Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=1>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:38][C:35]2[CH:36]=[CH:37][C:32]([Br:31])=[CH:33][C:34]=2[C:39]([F:42])([F:40])[F:41])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:26][CH2:27]1)=[O:12])([CH3:8])([CH3:7])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Reactant: FC(F)(F)c1cc(Br)ccc1S
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2ccc(Br)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 4-bromo-2-trifluoromethyl-benzenethiol yielded (2S,4R)-4-(4-bromo-2-trifluoromethyl-phenylsulfanyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless foam. MS: 436.2 and 434.2 [M+H-Boc]+.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[CH:5]=1>CO.O>[F:12][C:6]1[CH:5]=[C:4]([CH2:3][CH:2]=[O:1])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(CC(O)CO)cc1F
Solvent: O
Solvent: CO
Product: N#Cc1ccc(CC=O)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,3-dihydroxypropyl)-2-fluorobenzonitrile (500 mg, 2.6 mmol) in 10 mL of methanol and 3 mL of water was cooled to 0° C. by ice bath, then NaIO4 (820 mg, 3.8 mmol) was added and the mixture was stirred at 0° C. for two hours. The reaction was monitored according to TLC. The mixture was filtered and concentrated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and then purified by flash column chromatography to give 2-fluoro-4-(2-oxoethyl)benzonitrile. MS m/z: 164 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:9]1[CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Yield: 96.1 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.260 g, 0.98 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.360 g, 1.42 mmol), KI (37 mg, 0.22 mmol), and DIPEA (0.35 mL, 2.01 mmol) in DMF (5 mL) was heated at 60° C. for 17 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 415 mg (96%) of 5-cyano-2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester as a tan solid. To a cold (0° C.) solution of 5-cyano-2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (0.409 g, 0.937 mmol) in THF (4.5 mL) and MeOH (9 mL) was added LiBH4 (229 mg, 10.52 mmol) and the mixture was allowed to warm to room temperature overnight. The mixture was diluted with 1.0 N NaOH (10 mL) and extracted with CH2Cl2 (5×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.332 g (87%) of COMPOUND 29 as a white foam. 1H NMR (CDCl3) δ 1.61-1.77 (m, 3H), 2.05-2.14 (m, 1H), 2.30-2.44 (m, 2H), 2.51 (s, 6H), 3.71 (s, 2H), 4.11 (d, 2H, J=10.8 Hz), 4.46 (s, 2H), 4.94 (br s, 1H), 6.87-6.96 (m, 4H), 7.22-7.27 (m, 3H), 8.21 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 19.35, 25.70, 28.19, 51.31, 62.24, 67.36, 109.58, 119.48, 122.56, 129.25, 130.02, 132.00, 132.24, 138.53, 139.79, 145.29, 146.76, 159.25; ES-MS m/z 413 (M+H). Anal. Calcd. For C26H28N4O.1.0H2O2: C, 72.53; H, 7.02; N, 13.01. Found: C, 72.46; H, 6.73; N, 12.91.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][CH2:40][CH3:41])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH2:39][CH2:40][CH3:41])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: CCCOC(=O)Cl
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
120 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 120 mg of potassium carbonate were dissolved in 1.5 ml of water and 7.5 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.034 ml of propyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:5]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[CH:14]=1.[CH2:19]=O>C(O)C.[Pt]=O>[ClH:1].[CH3:19][N:11]1[CH2:10][CH2:9][C:8]2[CH:14]=[C:4]([O:3][CH3:2])[C:5]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:6][C:7]=2[CH2:13][CH2:12]1
Reactant: COc1cc2c(cc1S(C)(=O)=O)CCNCC2
Reactant: C=O
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1S(C)(=O)=O)CCN(C)CC2

Procedure:
A mixture of 8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (1 g, 3.5 mmol), 37% aqueous formaldehyde (1.1 g) and platinum oxide (0.1 g) in ethanol (25 ml) was shaken under an atmosphere of hydrogen (60 psi). The mixture was degassed, filtered and concentrated at reduced pressure to give 3-methyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=[O:32])[NH:24][C:23]3[CH:33]=[CH:34][CH:35]=[N:36][C:22]2=3)=[O:20])[CH2:14][CH2:13]1.[C:37]1([N:46]=[C:47]=[S:48])[CH:42]=[CH:41][CH:40]=[C:39]([N:43]=[C:44]=[S:45])[CH:38]=1.C(OCC)(=O)C>CN(C=O)C>[N:43]([C:39]1[CH:38]=[C:37]([NH:46][C:47]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25](=[O:32])[NH:24][C:23]4[CH:33]=[CH:34][CH:35]=[N:36][C:22]3=4)=[O:20])[CH2:14][CH2:13]2)=[S:48])[CH:42]=[CH:41][CH:40]=1)=[C:44]=[S:45]
Reactant: S=C=Nc1cccc(N=C=S)c1
Reactant: NCCCCCCCCCCN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCCCCCCCCCNC(=S)Nc3cccc(N=C=S)c3)CC2)c2ccccc21
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
5,11-Dihydro-11-[(4-[10-aminodecyl]-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one (2.8 mg, 5.7 μmol) was dissolved in 0.2 mL DMF and treated with 1,3-phenylenediisothiocyanate (6 mg, 31 μmol). After 0.5 h, ethyl acetate (1 mL) and petroleum ether (3 mL) were added, and the cloudy mixture was stored at 4° C. overnight. The supernatant was decanted from the oily residue. The residue solidified upon trituration with dry ether to give 2.0 mg (51% yield) of pure product (Rf =0.35, silica, chloroform:methanol:acetic acid, 85:10:5, by volume). FAB-MS spectrum showed a parent ion peak at 685 m/z (m+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.Cl.CN.[CH:15]([N:18](CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:18][CH3:15]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CC#N
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a suspension of 4-bromo-2-fluoro-1-nitrobenzene (3.0 g) in acetonitrile (100 mL) was added 3.7 g of methylamine hydrochloride followed by 12 mL of N,N-diisopropylethylamine. The mixture was stirred at 60° C. for 16 hours. After cooling down to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate (100 mL) and washed 3 times with water, then brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, providing 5-bromo-N-methyl-2-nitroaniline as an orange solid. The product was used in the next step without further purification.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:5]1=[O:22])(=O)C.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH3:25][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31]/[C:13](=[C:6]2\[C:5](=[O:22])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(C)cc2)c2ccccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(p-tolyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1)#[N:20]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:30][CH:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: N#Cc1ccc(C(=O)NN)cc1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 78.4 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (10.03 g, 37.3 mmol) and 4-cyano-benzohydrazide (6.02 g, 37.3 mmol) were coupled in an analogous procedure as described for the preparation of intermediate 3b. The crude product was purified by boiling in chloroform (100 mL) followed by cooling to 0° C. and filtration to yield product as a light yellow solid (12.05 g, 78%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.81 (br s, 2H), 8.08 (AA′XX′, J=8.6 Hz, 2H), 7.91 (AA′XX′, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.57 (d, J=7.0 Hz, 1H), 4.40 (m, 1H), 2.34 (dd, J=3.6, 6.9 Hz, 1H), 2.34 (s, 3H), 1.35 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]=O>>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][N:10]([CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]1)[CH3:28])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N1CCC(CNC[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Reactant: C=O
Product: CC(C)N1CCC(CN(C)C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Yield: 95.7 %

Procedure:
Using alkylation method B, N-[(R)-2-[(1-isopropyl-piperidin-4-ylmethyl)amino]-1-phenylethyl]carbamic acid tert-butyl ester (511 mg, 1.4 mmol) and paraformaldehyde (816 mg, 27 mmol) afforded 522 mg (98%) of the title compound as a crude residue that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([C@@H:9]2[O:31][C@H:30]([CH2:32][O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:20]([O:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:10]2[O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5](=[O:42])[NH:4][C:3]=1[NH2:43].[CH3:44]C1C=CC(S(O)(=O)=O)=CC=1>C(OC(OCC)OCC)C>[C:12]([O:11][C@@H:10]1[C@H:20]([O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:30]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:31][C@H:9]1[N:6]1[C:7](=[O:8])[C:2]2[NH:1][CH:44]=[N:43][C:3]=2[NH:4][C:5]1=[O:42])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1[nH]c(=O)n([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)c1N
Solvent: CCOC(OCC)OCC
Product: O=C(OC[C@H]1O[C@@H](n2c(=O)[nH]c3nc[nH]c3c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A mixture of 50 (4.30 g, 7.33 mmol), TsOH (catalytic amount), and triethylorthoformate (90 mL) was stirred at room temperature for 24 hr, concentrated, and the residue purified on a silica gel column (CHCl3:MeOH=30:1 v/v) to give compound 51 (2.20 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](O)[CH:28]=[CH:29][CH:30]=1.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)=[CH:6][CH:7]=1
Reactant: COc1cccc(O)c1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(OCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)c1
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (500 mg), 3-methoxyphenol (390 mg), tributylphosphine (640 mg) and tetrahydrofuran (20 ml) was added dropwise a toluene solution of diethyl azodicarboxylate (40%, 1.37 g) at room temperature, and the resulting mixture was stirred for 3 hours. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(3-methoxylphenoxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole (470 mg, 70%) was obtained as an oil from an ethyl acetate-hexane (2:3, v/v)-eluted fraction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([N:12]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)[CH3:13])=[O:11])[C:5]([CH3:24])=[CH:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[CH:21]1([CH2:20][N:17]2[CH2:18][CH2:19][CH:14]([N:12]([CH3:13])[C:10](=[O:11])[CH2:9][NH:8][C:6]3[C:5]([CH3:24])=[CH:4][N:3]=[C:2]([NH:32][CH2:31][C:30]4[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[N:7]=3)[CH2:15][CH2:16]2)[CH2:23][CH2:22]1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cnc(Cl)nc1NCC(=O)N(C)C1CCN(CC2CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2ncc(C)c(NCC(=O)N(C)C3CCN(CC4CC4)CC3)n2)cc1
Yield: 36 %

Procedure:
A solution of Compound 106 (93 mg), 4-methoxybenzylamine (345 μL) and diisopropylethylamine (45.5 μL) in n-butanol (1.5 mL) was stirred overnight under reflux. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1 to 4:1) to give 43 mg (36% yield) of the desired product as a white amorphous.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[C:12](O)=[C:11]([C:20](=O)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]2=[O:29])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[NH2:31][NH2:32].O>CN(C=O)C>[CH2:21]([C:20]1[C:11]2[C:10](=[O:29])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]=2[NH:32][N:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1cccc(-n2c(=O)c(C(=O)Cc3ccccc3)c(O)c3cccnc32)c1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(-n2c(=O)c3c(Cc4ccccc4)n[nH]c3c3cccnc32)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a suspension of 1-(3-cyanophenyl)-4-hydroxy-3-(1-oxo-2-phenylethyl)-1,8-naphthyridin-2 (1H)-one (314 mg, 0.82 mmol, prepared in Synthetic Example 29) in DMF (4 ml) was added hydrazine monohydrate (80%, 132 μl, 4.12 mmol, 4.0 eq.), and the mixture was stirred at 100 to 110° C. for 2 hours. The reaction mixture was admixed with water, and filtered to give precipitates which were washed with water and dried to afford 3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (287 mg, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[S:20][C:21](Br)=[CH:22][CH:23]=2)[N:9]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2].[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[S:20][C:21]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=3)=[CH:22][CH:23]=2)[N:9]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(Br)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 2-(5-bromothiophen-2-yl)-1-(2,6-dichlorophenyl)-1H-imidazole-4-carboxylic acid ethyl ester (335 mg, 0.75 mmol), 3-methanesulfonyl-phenylboronic acid (180 mg, 0.90 mmol), K2CO3 (0.32 g, 2.3 mmol), Cl2Pd(dppf)DCM (30 mg, 5 mol %) and H2O (0.4 mL) in DME (4 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 2 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 30:70 to 80:20) to give the title compound (313 mg, 80%) as a pale yellow solid, which was used in the next step without further purification. 1H-NMR (DCM-d2): δ 8.08 (m, 1H), 7.82 (m, 2H), 7.64 (s, 1H), 7.51-7.62 (m, 4H), 7.24 (d, 1H), 6.72 (d, 1H), 438 (q, 2H), 3.05 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:11](=[O:14])[CH:12]=[CH2:13])[CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: C=CC(=O)Cl
Reactant: COc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(OC)c(OC)c1
Yield: 29.3 %

Procedure:
1,2-dimethoxybenzene (135 mg), acryloyl chloride (118 mg), and aluminium chloride (199 mg) were reacted in dichloromethane (1.5 mL) at from −40° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (55 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
To 4-bromo-1-ethyl-2-nitrobenzene (20.0 g, 87 mmol) in 1,2-dimethoxyethane (150 ml) is added, at room temperature, 4-chlorophenylboronic acid (14.98 g, 96 mmol) and tetrakis-(triphenylphosphine)palladium(0) (2.0 g, 1.74 mmol) and nitrogen gas is bubbled through the mixture. After stirring for 10 minutes at 20° C., a solution of sodium carbonate (73.8 g, 0.696 mol) in water (350 ml) is added and mixture is refluxed for 16 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth, washing with ethyl acetate (200 ml). The mixture is poured into a separating funnel and the two phases are separated. The aqueous phase is extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 4′-chloro-4-ethyl-3-nitrobiphenyl (23.84 g) as a brown oil used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH2:18]([SH:21])[CH2:19][SH:20].B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:21][CH2:18][CH2:19][S:20]2)=[C:4]([CH3:16])[C:3]=1[CH3:17]
Reactant: Cc1c(Cl)nnc(C(=O)c2ccccc2)c1C
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(Cl)nnc(C2(c3ccccc3)SCCS2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a DCM solution of (6-chloro-4,5-dimethyl-pyridazin-3-yl)-phenyl-methanone (300 mg, 1.22 mmol) is added 1,2-ethandithiol (0.408 ml, 4.86 mmol) and BF3.OEt2 (0.154 ml, 1.216 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture is stirred at room temperature for 16 h. The reaction was charged with BF3.OEt2 (0.154 ml, 1.216 mmol) and 1,2-ethandithiol (0.408 ml, 4.86 mmol), and heated at 40° C. for 6 h. The reaction is quenched with sat. NaHCO3 at 0° C. and organic phase is washed with brine. The organic layer is dried over Na2SO4, filtered and concentrated to afford a yellow solid. The residue is loaded on silica gel and purified by flash chromatography, eluting with 20-80% EtOAc: heptane. Fractions containing the desired product are combined and concentrated to afford a white solid (280 mg, 73%).
Reaction SMILES: [F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[BH4-].[Na+]>C1COCC1.C(O)(C)C>[F:1][C:2]1[N:3]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
2-Fluoro-4-formyl-1-triphenylmethylimidazole was dissolved in a 2:1 (v/v) mixture of THF and isopropanol and treated with sodium borohydride at 20°. After 5 minutes the reaction was quenched with water. Extractive work-up and final trituration with MeOH gave 2-fluoro-4-hydroxymethyl-1-triphenylmethylimidazole. This was reacted with methanesulphonyl chloride and triethylamine in CH2Cl2 at ambient temperature to give 4-chloromethyl-2-fluoro-1-triphenylmethylimidazole. This was treated at ambient temperature in a water/THF solution with sodium azide, and crude product deprotected with toluene-p-sulphonic acid in CH2Cl2, to give 4-azidomethyl-2-fluoroimidazole as its toluene-p-sulphonate salt. This was reacted at 60° for 4 hours in DMF with t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate. The product was purified by silica gel chromatography at -20°, using as eluant CH2Cl2 /MeOH/HOAc 96:2:2 v/v/v, to give t-butyl 3-acetoxymethyl-7-(4-azidomethylimidazol-2-yl)aminoceph-3-em-4-carboxylate, having the following i.r. spectrum: νmax (film) 1680; 1725; 1745; 1790; 2110 cm-1.