Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:7]2[CH2:30][N:29](C(OC(C)(C)C)=O)[C:10]3=[N:11][C:12]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH:7]2[CH2:30][NH:29][C:10]3=[N:11][C:12]([C:22]4[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC(N2CCCCC2)C3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCC(N2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl 7-(piperidin-1-yl)-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 6) (90 mg, 0.180 mmol) in DCM (1 ml) was treated with TFA (0.501 mL, 6.50 mmol) and stirred at room temperature for 3 hours. The resulting mixture was diluted with DCM (3 ml) and washed with a saturated solution of sodium hydrogen carbonate. The organic portion was passed through a phase separating column and the solvent removed under reduced pressure to afford the titled compound;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[N:2]=1.C[N:11]1CCOCC1.ClC(OC(C)C)=O.N>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH2:11])=[O:9])[N:2]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cccnn1
Agent: CC(C)OC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1cccnn1
Temperature: -30 °C
Reaction time: 6 h
Yield: 20.4 %

Procedure:
To a cooled solution of pyridazine-3-carboxylic acid (1.0 g, 8.06 mmol) in tetrahydrofuran (40 mL) in a dry-ice bath was added 4-methyl-morpholine (0.9 g, 8.87 mmol) and isopropyl chloroformate (1.1 g, 8.87 mmol) slowly. The reaction was stirred at −30° C. for 6 hours, then an aqueous solution of ammonia (8 mL, 10% W/W) was added. The resulting mixture was stirred at room temperature overnight, washed with a saturated aqueous solution of potassium bisulfate (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 202.5 mg of the desired product (yield was 20.4%). MS obsd. (ESI+) [(M+H)+] 124, 1H NMR (400 MHz, CD3OD) δ ppm 9.45-9.35 (t, J=1.6 Hz, 1 H), 8.58 (s, 1 H), 8.23-8.15 (d, J=7.6 Hz, 1 H), 7.98-7.88 (m, 2 H).
Reaction SMILES: [N+:1]([O-:31])([O:3][C@@H:4]1[CH:21]2[C@:16]([CH3:22])([CH2:17][CH2:18][CH2:19][CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10]24OCCO[C:9]2(OCC[O:23]4)[CH2:8]3)[CH2:5]1)=[O:2].CC1C=CC(S(O)(=O)=[O:40])=CC=1.O.C([O-])(O)=O.[Na+]>CC(C)=O>[N+:1]([O-:31])([O:3][C@@H:4]1[CH:21]2[C@:16]([CH3:22])([CH2:17][CH2:18][C:19](=[O:40])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:23])[CH2:9][CH2:8]3)[CH2:5]1)=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12CCCCC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CCC(=O)CC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of 3,3:17,17-bis(ethylendioxy)androstane-6α-yl nitrate (2.50 g) and pTSA.H2O (6.05 g) in acetone (150 mL) was stirred at room temperature for 1.5 h. The solution was neutralized by addition of 5% aqueous NaHCO3, and acetone was evaporated. The aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, cyclohexane/acetone/CH2Cl2 70/15/15) to give the title compound II-aa as a white solid (1.66 g, 75%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.09 (ddd, 1H), 2.60-0.95 (m, 17H), 1.25 (s, 3H), 0.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(Cl)nc1Cl

Procedure:
To a solution of 2,6-dichloronicotinic acid (52 g, 0.27 mol) in benzene: MeOH (7:1, 1.0 L) was added dropwise a solution of (trimethylsilyl)diazomethane (1 M in heptane) until gas evolution ceased and the yellow color persisted (ca. 320 mL, 1.2 equiv.). The volatiles were removed and the residue was purified by chromatography on silica gel eluting with 7:1 hexane:ethyl acetate to give the product as a white solid.
Reaction SMILES: [Li]CCCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].O1CCCC1.ClCCCCC#C.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>CCCCCC>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:6]#[C:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCCC
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C#CCCCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CC1CCC1)(CCCC)CCCC
Reaction time: 6 h

Procedure:
To a solution of n-BuLi/hexane (7.28 mL, 18.2 mmol, 2.5 M) at −5° C. was added tetrahydrofuran dropwise, maintaining the temperature below +9° C. 6-Chloro-1-hexyne (1.00 mL, 8.92 mmol) was added at +5° C., and the solution was stirred for six hours. The reaction was quenched by the addition of tri-n-butyltin chloride (2.66 mL, 9.81 mmol), and was allowed to stir for an additional 10 minutes. The solution was poured into hexane, washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a colorless liquid which was used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=[C:8]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.I(O)(=O)(=O)=[O:29]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:29]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c(SC)cccc32)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c2cccc3S(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirring suspension of compound 98 (100 mg, 0.266 mmol) and iron (III) chloride (1.296 mg, 7.99 μmol) in acetonitrile (2 mL) after 5 minutes was added periodic acid (66.8 mg, 0.293 mmol) in one portion. The reaction mixture was left to stir at room temperature overnight then quenched with saturated sodium thiosulfate solution and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4, filtered and solvent evaporated. Purification via ISCO (0-40% EtOAc/Hexanes; 40 g silica gel column) afforded title compound 99 (60 mg, 57%) as a yellow solid. LRMS (ESI): (calc) 391.09. (found) 392.4 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].C(OC([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[C:3]2[N:15]=[C:25]([C@@H:24]([NH2:23])[CH3:28])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1c(F)cccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](N)c1nc2c(F)cccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A mixture of 3-fluoro-N1-phenylbenzene-1,2-diamine (440 mg, 2.18 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (454 mg, 2.40 mmol), HOAt (327 mg, 2.40 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (460 mg, 2.40 mmol) and 4-methylmorpholine (0.527 mL, 4.79 mmol) in anhydrous DCM (20 mL) was stirred at RT for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (10 mL) and heated to 70° C. for 2 h and then to 80° C. for 20 h. After cooling to RT, TFA (20 mL) was added and the mixture was stirred at RT for 1 h and 20 min. Volatiles were then removed in vacuo and the residue was dissolved in DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in TBME) affording (S)-1-(4-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a brown oil (396 mg, 71%). LCMS: RT 2.01 min [M−NH2]+ 239.1.
Reaction SMILES: C[C@H]1P(CCP2[C@H](C)CC[C@H]2C)[C@H](C)CC1.[CH3:17][O:18][C:19]1[CH:32]=[CH:31][C:22]2[C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][O:25][C:21]=2[CH:20]=1.[H][H]>CO>[CH3:17][O:18][C:19]1[CH:32]=[CH:31][C:22]2[CH:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:24][O:25][C:21]=2[CH:20]=1
Reactant: COC(=O)Cc1coc2cc(OC)ccc12
Reactant: [H][H]
Agent: C[C@@H]1CC[C@@H](C)P1CCP1[C@H](C)CC[C@H]1C
Solvent: CO
Product: COC(=O)CC1COc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.3 %

Procedure:
To a mixture of (1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (12 mg) and (R,R)-Me-BPE (6.5 mg) was added methanol (2.5 mL) sufficiently substituted by argon gas, and the mixture was stirred at room temperature for 15 min. This was added to methyl (6-methoxy-1-benzofuran-3-yl)acetate (55 mg), and the mixture was stirred at 70° C. for 3 hr under 0.7 MPa hydrogen atmosphere. The reaction mixture was quantified by HPLC. As a result, the enantiomeric excess was 52.8%, and the yield was 24.3%.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:5]2[CH:4]=[CH:3][NH:2]1.[Br:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20](Br)[C:17]=1[CH:18]=[O:19].C([O-])(=O)C.[K+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>>[Br:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([N:2]2[CH:3]=[CH:4][N:5]3[C:13]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[CH:7]=[C:6]3[C:1]2=[O:14])[C:17]=1[CH:18]=[O:19]
Reactant: O=Cc1c(Br)cc(F)cc1Br
Reactant: O=c1[nH]ccn2c3c(cc12)CCCC3
Agent: CC(=O)[O-]
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: [K+]
Product: O=Cc1c(Br)cc(F)cc1-n1ccn2c3c(cc2c1=O)CCCC3
Temperature: 100 °C
Yield: 49.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 121e (500 mg, 2.66 mmol), 2,6-dibromo-4-fluorobenzaldehyde (1.50 g, 5.32 mmol), and potassium acetate (521 mg, 5.32 mmol). After bubbling argon through the suspension for 30 minutes, 4,7-dimethoxy-1,10-phenanthroline (638.4 mg, 2.66 mmol) and cuprous iodide (506 mg, 2.66 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and then heated at 100° C. for 16 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×100 ml). The combined filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 3:1) to afford 121f (510 mg, 49%) as a yellow solid. MS: [M+H]+ 389.
Reaction SMILES: [CH2:1]([C:8]1[NH:12][C:11]([CH3:13])=[N:10][C:9]=1[CH:14]([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19]([O:26][CH2:27]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:1]([C:8]1[N:12]([CH2:27][O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([CH3:13])=[N:10][C:9]=1[CH:14]([CH3:16])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1nc(C(C)C)c(Cc2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C(C)C)c(Cc2ccccc2)n1COCc1ccccc1
Yield: 53.5 %

Procedure:
To a solution of 980 mg of 5-benzyl-4-isopropyl-2-methylimidazole (4.58 mmol) in 9.8 ml of dry dimethylformamide is added 238 mg of 60% oil suspension of sodium hydride (5.95 mmol) under ice cooling. Ten minutes later, 935 mg of benzyloxymethyl chloride (5.97 mmol) is dropwise added. One hour later, the reaction mixture is poured onto ice water and extracted with ethyl acetate. The extract is washed with saturated brine, dried over sodium sulfate, filtered and the liltrate is concentrated in vacuo. The crude product is chromatographed on a column of silica gel, eluting with ethyl acetate and n-hexane (1:1) to give 820 mg of the objective 5-benzyl-1-benzyloxymethyl-4-isopropyl-2-methylimidazole (I-42). Yield, 54.17%.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](O)=[O:8].S(Cl)([Cl:13])=O>>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([Cl:13])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(C(=O)O)C1(C)C
Product: CC1(C)C(C(=O)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask containing 2,2,3,3-tetramethylcyclopropane carboxylic acid (Aldrich, 13.5 g, 95 mmol) was added 30 mL of thionyl chloride (410 mmol, excess). This solution was warmed to reflux and stirred for 2 h. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The residue was azeotroped three times with 10 mL of benzene to remove any remaining thionyl chloride, and used without further purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:12][CH2:13][CH3:14])([CH2:6][NH:7][C:8](=S)[S:9]C)=[O:5])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C.O>[CH2:1]([O:3][P:4]([CH2:6][N:7]1[C:8]([SH:9])=[N:17][N:16]=[N:15]1)([O:12][CH2:13][CH3:14])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CNC(=S)SC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(Cn1nnnc1S)OCC

Procedure:
To a solution of 2.85 g (11.1 mmol) of methyl 1-diethoxyphosphinylmethyldithiocarbamate in 25 ml of ethanol was added a solution of 0.72 g (11.1 mmol) of sodium azide in 5 ml of water. The reaction mixture was refluxed for 2.5 hours then evaporated to near dryness. Water (20 ml) was added and the aqueous mixture was layered with 40 ml of ethyl acetate and acidified to pH 2.2 by addition of 6N sulfuric acid. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The ethyl acetate solutions were combined, dried (MgSO4) and evaporated to dryness to give 1-diethoxyphosphinylmethyltetrazole-5-thiol.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[C:7]([O:16][CH2:17][CH3:18])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10].C(N(CC)CC)C.C(N1C(=O)C2C(=CC=CC=2)NC1=O)CC>C1(C)C(C)=CC=CC=1>[CH2:1]([NH:4][C:5]([NH:10][C:9]1[C:8](=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([O:16][CH2:17][CH3:18])=[O:15])=[O:6])[CH2:2][CH3:3]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CCCN=C=O
Agent: CCCn1c(=O)[nH]c2ccccc2c1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCCNC(=O)Nc1ccccc1C(=O)OCC
Temperature: 110 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
A solution of propyl isocyanate (34.0 g, 0.40 mol) in xylene (100 ml) is metered, at room temperature, into a solution of ethyl anthranilate (66.1 g, 0.40 mol) in xylene (200 ml). After the addition has ended, the batch is stirred at 110° C. for 2 hours. Triethylamine (5.6 ml, 4.08 g, 0,040 mol) is added. Stirring is continued at 90° C. for a further 2 hours. The desired cyclization product 3-(propyl)-2,4(1H,3H)-quinazolinedione cannot be detected in the reaction solution by thin-layer chromatography. After cooling, the precipitate is filtered off with suction, washed with 3×25 ml of xylene and dried. 67.0 g of ethyl N-(propylcarbamoyl)anthranilate (yield: 66.9% of theory) of melting point 98° to 99° C. are obtained.
Reaction SMILES: [NH2:1][C@@:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([Br:18])[N:12]=1)([CH3:10])[CH2:3][C@H:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[N+:19]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]=[C:29]=S)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>CC#N>[Br:18][C:13]1[N:12]=[C:11]([C@:2]2([CH3:10])[CH2:3][C@H:4]([C:5]([F:6])([F:7])[F:8])[O:9][C:29]([NH:28][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:32][CH:31]=3)=[N:1]2)[C:16]([F:17])=[CH:15][CH:14]=1
Reactant: C[C@](N)(C[C@H](O)C(F)(F)F)c1nc(Br)ccc1F
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(c2nc(Br)ccc2F)C[C@H](C(F)(F)F)OC(NC(=O)c2ccc([N+](=O)[O-])cc2)=N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4S)-4-amino-4-(6-bromo-3-fluoropyridin-2-yl)-1,1,1-trifluoropentan-2-ol (7f, 0.183 g, 0.553 mmol) in MeCN (3 mL) was added 4-nitrobenzoyl isothiocyanate (Matrix, 0.150 g, 0.719 mmol). The mixture was stirred at room temperature for 30 min. Additional 4-nitrobenzoyl isothiocyanate (30 mg) was added and the reaction was allowed to stir for additional 20 min. N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (Aldrich, 0.170 g, 0.884 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.241 mL, 1.382 mmol) was added and the reaction mixture was heated to 70° C. for 1 h. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated washed with brine, and dried over sodium sulfate. The filtrate was concentrated under reduced pressure and the crude material was purified by silica gel chromatography (0-60% EtOAc/hexanes) to obtain the title compound as an off-white solid. MS m/z=505/507 [M]+/[M+2]+. Calculated: 505.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH2:21]=[O:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21][OH:22])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1-n1ccnc1
Reactant: C=O
Product: O=C(c1ccccc1)c1cc(Br)ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 5-bromo-2-(imidazol-1-yl)benzophenone is heated in a bomb with 37% aqueous formaldehyde solution to give 5-bromo-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[H-].[Na+].[NH2:13][C:14]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.C(OCC)C>CS(C)=O>[NH2:13][C:14]1[CH:19]=[C:18]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:9][CH3:10])[CH:4]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: COc1cc(O)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1cc(Oc2ccnc(N)c2)ccc1N
Temperature: 25 °C
Yield: 31.5 %

Procedure:
4-Amino-3-methoxyphenol (5.88 g) was dissolved in dimethyl sulfoxide (80 ml) while stirring, and then 60% sodium hydride (1.6 g) was added thereto gradually under a nitrogen stream, followed by stirring for 20 min. 2-amino-4-chloropyridine (2.75 g) was then added thereto, followed by stirring at 160° C. for 8 hrs. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether was then added to precipitate crystals. The crystals were filtered and dried under aeration to provide the titled compound (1.56 g, 34%) as pale brown crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH2:17])[C:13]([O-:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19](=[CH2:21])[CH3:20].O>O1CCOCC1.S(=O)(=O)(O)O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][NH2:17])[C:13]([O:15][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(CN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-(S)-(benzyloxycarbonyl)amino-3-aminopropionate (Fluka) (5.25 g, 22 mmol) in dioxane (75 mL) and conc. sulfuric acid (9 mL) was cooled to 0° C. and treated with 100 mL isobutylene in a Fisher Porter high pressure apparatus. The reaction was allowed to warm to room temperature and was stirred for 24 h. The reaction was vented, then poured into water (200 mL) to give an acidic solution that was extracted with ether (2×50 mL). The aqueous layer was carefully basified with conc. NaOH to pH 11-12 and extracted with 3×150 mL EtOAc. The EtOAc was removed in vacuo and the residue was azeotroped with toluene and dried under vacuum to give 4-1 as an oil. Rf (5% MeOH/CHCl3 saturated with NH3) 0.31. 1H NMR (400 MHz, CDCl3) δ7.3 (m, 5H), 5.6 (bs, 1H), 5.1 (s, 2H), 4.22 (bs, 1H), 3.05 (m, 2H), 1.45 (s, 9H), 1.4-1.2 (b, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[CH3:12][C:13]1[CH:22]=[CH:21][C:16]([CH:17]=[N+:18]([CH3:20])[CH3:19])=[CH:15][CH:14]=1.CC1C=CC(C=O)=CC=1.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:17]([N:18]([CH3:19])[CH3:20])[C:16]1[CH:21]=[CH:22][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(C=[N+](C)C)cc1
Agent: CNC
Agent: Cc1ccc(C=O)cc1
Agent: [Cl-]
Product: Cc1ccc(C(c2c[nH]c3ccc(Cl)cc23)N(C)C)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and (4-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 4-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([NH:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)NCCc2ccc(Cl)cc2)ccc1Cl
Reaction time: 8 h

Procedure:
2-Chloro-5-chlorosulfonyl benzoic acid, 3.5 g. (0.014 mole), is added to a solution of 2-(p-chlorophenyl)ethylamine, 6.5 g. (0.042 mole) in 25 ml. methylene chloride. The resulting slurry is stirred overnight and filteredto recover 9.7 g. of residue. This is recrystallized three times from aqueous isopropanol, then dissolved in 1N aqueous sodium hydroxide, washedthree times with ether, and then acidified with conc. hydrochloric acid. The resulting precipitate is recrystallized twice from aqueous isopropanolto yield the desired product, m.p. 176°- 178° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:9]
Reactant: CCOC(=O)c1ncc2c(-c3ccc(OC)cc3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2noc3c(O)c(C(=O)NCC(=O)O)ncc23)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Ethyl 7-hydroxy-3-(4-methoxyphenyl)isoxazolo[4,5-c]pyridine-6-carboxylate (0.12 g, 0.38 mmol) was dissolved in 10 mL of DMF. Glycine (0.574 g, 7.64 mmol) and sodium ethoxide (0.391 g, 5.73 mmol) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 94 mg of the title compound. MS: (+) m/z 344.37 (M+1).