Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Br:11])[CH2:7][C@:6]1([C:15](=[O:16])[NH:14][C:13](=[O:17])[N:12]1[CH3:18])[CH2:5]2.[O:19]=[C:20]1[N:24]([CH2:25][C:26](O)=[O:27])[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[N:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][C@@:6]3([C:15](=[O:16])[NH:14][C:13](=[O:17])[N:12]3[CH3:18])[CH2:7]2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[CH2:25][N:24]1[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[N:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:20]1=[O:19]
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1cc(N)c(Br)cc1C2
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)[C@]12Cc1cc(Br)c(NC(=O)Cn3c(=O)n(-c4ccccn4)c4ccccc43)cc1C2
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of (S)-5′-amino-6′-bromo-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (50 mg, 0.161 mmol, described in Intermediate 18) and (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (52 mg, 0.193 mmol, described in Intermediate 16) in DMF (1 mL) were added N,N-diisopropylethylamine (0.028 mL, 0.161 mmol), followed by PyBOP (126 mg, 0.242 mmol). The reaction mixture was heated to 40° C. for 5 h, then PyBOP (126 mg, 0.242 mmol) was added and heating was continued for 18 h. The cooled mixture was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=563 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH:17]([F:19])[F:18])[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:27]N1C(=O)CCC1=O>C(#N)C>[Br:27][C:11]1[C:12](=[O:15])[O:13][CH2:14][C:10]=1[N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:16][CH:17]([F:19])[F:18]
Reactant: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1OCC(N(Cc2ccc(Cl)nc2)CC(F)F)=C1Br
Reaction time: 3 h
Yield: 78.6 %

Procedure:
313 mg (1.08 mmol) of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one (1) are dissolved in 20 ml of acetonitrile, and 166 μl (1.19 mmol) of triethylamine and 386 mg (2.17 mmol) of N-bromosuccinimide are added at room temperature. After 3 hours of stirring, the mixture is concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 312 mg (63% of theory) of 3-bromo-4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one.
Reaction SMILES: [CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=[O:28])[CH:23]([O:26][CH3:27])[O:24][CH3:25])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:37]([N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH2:40])[CH3:38]>C(O)(=O)C>[CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/[NH:40][N:39]([CH2:37][CH3:38])[C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])=[CH:21]/[C:22](=[O:28])[CH:23]([O:26][CH3:27])[O:24][CH3:25])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCN(N)C(=O)OC(C)(C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(=O)C(OC)OC)SC)nc21
Solvent: CC(=O)O
Product: CCN(N/C(=C\C(=O)C(OC)OC)Nc1nc2c(cc(C(=O)N(C3CC3)C3CC3)n2CC)c2c1ncn2C)C(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of (Z)-N,N-dicyclopropyl-4-(4,4-dimethoxy-1-(methylthio)-3-oxobut-1-enylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 101A, 160 mg, 0.312 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (125 mg, 0.780 mmol) in acetic acid (2 mL) wan stirred at 35° C. overnight. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 2-8% methanol/dichloromethane). (Z)-tert-Butyl 2-(1-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4,4-dimethoxy-3-oxobut-1-enyl)-1-ethylhydrazinecarboxylate (195 mg, 0.312 mmol, 100% yield) was obtained as a yellow solid.
Reaction SMILES: N1C=CC=C1/C=C1\C(=O)N(C#C)C2C\1=C[C:13]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12]C=2.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:34]\[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41].C[Si](C#C)(C)C.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:41][O:40][C:39]1[CH:38]=[CH:37][NH:36][C:35]=1/[CH:34]=[C:27]1\[C:28](=[O:33])[NH:29][C:30]2[C:26]\1=[CH:25][C:24]([C:12]#[C:13][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:32][CH:31]=2
Reactant: C#CN1C(=O)/C(=C\c2ccc[nH]2)c2cc([Si](C)(C)C)ccc21
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(C#C[Si](C)(C)C)cc21

Procedure:
This compound was prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-5-(trimethylsilyl)-ethynyl-2H-indol-2-one in Example 81 above. In this example, (Z)-5-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (740 mg, 2.32 mmol) (from Example 91) was coupled with (trimethylsilyl)acetylene (640 mg, 6.52 mmol) (Aldrich) using CuI (40 mg, 0.21 mmol) (Aldrich) and (Ph3P)2PdCl2 (90 mg, 0.13 mmol) (Aldrich) as catalyst in 10 mL DMF and 10 mL triethylamine at 70° C. for 22 hours to give (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-(trimethylsilyl)ethynyl-2H-indol-2-one. (Yield 410 mg, 52%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][NH:4][CH2:3]1.[CH:6]1([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[C:24](F)[CH:23]=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])[CH:17]=2)=[O:11])[CH2:8][CH2:7]1>>[CH:6]1([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[C:24]([N:4]4[CH2:5][CH:2]([OH:1])[CH2:3]4)[CH:23]=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])[CH:17]=2)=[O:11])[CH2:8][CH2:7]1
Reactant: OC1CNC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CC(O)C2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 3-hydroxyazetidine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(3-hydroxyazetidin-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.67 (m, 2H), 2.28 (s, 3H), 2.84 (m, 1H), 3.79 (m, 2H), 4.29 (t, 2H), 4.63 (m, 1H), 5.82 (d, 1H), 6.48 (m, 2H), 7.28 (d, 1H), 7.56 (d, 1H), 7.95 (s, 1H), 8.04 (d, 1H), 8.37 (s, 1H), 9.87 (s, 1H); Mass Spectrum: M+Na+ 433.
Reaction SMILES: [C:1]1([C@@H:7](N2CCCCC2)[C:8](O)=[O:9])C=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1[C@@H]1CCCN1C(OC(C)(C)C)=O>>[CH2:8]([OH:9])[CH3:7].[CH3:8][CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)[C@@H](c1ccccc1)N1CCCCC1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc[nH]1
Product: CCCCCCC
Product: CCO

Procedure:
Relative retention time: 3.25 min (R), 5.78 minutes (S)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:5][NH:4][C:3]1=[S:17].[C:18]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][N:2]1[C:3]([S:17][CH3:18])=[N:4][N:5]=[C:6]1[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1
Reactant: Cn1c(-c2ccc3ccccc3c2)n[nH]c1=S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nnc(-c2ccc3ccccc3c2)n1C

Procedure:
A mixture of 2,4-dihydro-4-methyl-5-(2-naphthyl)-3H-1,2,4-triazole-3-thione (5.26 g, 2.18×10-2 mole), K2CO3 (3.01 g, 2.18×10-2 mole), methyl iodide (1.5 ml, 2.4×10-2 mole), and acetone (65 ml) was stirred and warmed to reflux. After refluxing overnight, the solvent was evaporated at reduced pressure and the concentrate was treated with water. The aqueous mixture was extracted with EtOAc three times. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure to yield the desired product. Crystallization from Et0Ac afforded colorless plates, Mp 177°-179° C.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]2[S:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][NH:22][C:21]4=[O:25])[N:12]=3)=[CH:10][C:6]=2[CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:27]=[CH:26][C:7]2[S:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][NH:22][C:21]4=[O:25])[N:12]=3)=[CH:10][C:6]=2[CH:5]=1
Reactant: O=C1NCCN1CCNc1nccc(-c2cc3cc([N+](=O)[O-])ccc3s2)n1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2sc(-c3ccnc(NCCN4CCNC4=O)n3)cc2c1
Reaction time: 5 h

Procedure:
A mixture of 1-(2-(4-(5-nitrobenzo[b]thiophen-2-yl)pyrimidin-2-ylamino)ethyl)imidazolidin-2-one (50 mg) and palladium (10% on activated carbon, 10 mg) in ethanol (10 mL) was stirred under hydrogen (1 atm) for 5 h. The mixture was filtered through Celite and washed with methanol/dichloromethane. The solvent was removed in vacuo and the product was purified by flash chromatography eluting with NH3 in methanol (1 M)/DCM (1:20) to give the title compound as a slightly yellow solid (32 mg, 69%). MS (M+H)+ 355.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C1(C)C=CC=CC=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl>[N:25]([C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([C:21]([F:20])([F:29])[F:30])[CH:23]=1)=[C:5]=[O:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triphosgene (0.75 g) was added to anhydroue toluene (10 ml) under nitrogen protection, and then a solution of 3-trifluoromethylaniline (0.8 g) in dichloromethane (15 ml) was added dropwise in an ice-bath. After addition, the reaction mixture was stirred at room temperature for 15 min, and then heated to 80° C. for 6 h. The completion of the reaction was indicated by TLC. The reaction mixture was concentrated under reduced pressure to give the product as oil, which then was solidified.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][CH2:12][C:13]1[N:18]=[C:17]2[S:19][C:20]3[CH2:21][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24][C:25]=3[C:16]2=[C:15]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[C:14]=1[Cl:43].O>N1C=CC=CC=1>[CH2:26]([N:22]1[CH2:23][CH2:24][C:25]2[C:16]3[C:17]([S:19][C:20]=2[CH2:21]1)=[N:18][C:13]([CH2:12][NH:11][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)=[C:14]([Cl:43])[C:15]=3[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2c(Cl)c(CNC(=O)c3cccnc3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Nicotinoyl chloride hydrochloride (0.18 g) was added to a solution of the compound (0.29 g) obtained in Example 18B in pyridine (4 ml), the mixture was stirred at room temperature for 1 hour, poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-2-(nicotinoylaminomethyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine (0.2 g, 51%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 124 to 125° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1.[OH-:15].[Na+].Cl>O>[Br:7][C:8]1[N:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:14]([OH:2])=[O:15]
Reactant: Cc1cccnc1Br
Reactant: [OH-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccnc1Br
Temperature: 25 °C

Procedure:
Potassium permanganate (18.4 g, 116 mmol) was dissolved in water (400 mL) and added to 2-bromo-3-methylpyridine (10.0 g, 58 mmol) and refluxed for 16 hours. After cooling to room temperature, the slurry was filtered through a celite plug and rinsed with water and chloroform. The entire filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted again with CHCl3 and acidified with 6N HCl to pH 1. A white solid was obtained on standing (2.08 g of product). The pH of the remaining aqueous was adjusted to pH 4 with 2M NaOH and 2M HCl, then concentrated to <100 mL. A white precipitate was filtered. The pH was adjusted to 4 and the mixture filtered again, combining the isolated solids for a total of 3.88 g of product. The filtrate was concentrated again to <100 mL and adjusted to pH 1.5 and an additional quanitity of white solid was obtained (1.80 g), for a combined yield of 3 crops, (8.76 g, 66%). 1H NMR (DMSO-d6): δ13.76 (bs, 1H), 8.46 (m, 1H), 8.09 (dd, 1H, J=7.7, J′=2.2), 7.51 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7](O)[CH:6]=2.[C:14](=[O:17])([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:20]([O:13][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][C:7]([O:17][CH2:14][C:2]1[CH:3]=[CH:4][CH:5]=[CH:10][CH:11]=1)=[CH:8][CH:9]=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc2cc(Br)c(O)cc2c1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2ccc(OCc3ccccc3)cc2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
3-Bromonaphthalene-2,7-diol (1.40 g, 5.88 mmol) is dissolved in 20 mL of DMF. Potassium carbonate (2.44 g, 17.6 mmol) is added and the mixture is heated to 60° C. Benzyl bromide (2.10 mL, 17.64 mmol) is added and heating is continued for 5 h, after which time the reaction is poured into water and extracted with MTBE. The combined organics are dried and evaporated to afford 3,6-bis-benzyloxy-2-bromonaphthalene as a brown solid, which is of sufficient purity to take on to the next step.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40][C:41]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH2:15][Cl:16])[CH2:13][S:14][C@H:9]12)=[O:6].ClC1C=CC=C(C(OO)=[O:68])C=1>C1C=CC=CC=1>[CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40][C:41]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:12]([CH2:15][Cl:16])[CH2:13][S:14](=[O:68])[C@H:9]12)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: c1ccccc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g (2.97 mmol) of benzhydryl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate was dissolved in 25 ml of benzene, and 640 mg (3.27 mmol) of m-chloroperbenzoic acid was added under cooling with ice. The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and extracted with ethyl acetate. The extracted solution was washed with a 5% sodium bisulfite aqueous solution and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby the above identified compound was obtained as a powdery substance.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C@@H:9]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:23][O:24][CH:25](OC)[O:26][CH3:27]>CO>[CH2:1]([N:8]([CH3:17])[C@@H:9]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:25]([O:26][CH3:27])[O:24][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)[C@H](C=O)C1CCCC1
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(OC)[C@H](C1CCCC1)N(C)Cc1ccccc1
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of (S)-2-(benzyl(methyl)amino)-2-cyclopentylacetaldehyde (7.9 g, 34 mmol, 1.0 eq) in MeOH (200 mL) was added concentrated H2SO4 (12.5 g, 127 mmol, 3.7 eq) drop-wise at 0° C. The reaction mixture was stirred for 10 min, then trimethylorthoformate was added (33 g, 311 mmol, 9.0 eq.) at 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then heated to reflux for overnight. After cooled, the solvent was evaporated under reduced pressure, and the obtained residue was poured into sat NaHCO3 (300 mL, aq), extracted with ethyl acetate (300 mL). The organic layer was washed with brine, dried over sodium sulphate and evaporated to give a residue, which was purified by column chromatography on silica to yield the product 6 (8.6 g, 90% for two steps) as a light color oil.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH2:13]O)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[CH:9]=2)[N:4]=1)[CH3:2].O=S(Cl)[Cl:19]>C(Cl)Cl>[ClH:19].[Cl:19][CH2:13][C:12]1[C:3]([CH2:1][CH3:2])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:15][CH3:16])=[CH:7][CH:6]=2
Reactant: O=S(Cl)Cl
Reactant: CCc1nc2ccc(OC)cc2cc1CO
Solvent: ClCCl
Product: CCc1nc2ccc(OC)cc2cc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (2-ethyl-6-methoxyquinolin-3-yl)-methanol SMA 44008 (150 mg, 0.69 mmol) in dry CH2Cl2 (20 mL) at 0° C. under N2 in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (1.0 mL, 13.8 mmol) and the mixture was stirred for 2 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-chloromethyl-2-ethyl-6-methoxyquinoline hydrochloride SMA 44014 as a brown solid (197 mg, >100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[NH2:5].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[CH:48]=[C:47]([CH3:49])[O:46][N:45]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:32]([NH:43][C:44]2[CH:48]=[C:47]([CH3:49])[O:46][N:45]=2)=[O:34])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: Cc1cc(N)no1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4cc(C)on4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.2 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (42 mg) was dissolved in chloroform (2.0 ml) and triethylamine (0.13 ml) to prepare a solution. A solution of triphosgene (19 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 3-amino-5-methylisoxazole (14 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated and was evaporated to dryness. Diethyl ether was added to the resultant solid, and the solution was filtered. The filtrate was concentrated, and methyl alcohol was added to the residue. The resultant crystal was collected by filtration to give the title compound (8.8 mg, yield 15%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.[N:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)=[N+:11]=[N-:12].S(Cl)(Cl)=O.C(N(CC)CC)C>O1CCCC1>[N:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]2)=[O:18])=[CH:20][CH:21]=1)=[N+:11]=[N-:12]
Reactant: NC1CCC=CCCC1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=Nc1ccc(C(=O)NC2CCC=CCCC2)cc1
Yield: 73 %

Procedure:
This example describes the preparation of an azidoaryl-substituted cyclooctene by reaction of an acid chloride-substituted phenyl azide with 5-aminocyclooctene. The reactions are illustrated in Scheme 4. 4-Azidobenzoic acid was converted to the corresponding acid chloride (10) with thionyl chloride and triethylamine in dry tetrahydrofuran. An excess of 5-aminocyclooctene was then introduced to the solution of the acid chloride at 0° C. to form the azidoaryl-substituted cyclooctene, 4-azido-N-4-cycloocten-1-yl-benzamide (9), which was purified by recrystallization from diethyl ether/hexane in 73% yield. The product was characterized by proton and carbon-13 nuclear magnetic resonance spectroscopy (1H and 13C NMR), as well as Fourier Transform Infrared (FTIR) spectroscopy. Key features in the characterization of 4-azido-N-4-cycloocten-1-yl-benzamide included the presence of the amide carbonyl in the 13C NMR spectrum at 165.1 parts per million (ppm), and a characteristic azide signal in the IR spectrum at 2120 reciprocal centimeters (cm−1).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([Br:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N+:20]([O-])=O)[C:6]1=[O:23])[CH:2]=[CH2:3].N1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([Br:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:6]1=[O:23])[CH:2]=[CH2:3]
Reactant: C1CCNC1
Reactant: C=CCON1C(=O)c2ccc([N+](=O)[O-])c3cc(Br)cc(c23)C1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCON1C(=O)c2ccc(N3CCCC3)c3cc(Br)cc(c23)C1=O

Procedure:
Following the procedure of Example W1, a mixture of the 2-allyloxy-5-bromo-7-nitro-benzo[de] isoquinoline-1,3-dione from above, pyrrolidine (0.43 g, 6.0 mmol) and triethyl amine (1.2 g, 12 mmol) in DMF (10 mL) was reacted to give 0.91 g of the title compound.