Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\C(C2C=CC3C=CSC=3C=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=O)=[CH:46][C:45]=1[C:53]([F:56])([F:55])[F:54]>>[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](/[N:31]=[C:14]2/[N:13]([C@H:10]3[CH2:9][CH2:8][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:2])[CH3:3])[CH2:12][CH2:11]3)[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/2)=[O:50])=[CH:46][C:45]=1[C:53]([F:56])([F:55])[F:54]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)c(C(F)(F)F)c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 43.8 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 4-fluoro-3-(trifluoromethyl)benzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-(trifluoromethyl)benzamide (43.8% yield). MS m/z=619.4 [M+H], calc 618.67 for C31H38F4N6O3.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]CC3C=CC=CC=3)=[CH:10][CH:9]=2)[NH:6][CH:7]=1>[Pd].CCO>[OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[NH:6][CH:7]=1
Reactant: OCc1c[nH]c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd]
Solvent: CCO
Product: OCc1c[nH]c(-c2ccc(O)cc2)n1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A suspension of 4 (5 g, 0.018 mol), EtOH (250 ml) and 10% Pd/C (1.7 g) was hydrogenated on a Parr shaker at 50 psi. After shaking overnight, the suspension was filtered under N2 through a super cel pad. The solution was concentrated to dryness to yield 3.2 g (94%) of 5. An analytical sample was prepared by crystallization from CH3CN; m.p. 212°-214° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1([Cl:15])[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:5][C:6]1([Cl:15])[CH2:8][CH:7]1[C:9]1[CH:10]=[CH:11][C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=1
Reactant: ClC1(Cl)CC1c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C2CC2(Cl)Cl)cc1
Temperature: 4 °C

Procedure:
Nitric acid (25 g.) was added during three hours to a mixture of (2,2-dichlorocyclopropyl)benzene (45 g.), water (13 g.), acetic acid (40 g.) and concentrated sulfuric acid (177 g.) with cooling (to 3-5° C.). The resulting mixture was quenched in a mixture of ice (400 g.) and chloroform (200 g.). The layers were separated and the aqueous layer was washed with chloroform (100 g.). The chloroform layers were combined and washed with aqueous sodium carbonate (5%, 300 ml.). The sodium carbonate layer was backwashed with chloroform (75 g.). The combined chloroform extracts were dried, fitered and concentrated, affording p-(2,2-dichlorocyclopropyl)nitrobenzene mixed with the ortho isomer (57 g.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccn1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-acetamidophenol (120 g; 796 mmol), 2-picolyl chloride hydrochloride (130.6 g; 796 mmol), and powdered potassium carbonate (330 g; 2.39 mol) in 1500 mL DMF was stirred at ambient temperature for 7 days. The reaction was poured into brine and the precipitate was collected by vacuum filtration. The solids were washed with water followed by diethyl ether. The reaction yielded N-acetyl-4-(pyrid-2-ylmethoxy)aniline as a beige solid.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:51]([O:55][C:56](=[O:63])[C@H:57]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH2:58])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C.C(Cl)CCl>[C:51]([O:55][C:56](=[O:63])[C@@H:57]([NH:58][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:30])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:28])[CH2:59][CH:60]([CH3:61])[CH3:62])([CH3:54])([CH3:53])[CH3:52]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
To a solution of 250 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 4 ml DMF were added 124 mg HOAt, 174 mg EDC, 0.37 ml DIPEA and 136 mg leucine tert-butyl ester hydrochloride. After stirring for 12 h it was concentrated and the residue dissolved in dichloromethane. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[CH:6]1[C:11]2=[N:12][S:13][N:14]=[C:10]2[C:9]([NH:15][C:16]2[NH:20][CH2:19][CH2:18][N:17]=2)=[C:8]([Cl:21])[CH:7]=1>C(O)C>[CH:6]1[C:11]2=[N:12][S:13][N:14]=[C:10]2[C:9]([NH:15][C:16]2[NH:20][CH2:19][CH2:18][N:17]=2)=[C:8]([Cl:21])[CH:7]=1.[C:1]([O-:5])(=[O:4])[CH2:2][OH:3]
Reactant: O=C(O)CO
Agent: Clc1ccc2nsnc2c1NC1=NCCN1
Solvent: CCO
Product: O=C([O-])CO
Temperature: 2.5 °C

Procedure:
To a solution of 3.0 g of glycolic acid in 6 ml of ethanol, 3.0 g of the tizanidine base (99.15% HPLC) are added. After brief heating to boil a solution results, from which a crystalline precipitated product starts to separate. After cooling to 0 to 5° C. and aspiration 2.8 g of tizanidine glycolate are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH2:19][CH2:20][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:22][CH:23]=2)[CH:3]=1.[NH2:28][C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([C:18]3[CH2:19][CH2:20][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:22][CH:23]=3)[CH:3]=[C:2]([NH:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1cc(C2=CCN(S(C)(=O)=O)CC2)cc(Cl)n1)c1ccc(F)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(C2=CCN(S(C)(=O)=O)CC2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
115 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridine-2-amine, 40 mg of 2-aminopyrazine, 53 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 40 mg of sodium t-butoxide and 26 mg of tris(dibenzylideneacetone)dipalladium were added in turn to 5 ml of degassed toluene, and the mixture was stirred at 100° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 89 mg of the objective compound as pale brown powder.
Reaction SMILES: OCC[N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:14]([O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH:5]=[CH:6]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCn1ccc2cc(OCc3ccccc3)ccc21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Yield: 138.3 %

Procedure:
Crude N-(2-hydroxyethyl)-5-benzyloxyindole (11.09 g, 42.1 mmol), acetic anhydride (4.36 mL, 46.3 mmol), triethylamine (6.50 mL,46.3 mmol), and DMAP (100 mg) were stirred together in THF for 1 hour before standard aqueous workup provided N-2-acetoxyethyl)-5-benzyloxyindole as a clear oil (13.0 g, 99%). 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J=8.1 Hz, 2H), 7.42 (t, J=8.1 Hz, 2H), 7.35 (s, 1H), 7.27 (d, J=8.9 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 7.01 (dd, J=2.4, 8.1 Hz, 1H), 6.47 (dd, J=0.8, 3.1 Hz, 1H),5.14(s,2H), 4.37 (t, J=5.0 Hz 2H), 4.31(t, J=5.0 Hz, 2H), 2.02 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.[F:53][C:54]1[CH:63]=[CH:62][C:61]([CH2:64][NH:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:60][C:55]=1[C:56]([O:58][CH3:59])=[O:57].[OH-].[Na+]>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:65]([CH2:64][C:61]3[CH:62]=[CH:63][C:54]([F:53])=[C:55]([CH:60]=3)[C:56]([O:58][CH3:59])=[O:57])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[O:19])=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCNCc1ccc(F)c(C(=O)OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 4-(4-butylphenylethynyl)benzoic acid (312 mg; 1.12 mmol) in DCM (15 mL) were added HOBT (181 mg; 1.35 mmol), EDC-HCl (258 mg; 1.35 mmol) and DIEA (362 mg; 2.81 mmol). The mixture was stirred for 10 min at room temperature under N2 atmosphere before the addition of methyl 2-fluoro-5-[(hexylamino)methyl]benzoate (300 mg; 1.12 mmol). The reaction mixture was then stirred at 25° C. under N2 atmosphere overnight. It was diluted in DCM (100 mL) and poured into NaOH (1N, 75 mL). The organic layer was washed with brine (100 mL), dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure. Purification by flash chromatography using silicagel (c-Hex/EtOAc, gradient from 9:1 to 1:1) gave 350 mg (59%) of the title compound as a white powder. HPLC, Rt: 6.19 min (purity=99.7%). LC/MS, M+(ESI): 528.3. 1H NMR (CDCl3) δ: 7.91 (m, 1H), 7.55 (m, 3H), 7.41 (m, 4H), 7.15 (m, 3H), 4.72 (m, 1H), 4.50 (m, 1H), 3.93 (s, 3H), 3.42 (m, 1H), 3.15 (m, 1H), 2.61 (t, J=5.5 Hz, 2H), 1.59 (qt, J=7.7 Hz, 2H), 1.2 (m, 10H), 0.92 (t, J=7.3 Hz, 3H), 0.8 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([S:13]([CH3:15])=[O:14])=[N:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.CN1C2C(=CC=CC=2)C(=O)C(S(C)(=O)=O)=N1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([S:13]([CH3:15])(=[O:25])=[O:14])=[N:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: Cn1nc(S(C)=O)c(=O)c2ccc(Cl)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cn1nc(S(C)(=O)=O)c(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cn1nc(S(C)(=O)=O)c(=O)c2ccc(Cl)cc21

Procedure:
This was prepared by oxidizing a solution of 10 g of 7-chloro-1-methyl-3-(methylsulfinyl)-4(1H)-cinnolinone in 500 ml of CHCl3 with 7.5 g of m-chloroperbenzoic acid in analogous fashion to 1-methyl-3-(methylsulfonyl)-4(1H)-cinnolinone. The material was recrystallized from CH3CN, m.p. 270°-72°; yield 7.5 g (71%).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:14]([CH2:12][CH3:13])[C:15]2=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCN1C(=O)CN(c2ccccc2)C1=O
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of N-phenyl glycine (30.2 grams, 0.2 moles), ethylisocyanate (17.8 grams, 0.25 moles) and 30 ml of toluene was refluxed for 9 hours and allowed to stand overnight at room temperature (21° C.). The suspended product was collected by filtration and washed with toluene. After drying (21° C.) it was crystallized from ethanol to produce 17 grams (42% yield) of the above-identified product having a melting point of about 142° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:10]3[N:11]([C:13]([C:16]4[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]5[CH2:25][CH2:24]5)=[O:21])=[CH:18][CH:17]=4)=[CH:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1([C:7]2[N:8]=[C:9]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:10]3[N:11]([C:13]([C:16]4[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]5[CH2:24][CH2:25]5)=[O:21])=[CH:18][CH:17]=4)=[CH:14][N:15]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)CNc1nc(C2=CCCCC2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)CNc1nc(C2CCCCC2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a solution of 52 mg (0.12 mmol) 4-{6-(cyclohex-1-en-1-yl)-8-[(2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide (example 1-3) in 8 mL ethanol was added 5 mg 10% Pd/C and the mixture was stirred at rt and normal pressure overnight under hydrogen atmosphere. The mixture was filtered and purified by HPLC to yield 20.8 mg (40%) of the title compound. UPLC-MS: RT=1.39 min; m/z (ES+) 432.6 [MH+]; required MW=431.6. 1H-NMR (CDCl3): δ=0.65 (2H), 0.89 (2H), 1.02 (6H), 1.17-1.54 (5H), 1.67-2.07 (6H), 2.42 (1H), 2.94 (1H), 3.47 (2H), 6.06 (1H), 6.39 (1H), 7.34 (1H), 7.53 (1H), 7.59 (2H), 7.89 (2H) ppm.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1.[Cl-].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.O>[C:23]1([NH:22][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([O:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[CH:13][CH:14]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(Oc2ccc3ccccc3c2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc(Oc2ccc3ccccc3c2)cc1
Temperature: 35 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
Under an atmosphere of nitrogen, 53 mg (0.20 mmol) of 4-(2-naphtyloxy) benzoic acid was suspended in 5 ml of dried methylene chloride, to which were added 56 mg (0.44 mmol) of oxyalyl chloride and then 1 drop of DMF with a pipette. The mixture was stirred at 35° C. for 1.5 hours. The reaction mixture was concentrated with an evaporator, and the residue was dissolved in 5 ml of dried methylene chloride. Under an atmosphere of nitrogen, the solution, while being cooled with ice, was added dropwise to a solution of 19 mg (0.20 mmol) of aniline and of 22 mg (0.22 mmol) of triethyl amine in dried methylene chloride (5 ml), and the resulting mixture was stirred for 4 hours in an ice bath, and then stirred overnight at room temperature. Water was added to the reaction mixture, and extracted with methylene chloride twice. The organic phase was washed with brine dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give 27 mg (40% yield) of N-phenyl-(4-(2-naphthyloxy)benzamide). White solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1.C(N(CC)CC)C>C(O)CO>[N:32]1[CH:33]=[CH:34][N:35]=[CH:36][C:31]=1[N:23]1[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]2[CH:26]=[CH:27][C:14]([NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22]1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: Clc1cnccn1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(c2cnccn2)CC1
Yield: 38.5 %

Procedure:
A mixture of 2.00 g (0.005 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine [U.S. Pat. No. 4,025,629] 0.57 g (0.005 mol) of 2-chloropyrazine, and 0.505 g (0.005 mol) of triethylamine is heated in 20 ml of ethylene glycol at 75° C. for 24 hours and at 95° C. for 24 hours. The mixture is partitioned with 1 N toluenesulfonic acid in water and methylene chloride. The aqueous phase is made basic and extracted with methylene chloride. The organic phase is dried with anhydrous sodium sulfate and concentrated. The residue is chromatographed (4% methanol/1/2% ammonium hydroxide/methylene chloride) to yield 0.92 g (38%) of 1-(2-pyrazinyl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine. This is re-crystallized from methylene chloride to give 0.48 g of the pure product of melting point 260°-261° C. The IR spectrum is consistent with the named structure.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:20]=[CH:19][O:18][CH:17]=2)=[CH:11][C:10]=1[CH3:21].C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O>[Br:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH2:17][O:18][CH2:19][CH:20]=2)=[CH:11][C:10]=1[CH3:21]
Reactant: Cc1cc(-c2ccoc2)cc(C)c1Br
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2=CCOC2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylsilane (3.67 mL) is added dropwise to a solution of 3-(4-bromo-3,5-dimethylphenyl)furan (580 mg) in trifluoroacetic acid and the resulting mixture is stirred at room temperature for 3 h. Saturated aqueous NaHCO3 solution is added and the aqueous phase is separated and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 95:5) to give the title compound. LC (method 9): tR=1.16 min; Mass spectrum (ESI+): m/z=251, 253 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[C:40](=[O:41])[N:11]2[C:12]([C:24]([O:26]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:25])=[C:13]([CH:16]=[CH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:14][S:15][C@H:10]12.C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>ClCCl>[NH2:8][CH:9]1[C:40](=[O:41])[N:11]2[C:12]([C:24]([OH:26])=[O:25])=[C:13]([CH:16]=[CH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:14][S:15][C@H:10]12
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnc3)CS[C@H]12
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC1C(=O)N2C(C(=O)O)=C(C=Cc3cccnc3)CS[C@H]12
Reaction time: 1.5 h
Yield: 36.8 %

Procedure:
Trifluoroacetic acid (15.2 ml) was added to a suspension of benzhydryl 7-amino-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (cis-trans mixture) (8.0 g) and anisole (7.4 ml) in dichloromethane (40 ml) at ambient temperature and the mixture was stirred for 1.5 hours at the same temperature. To the resulting solution was added diisopropyl ether (200 ml) and stirred. The precipitate was collected by filtration and washed with diisopropyl ether. The precipitate was added to a mixture of water and ethyl acetate and the mixture was adjusted to pH 7 with 20% potassium carbonate. The separated aqueous layer was adjusted to pH 4.5 with 10% hydrochloric acid under ice-cooling. The precipitate, whose main component was the desired trans isomer, was filtered off and added to water. The mixture was adjusted to pH 7.0 with saturated aqueous sodium bicarbonate. After removal of an insoluble substance, the aqueous filtrate was adjusted to pH 4.5 with 10% hydrochloric acid under ice-cooling. The resulting precipitate was filtered, washed with ice-cooled water and dried over phosphorus pentoxide in vacuo to give 7-amino-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (trans isomer) (1.9 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[S:14][C:13]([S:15]([N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)(=[O:17])=[O:16])=[CH:12][CH:11]=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:10]2[S:14][C:13]([S:15]([N:18]3[CH:22]=[CH:21][CH:20]=[CH:19]3)(=[O:16])=[O:17])=[CH:12][CH:11]=2)=[CH:2]1
Reactant: OB(O)c1ccsc1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: O=S(=O)(c1ccc(-c2ccsc2)s1)n1cccc1

Procedure:
N-[5-(3-thienyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 3-thienylboronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole in quantitative yield. This was purified by recrystallization using hexane/ethyl acetate as solvent.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])[CH3:6].CCN(CC)CC.C(Cl)Cl>O>[CH2:5]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][C:1](=[O:3])[CH3:2])[CH3:6]
Reactant: CCc1ccccc1N
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1NC(C)=O
Yield: 100 %

Procedure:
Acetyl chloride was slowly added to a chilled mixture of 2-ethylaniline (12.1 g, 100 mmol), Et3N (20 mL, 145 mmol) and DCM (200 mL). Water (200 mL) was added and the layers separated. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to give the title compound as a yellow solid (16 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.75 (1H, d, J=8.0 Hz), 7.20-7.24 (2H, m), 7.47 (1H, d, J=7.2 Hz), 6.95 (1H, s), 2.61 (2H, q, J=7.2 Hz), 2.21 (3H, s), 1.24 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([OH:15])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:28]([NH2:31])[CH:29]=[CH2:30]>CN(C)C=O>[CH2:28]([NH:31][C:13]([C:3]1[N:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[CH:8][C:7]=2[Br:12])=[O:15])[CH:29]=[CH2:30]
Reactant: C=CCN
Reactant: Nc1c(C(=O)O)nnc2c(Br)cccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCNC(=O)c1nnc2c(Br)cccc2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To an ice-cooled suspension of 4-amino-8-bromo-cinnoline-3-carboxylic acid (360 mg, 1.34 mmol) in dimethylformamide (5 mL) was added CDI (370 mg, 2.3 mmol) and the mixture was stirred at room temperature for 1 hour. Additional DMF (14 mL) was added to enable stirring. After an additional 1 hour at room temperature, the mixture was treated with allyl amine (120 uL, 91 mg, 1.60 mmol) in one portion. The reaction was stirred at room temperature for 1 hour and then concentrated. Purification on silica gel using a gradient of 20 to 80% ethyl acetate in hexanes afforded the title compound (300 mg, 73%). 1H NMR (300.132 MHz, CDCl3) δ 8.14 (dd, J=7.4, 1.0 Hz, 1H), 7.83 (dd, J=8.4, 1.0 Hz, 1H), 7.51 (dd, J=8.4, 7.5 Hz, 1H), 6.04-5.91 (m, 1H), 5.33 (dq, J=17.1, 1.6 Hz, 1H), 5.21 (dq, J=10.4, 1.4 Hz, 1H), 4.15 (ddt, J=6.2, 5.8, 1.6 Hz, 2H). MS APCI, m/z=307/309 (M+H). HPLC 1.59 min.