[S:18][C:10]=3[C:9]=2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: COCn1c(-c2ccc(Cl)cc2)c(C2CCCCC2)c2sc(C(=O)OC)c(C=O)c21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)[nH]c2c1C=O
Yield: 70 %

Procedure:
A solution (0.11 M) of methyl 5-(4-chlorophenyl)-6-cyclohexyl-3-formyl-4-(methoxymethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dioxane/aqueous HCl (6 N) (1:1) was heated at 130° C. under microwave irradiation for 10 min. After dilution with AcOEt, the resulting solution was basified with solid NaHCO8 and extracted with AcOEt. The combined organic phase was washed with brine, dried and concentrated under reduced pressure. The crude was triturated with Et2O/petroleum ether (1:9) to afford the title compound (70%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:7]=1[F:17])[CH3:2].[Li]C(CC)C.[I:24]I.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[C:7]([F:17])=[CH:8][CH:9]=[C:10]([O:12][C:13]([F:15])([F:14])[F:16])[C:11]=1[I:24])[CH3:2]
Reactant: II
Reactant: CCOC(=O)Nc1cc(OC(F)(F)F)ccc1F
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1c(F)ccc(OC(F)(F)F)c1I
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2 (31.34 g, 117.2 mmol) in THF (180 mL) at −78° C. is added sec-BuLi (1.4 M in cyclohexane, 200 mL, 280 mmol) dropwise over a 1 h period. After 20 min, a solution of I2 (44.6 g, 175.8 mmol) in THF (150 mL) is added dropwise over a 30 min period. This mixture is then stirred at −78° C. for 30 min. Saturated NH4Cl is added, and the cooling bath is removed. The reaction mixture is partitioned between H2O and EtOAc. The two layers are separated, and the organic layer is washed with 10% Na2SO3, H2O, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is suspended in DCM (50 mL), and heptane (300 mL) is added. The white powder 3 (18.1 g, 39%) from the resulting suspension is collected by suction filtration and air-dried. The filtrate is concentrated in vacuo, and the residue is suspended in heptane (200 mL). Another batch of 3 (3.8 g, 8%) is collected by suction filtration and air-dried. Additional product can be obtained by purifying the filtrate via silica gel chromatography. 1H NMR (CDCl3) δ 7.30-17.10 (m, 2H), 6.16 (br s, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H); 19F NMR (CDCl3) δ −56.90 (s, 3F), −114.35 (d, J=8.5 Hz, 1F); MS 394 (M+1, 100%), 374, 364, 321, 267.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12][C:13]([CH2:16]OS(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O>C(Cl)Cl>[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12][C:13]([CH2:16][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[N:14][CH:15]=1)=[O:9]
Reactant: C1CCNCC1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(COS(C)(=O)=O)nc1-c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(CN2CCCCC2)nc1-c1ccccc1
Reaction time: 16 h
Yield: 81.7 %

Procedure:
To a solution of 0.40 g (0.73 mmol) methanesulfonic acid 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-phenyl-pyrimidin-2-ylmethyl ester in 5 ml CH2Cl2 added 0.11 ml (1.1 mmol) piperidine were added. The reaction mixture was stirred for 16 hrs. at RT and than poured into H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 10:1) to give 0.32 g (81%) 4-phenyl-2-piperidin-1-ylmethyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a pale yellow waxy solid, MS (ISP): 537.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:25]2[CH:24]=[C:23]([C:26](O)=[O:27])[CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13](=[O:12])[C:25]=4[CH:24]=3)=[O:27])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1-2
Reactant: Nc1ccc2cccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc2cccnc2c1)c1ccc2c(c1)C(=O)c1ccccc1-2
Temperature: 25 °C

Procedure:
To a solution of 7-aminoquinoline (D55) (35 mg, 0.24 mmol) in DCM (3 ml) was added 9-oxo-9H-fluorene-2-carboxylic acid (60 mg, 0.27 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (68 mg, 0.36 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) and the reaction stirred at room temperature then at reflux until complete by tlc. After cooling to room temperature the resultant precipitate was filtered off to give the title compound as an off-white solid. MS(ES): MH+ 351, M-H+ 349
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:8]([C:10]3[S:14][C:13]4=[C:15]([S:18][CH3:19])[N:16]=[CH:17][N:12]4[CH:11]=3)[CH2:9][C@H:5]12)[CH3:3].[OH:35]OS([O-])=O.[K+]>>[OH:1][C@@H:2]([C@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])=[C:8]([C:10]3[S:14][C:13]4=[C:15]([S:18]([CH3:19])=[O:35])[N:16]=[CH:17][N:12]4[CH:11]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4C3)sc12
Reactant: O=S([O-])OO
Agent: [K+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(C)=O)c4s3)C[C@H]12
Yield: 40.5 %

Procedure:
A reaction was carried out in the same manner as in Example 44-b), except that 639 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate and 1.57 g of oxone were used as the starting compounds. The reaction product was purified by column chromatography on silica gel (dichloromethane:methanol=20:1 to 10:1) to give 267 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfinylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a Mixture of Diastereomers).