Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].C1(C)C=CC=CC=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]#[N:20].Cl.[C:22](=O)([O:25]C)[O:23][CH3:24]>O>[C:19]([CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])[C:22]([O:23][CH3:24])=[O:25])#[N:20]
Reactant: COC(=O)OC
Reactant: N#CCc1ccccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)c1ccccc1F
Temperature: 75 °C
Yield: 97.1 %

Procedure:
Sodium methoxide (51.84 g) was added to dry toluene (815 mL) in a 1 L reactor under a nitrogen atmosphere. The reaction mixture was heated to 75° C., and then a mixture of 2-fluorobenzeneacetonitrile (100 g) in dimethyl carbonate (131.64 g) was added at 70-74° C. over a period of 45 minutes. The reaction mixture was further maintained at this temperature (70-75° C.) for an additional 4.5 hours. The reaction mixture was then cooled to 25-30° C. and added to a mixture of HCl (110 g, 35.2 wt %) diluted with water (300 mL) at 10-15° C. using an addition funnel. The resulting layers were separated, and the aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×200 mL), dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound as a brown oily liquid (138.8 g, 94.8% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C@@H:7]([C:16]([O:18][CH3:19])=[O:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[O:37]=[C:38]1[CH:42]=[CH:41][C:40](=[O:43])[N:39]1[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([NH:51][CH2:52][C:53](O)=[O:54])=[O:50]>CN(C)C=O>[C:12]([O:11][C:9]([NH:8][C@H:7]([C:16]([O:18][CH3:19])=[O:17])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:53](=[O:54])[CH2:52][NH:51][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][N:39]2[C:38](=[O:37])[CH:42]=[CH:41][C:40]2=[O:43])=[CH:21][CH:20]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: O=C(O)CNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)CNC(=O)CCCCCN2C(=O)C=CC2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
To a solution of methyl 4-amino-N-(tert-butoxycarbonyl)-L-phenylalaninate (4.1 g, 15.3 mmol, 1 eq.) in dry N,N-dimethylformamide (70 mL) was added N,N′-Dicyclohexylcarbodiimide (2.9 g, 15.3 mmol, 1 eq.) at 0° C. The mixture was stirred at 0° C. for 30 minutes. A solution of 2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)acetic acid (3 g, 10.2 mmol, 0.66 eq.) in dry N,N-dimethylformamide (20 mL) was added at 0° C. The mixture was stirred at room temperature for 3 days. The mixture was filtered. The filtrate was poured into ice water (200 mL) and extracted with EtOAc (200 mL×3). The extract was washed with brine (200 mL), dried over Na2SO4 and concentrated in vacuo to afford #251 (1.8 g, 32.3% yield) as a light yellow solid. HPLC (Protocol Q2) [M+Na+] 567.3, retention time=1.02 min
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[O:30][CH3:31])=[CH:7][CH:8]=[C:9]([NH:14][C:15]([C:18](OC)=[O:19])([CH3:17])[CH3:16])[C:10]=1[N+:11]([O-])=O)=[O:4].[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]2[NH:11][C:18](=[O:19])[C:15]([CH3:16])([CH3:17])[NH:14][C:9]=2[CH:8]=[CH:7][C:6]=1[C:22]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[O:30][CH3:31])=[O:4]
Reactant: COC(=O)c1c(-c2c(OC)cccc2OC)ccc(NC(C)(C)C(=O)OC)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1c(-c2c(OC)cccc2OC)ccc2c1NC(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of biphenyl vi (800 mg, 1.85 mmol) in EtOH (20 mL) was added tin(II) chloride (1.76 g, 9.26 mmol). The mixture was heated at reflux for 16 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (50 mL) and basified with saturated aqueous NaHCO3. The resulting white suspension was stirred at room temperature for 30 min, then filtered through celite and the precipitate was washed by EtOAc (3×20 mL). The two layers were separated and the organic layer was collected. The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine and dried over MgSO4. After the solvent was removed under reduced pressure, the residue was purified by flash chromatography (EtOAc/hexane, 40% to 70%) to yield vii as a light yellow solid (500 mg, 73%). 1H NMR (CDCl3): δ 7.93 (br s, 1H), 7.14 (t, J=8.4 Hz, 1H), 6.73 (m, 2H), 6.51 (d, J=8.4 Hz, 1H), 3.62 (s, 6H), 3.37 (s, 3H), 1.34 (s, 6H). Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C, 65.00; H, 5.73; N, 7.31.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cccc(-c2noc3cc(F)ccc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2noc3cc(F)ccc23)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
Combine 6-fluoro-3-(3-methoxy-phenyl)-benzo[d]isoxazole (30 g, 0.123 mol) and dichloromethane (anhydrous, 360 mL) under nitrogen atmosphere and cool (0° C.). Slowly add 1.0 M solution of boron tribromide in dichloromethane (370 mL, 0.370 mol) over 1 hour and stir at 0° C. for 3 hours. TLC indicates that all starting material is consumed. Quench the reaction mixture with 150 mL methanol, concentrate and azeotrope off the boron tribromide two more times with methanol. Dissolve the material in ethyl acetate, wash with K2CO3, saturated sodium chloride, dry (MgSO4) and concentrate. Triturate in heptane:dichloromethane (9:1), filter and wash with heptane and dry in the oven to give the title compound (26.93 g, 95% Yield). NMR and microanalysis (C, H, N) are consistent with the final, desired compound. mp=144-145° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18](Cl)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
Charge 7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (0.37 g, 1.00 mmoles), K2CO3 (0.28 g, 2.00 mmoles) and anhydrous morpholine (3 mL) to a round bottom flask equipped with a magnetic stir bar and N2 inlet. Stir the yellow mixture at 100° C. for about 4 hr., during which time the reaction becomes homogeneous. Cool the reaction mixture to room temperature, add H2O (10 mL) and stir the heterogeneous reaction mixture overnight at room temperature. Collected the yellow solid by filtration, wash with H2O and allowed to air dry overnight to give the crude title compound (391 mg). Recrystallize from isopropyl alcohol (3 mL) to yield the title compound as a light yellow crystalline solid (380 mg, 90.6% yield, >99% by LC). MS (ES)=420 (M+1). 1H NMR (CDCl3)=6.45 (1H, s); 3.81 (m, 4H); 3.62 (1H, m); 3.50 (m, 4H); 2.6 (3H, s); 2.45 (3H, s); 1.85 (4H, m); 0.9 (6H, t).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9]>>[C:7]([O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C1=COCCC1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OC1CCCCO1

Procedure:
Dihydropyrane was added to methacrylic acid by the use of an acid catalyst to obtain tetrahydropyranyl methacrylate (Compound (III-g)).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Si:49]([O:56][CH2:57][C@@H:58](O)[CH3:59])([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>O>[Si:49]([O:56][CH2:57][C@H:58]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)[CH3:59])([C:52]([CH3:53])([CH3:54])[CH3:55])([CH3:51])[CH3:50]
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2cccc(O[C@H](C)CO[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.8 %

Procedure:
To a solution of 2-methylquinolin-8-ol (0.40 g, 2.5 mmol) in tetrahydrofuran (2.1 mL, 2.5 mmol) was added triphenylphosphine (1.6 g, 6.3 mmol), diethyl azodicarboxylate (0.63 mL, 4.0 mmol), and (S)-1-(tert-butyldimethylsilyloxy)propan-2-ol (0.62 g, 3.3 mmol). The resultant mixture was allowed to stir at ambient temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to provide the title compound (0.33 g, 40%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CS(Cl)(=O)=O.[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[CH2:21]([N:20]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCNC
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCCN(C)Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To methyl 3-(hydroxymethyl)-5-methylbenzoate prepared by the method in Example SP-177 (1.1 g, 6.1 mmol), in anhydrous methylene chloride (10 mL) is added methanesulfonyl chloride (663 μL, 8.6 mmol) at −30° C., and the reaction is warmed to 0° C. The reaction stirred 1 h, then filtered. The filtrate is added to N-methylbutylamine (2.1 mL, 18.3 mmol), and the reaction stirred at room temperature 16 h. The solution is concentrated under reduced pressure. Purification by flash chromatography affords the title compound in pure form. ESI MS m/z 250.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:35])([F:34])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].Cl[CH2:39][S:40][CH3:41]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:33])([F:34])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:39][S:40][CH3:41])[CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CSCCl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCN1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C)CC1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one (200 mg, 0.38 mmol, 1.00 equiv), tetrahydrofuran (10 mL), sodium hydride (30 mg, 0.75 mmol, 2.00 equiv, 60%), chloro(methylsulfanyl)methane (149 mg, 1.54 mmol, 4.00 equiv). The resulting solution was stirred for 1 h at 50° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel TLC-plate with ethyl acetate/petroleum ether (1/1). This resulted in 60 mg (27%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]-3-[(methylsulfanyl)methyl]imidazolidin-4-one as yellow oil.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4][C:3]2[NH:16][C:17]4[C:22]([C:23](=[O:24])[C:2]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3.[OH-].[Na+].S(=O)(=O)(O)O.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+]>CO>[CH:20]1[CH:21]=[C:22]2[C:23]([C:2]3[C:3]([NH:16][C:17]2=[CH:18][CH:19]=1)=[CH:4][C:5]1[C:14]([C:13]2[C:8]([NH:7][C:6]=1[CH:1]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])=[O:24]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12

Procedure:
10 Parts of the 6,13-dihydroquinacridone obtained in Example 9 and 80 parts of methanol were charged into a 200-ml flask having a refluxer, and stirred. 12 Parts of a 50% NaOH aqueous solution was added, and the mixture was stirred at 40° C. for 30 minutes to form a salt. 26 Parts of 10% sulfuric acid was added dropwise to hydrolyze the salt, and the reaction mixture was refluxed under heat for 1 hour. 10 Parts of sodium m-nitrobenzenesulfonate was added, and immediately therafter, 50 parts of a 50% NaOH aqeuous solution was added. Then, the mixture was refluxed for 4 hours to give 9.88 parts (99.4% of the theoretical yield) of an unsubstituted quinacridone having an excellent particle diameter as a pigment.
Reaction SMILES: C[O-].[Na+].[C:4](O)(=[O:6])C.C(O)(=O)C.IC1C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1.Cl>CO>[CH3:4][O:6][CH:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Ic1ccccc1
Product: COC(=O)C(OC)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 15.6 %

Procedure:
A 28% solution of sodium methoxide in methanol (12.8 g) and iodobenzene diacetate (7.15 g) were added to a solution of methyl 4-methoxyphenylacetate (4.0 g) in methanol (60 mL), and the reaction solution was stirred at room temperature for five days. 1 N hydrochloric acid (67 ml) was added dropwise to the reaction solution under ice-cooling, and methanol was evaporated from the reaction solution under reduced pressure. Ethyl acetate was added to the remaining aqueous layer, and the organic layer was separated. The resulting organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) to obtain 725 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: C[S-]
Reactant: Clc1cc(Cl)ncn1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
4,6-Dichloropyrimidine (2.0 g, 13.42 mmol) was dissolved in THF (10 mL), treated with sodium thiomethoxide (0.988 g, 14.10 mmol) and the resulting mixture was stirred at room temperature under argon for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and brine. The ethyl acetate layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the desired product as a white solid (623 mg);
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:19][C:20]([O:22]CC)=O)([O-])=O>C(O)C.O.[Fe]>[O:22]=[C:20]1[CH2:19][C:7]2[C:6](=[C:11]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)Cc1cccc(Sc2ccccc2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: O=C1Cc2cccc(Sc3ccccc3)c2N1

Procedure:
A suspension of iron powder (1.5 g.) and ammonium chloride (0.15 g.) in a mixture of ethanol (7 ml.) and water (7ml.) was refluxed with stirring. Ethyl 2-(2-nitro-3-phenylthiophenyl)acetate (1.6 g.) was added to the suspension, and the mixture was refluxed for 7 hours and filtered. The filtrate was evaporated to dryness under reduced pressure, and residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The oily residue was dissolved in ethanol (10 ml.) and heated with conc. hydrochloric acid (0.1 ml.). The precipitating crystals were collected by filtration and dried to give the captioned compound (0.9 g.). mp 160° to 161° C.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1.[BH4-].[Na+]>O1CCCC1.O>[CH3:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([OH:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC(O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C

Procedure:
To a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C) in tetrahydrofuran, add sodium borohydride dissolved in water, After 3-4 hours of stirring at room temperature, quench with an acid. The organic layer can be taken in dichloromethane, wash with water, aqueous sodium bicarbonate, and brine, dry over Na2SO4, filter and concentrate. If needed, the compound can be purified by flash chromatography on silica gel column (EtOAc:Hex).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[Br:24].IC>O1CCCC1>[Br:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[CH:16]([CH3:1])[C:15]([O:14][CH3:13])=[O:25]
Reactant: [Li]CCCC
Reactant: COC(=O)Cc1cc(Cl)ccc1Br
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)c1cc(Cl)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium (1.67 mL of a 2.5 M solution in hexanes, 4.17 mmol) was added dropwise via syringe to a stirred solution of diisopropylamine (0.61 mL, 4.36 mmol) in tetrahydrofuran (10 mL) at −78° C. After approximately 10 min, the reaction mixture was warmed to 0° C. and aged for another 10 min. After re-cooling to −78° C., a solution of methyl (2-bromo-5-chlorophenyl)acetate (1-2) (1.00 g, 3.79 mmol) in tetrahydrofuran (10 mL) was added dropwise via syringe and the resulting yellow mixture was stirred at −78° C. for approximately 30 min. Iodomethane (0.35 mL, 5.69 mmol) was added and after 1 h, the reaction mixture was warmed to ambient temperature and quenched with saturated aqueous ammonium chloride. The resulting mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-20% ethyl acetate/hexanes as eluent) furnished 2-1 as a colorless oil (1.00 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42][NH2:43])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42][NH:43][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)=[CH:33][CH:32]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-benzoic acid (Example 41 before reverse phase chromatography, 0.08 g, 0.185 mmol), (2-aminoethyl)-carbamic acid tert-butyl ester (0.036 g, 0.2 mmol), N—N-Diisopropylethylamine (0.08 mL, 0.46 mmol) and HBTU (0.076 g, 0.2 mmol) are mixed in 10 mL of DMF and stirred at RT for 8 h under nitrogen. The crude mixture is diluted with EtOAc (30 mL) and extracted with saturated NaHCO3. The organic phase is separated and washed with saturated brine, dried (Na2SO4), filtered, evaporated to a solid mass. The crude product is purified by MPLC on silica gel (80% EtOAc/Hexanes, 1% MeOH) to yield the title compound, 0.059 g (56%), as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.[CH2:12]([C:14]1[S:18][C:17]([CH3:19])=[N:16][N:15]=1)[CH3:13]>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH2:12]([C:14]1[S:18][C:17]([CH:19]=[CH:10][C:3]2[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=2)=[N:16][N:15]=1)[CH3:13]
Reactant: CCc1nnc(C)s1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCc1nnc(C=Cc2ncc([N+](=O)[O-])n2C)s1

Procedure:
A solution of 15.5 g of 1-methyl-5-nitroimidazole-2carboxaldehyde in 50 ml of acetic acid and 25 ml of acetic anhydride is added at reflux temperature over a period of 10 hours to 12.8 g of 5-ethyl-2-methyl-1,3,4-thiadiazole and 0.5 g of ZnCl2 which have been dissolved in 100 ml of acetic acid and 50 ml of acetic anhydride. The mixture is kept at reflux temperature for a further 20 hours and the solvent is then evaporated. The residue is washed with acetone and passed through a ready-to-use silica gel column (Type A of Messrs. Merck) and eluted with CHCl3 /CH3OH=98 : 2. 5.6 g of the abovementioned reaction product with a melting point of 165° C. is obtained; this corresponds to 21% of the theory.