Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]([F:18])[F:17])[NH:12][C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]([F:17])[F:18])[N:12]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:25]=3[CH3:34])[C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Br)c2nc(C(F)F)[nH]c2c1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cn2c(C(F)F)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a 100 mL round bottomed flask containing DMF (30 mL) was added 4-bromo-2-(difluoromethyl)-6-nitro-1H-benzo[d]imidazole (3.2 g, 10.96 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (1.60 mL, 9.48 mmol) and potassium carbonate (2.3 g, 16.64 mmol). The resultant suspension was heated to 65° C. and after stirring for 2 hrs the mixture was allowed to cool to rt and diluted with 35 mL H2O. The resulting slurry was extracted several times with EtOAc, the organic dried over Na2SO4 and concentrated to give a thick oil which was adsorbed onto a silical gel column and was eluted with EtOAc/Hex 10% to 20% gradient over 15 column volumes on a 25 g silica column. The fractions containing desired product were combined and concentrated desired product (1.54 g, 3.32 mmol, 30.3% yield) as a light orange powder. LC/MS: MS (ES+) m/e 464.2 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.52 (d, J=1.77 Hz, 1H), 8.07 (d, J=2.02 Hz, 1H), 7.66 (d, J=7.83 Hz, 1H), 7.20 (d, J=3.79 Hz, 1H), 7.07 (s, 1H), 6.94 (s, 1H), 6.52 (d, J=8.08 Hz, 1H), 5.73 (s, 2H), 2.58 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[H-].[Na+].Br[CH2:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[C:13]([CH3:18])=[CH:12][CH:11]=1.O>C1COCC1>[C:16]([C:14]1[N:15]=[C:10]([CH2:9][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[CH:11]=[CH:12][C:13]=1[CH3:18])#[N:17]
Reactant: CNC(C)=O
Reactant: Cc1ccc(CBr)nc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccc(C)c(C#N)n1
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A solution of N-methylacetamide (416 mg, 5.69 mmol) in THF (15 mL) at room temperature was treated with NaH (228 mg, 5.69 mmol), stirred for 15 min, treated with 6-bromomethyl-3-methylpyridine-2-carbonitrile (1.0 g, 4.74 mmol), stirred for 16 h, poured into water (50 mL), extracted with EtOAc (3×15 mL) and the combined organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (665 mg, 69%) as a yellow oil; NMR δH (400 MHz, CDCl3) 2.15 (3H, s), 2.53 (3H, s), 3.09 (3H, s), 4.65 (2H, s), 7.43 (1H, d, J 8.0 Hz) and 7.61 (1H, d, J 8.0 Hz); M/Z 204 (M+H)+
Reaction SMILES: [O:1]=[C:2]([CH3:12])[CH2:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13](=O)(O)[O-].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[O:1]=[C:2]([CH3:12])[CH2:3][CH:4]1[CH:6]([C:7]([O:9][CH3:13])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC(=O)CC1C(C(=O)O)C1(C)C
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)C1C(CC(C)=O)C1(C)C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
10 g of 3-(2-oxopropyl)-2,2-dimethyl-cyclopropane carboxylic acid in 100 ml of acetone were heated to 30° C. to 34° C. in the presence of 7.35 g of potassium bicarbonate and 5 ml of dimethyl sulfate. After 4 hours of stirring, 0.85 ml of dimethyl sulfate were added and the reaction medium was held at 30° to 34° C. for 20 hours. After filtration, the product was taken up in ethyl ether and the solvent was evaporated. The residue was chromatographed on silica (eluant: hexane - ethyl acetate 8-2) to obtain 10.43 g of the expected product.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[NH:8][C:9]([NH2:18])=[C:10]2[C:14]([N:15]=1)=[N:13][C:12]([O:16][CH3:17])=[N:11]2)[CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>CN(C=O)C>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][N:13]1[C:12]([O:16][CH3:17])=[N:11][C:10]2[C:14]1=[N:15][C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])=[N:8][C:9]=2[NH2:18]
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine (1 g, 2.74 mmol) and potassium carbonate (0.946 g, 6.84 mmol) in DMF (12.5 ml) were stirred under nitrogen and heated to 50° C. for 1 hour. The mixture was then allowed to cool to ambient temperature and 1-bromo-4-chlorobutane (0.315 ml, 2.74 mmol) was added and stirring was continued under nitrogen at ambient temperature overnight. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate and the combined organic extracts were washed with saturated brine and passed through a hydrophobic frit and evaporated in vacuo. The residue (1.0322 g) was dissolved in dichloromethane and loaded onto an amino cartridge (70 g) and eluted using a 0-100% ethyl acetate in cyclohexane gradient over 40 minutes. Product fractions were combined and evaporated to give the title compound as an off-white solid (667 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([NH:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32].CN(C=O)C>O>[OH:17][CH2:16][C@H:15]([NH:14][C:12]([C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:3]2=[N:10][C:9]=1[CH3:11])=[O:13])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(O)cccn12
Reactant: CC(C)CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCCC(C)C)cccn12
Reaction time: 0.5 h

Procedure:
100 mg (0.34 mmol) of 8-hydroxy-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]-pyridine-3-carboxamide, 246 mg (0.76 mmol) of caesium carbonate and 75 mg (0.38 mmol) of 1-iodo-3-methylbutane were added to 4.9 ml of dry DMF, and the mixture was stirred for 30 min in an oil bath preheated to 60° C. After cooling, about 40 ml of water were added to the reaction mixture and the solution formed was extracted three times with ethyl acetate. The combined organic phases were concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: water/methanol gradient with addition of 0.1% TFA). All product-containing fractions were combined and concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered, concentrated and dried under high vacuum. This gave 82 mg of the target compound (66% of theory, purity 100%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][C:13](=[O:14])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[BH4-].[Na+].[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CO.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([O:14][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: O=C1CCn2c1cc1cc(Br)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCn2c1cc1cc(Br)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a suspension of 7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (1.1 g, 4.4 mmol) in MeOH (20 mL), cooled to 0° C., was added NaBH4 (0.33 g, 8.8 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with H2O and then extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated to afford a white solid which was used without further purification. The crude solid was dissolved in CH2Cl2 (20 mL) and TBSCl (0.7 g, 4.4 mmol) and imidazole (0.33 g, 4.4 mmol) were added. After stirring at room temperature for 1 h, the reaction mixture was poured into H2O and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated to afford the title compound as a white solid (1.26 g, 79%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)cc3)CC2)cc1-c1ccccc1

Procedure:
101 mg (68%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.312 mmol), 1-(4-chlorophenyl)piperazine (84 mg, 0.312 mmol), DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C.Cl>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CN(C)CCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCCCCCCCCCCN
Yield: 66.7 %

Procedure:
N,N-Dimethyl N-(11-phthalimidoundecyl)amine (22.9 g) (Example 11) was added to hydrazine hydrate (3.54 g) in ethanol (200 ml), and refluxed for 7 hours. The solvent was removed leaving a white solid, which was partially dissolved in dilute hydrochloric acid and filtered. The pH of the filtrate was adjusted to pH 14 using NaOH (1M) whereupon a brown oil separated from the aqueous phase and was extracted with ether. The organic extract was dried and evaporated to give N,N-dimethyl-N-(11-aminoundecyl)-amine as a brown oil (9.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]1[N:13]=[CH:14][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:17]([N:15]1[CH:16]=[C:12]([CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[N:13]=[CH:14]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 51.8 %

Procedure:
1.22 g of p-hydroxybenzaldehyde and 4.08 g of 4-chloromethyl-1-tritylimidazole were dissolved in 40 ml of N,N-dimethylformamide, followed by adding 1.66 g of anhydrous potassium carbonate and subsequently stirring at room temperature for 40 hours. The thus prepared reaction solution were partitioned between water and benzene, and the resulting organic layer was concentrated to dryness. The resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an elution solvent, and the thus purified product was crystallized from a n-hexane/benzene solvent system. In this way, 2.3 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16]Br)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[I-:18].[Na+]>C(C(C)=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][I:18])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: [I-]
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(N)n1
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)/C(=N\OCCI)c1csc(N)n1
Yield: 90.5 %

Procedure:
80.55 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-bromoethoxy)imino]-acetate and 187.4 g of sodium iodide are boiled under reflux in 1.5 l of methyl ethyl ketone for 1.5 hours. After removal of the solvent by evaporation, the residue is partitioned between 0.6 l of water and 0.2 l of ethyl acetate, the aqueous phase is back-extracted twice with 0.2 l of ethyl acetate each time, the organic extracts are thereupon combined, washed with 0.2 l of aqueous 15% sodium chloride solution, dried and evaporated. The residue is recrystallized from 0.7 l of toluene. 83.5 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-iodoethoxy)imino]acetate are obtained.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1.O.[NH2:32][NH2:33]>CN(C=O)C>[C:28]([C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:33][N:32]=2)[CH:27]=[CH:26][CH:25]=1)#[N:29]
Reactant: NN
Reactant: N#Cc1cccc(CCC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)c1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Yield: 93.2 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(3-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (495 mg, 1.25 mmol, prepared in Synthetic Example 12) in DMF (12 ml) was added hydrazine monohydrate (80%, 148 μl, 3.69 mmol, 3.0 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-[2-(3-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (456 mg, 93%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:27]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O>>[O:16]=[C:10]1[C:9](=[CH:17][C:19]2[NH:20][C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=3[C:27]=2[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]c2c1CCCC2

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([CH2:27][C:28](=[O:40])[N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:25]([CH3:41])[NH:24][C:23]=1[CH:42]=O.N1CCCCC1>C(O)C>[CH3:21][C:22]1[C:26]([CH2:27][C:28](=[O:40])[N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:25]([CH3:41])[NH:24][C:23]=1/[CH:42]=[C:14]1\[C:15](=[O:20])[NH:16][C:17]2[C:13]\1=[CH:12][C:11]([S:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[CH:19][CH:18]=2
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCC[C@H]1CN1CCCC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 3,5-dimethyl-4-[2-oxo-2-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethyl]-1H-pyrrole-2-carbaldehyde (110 mg, 1 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated, triturated with methanol, filtered and washed wit DCM to give the titled compound as a pale orange solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:20](=O)[CH2:21]Br)[C:5]([NH:7][CH:8]1[C:18](=[O:19])[N:10]2[C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6].[NH2:24][C:25]([NH2:27])=[S:26].C([O-])(=O)C.[Na+].C(OC(C)C)(C)C>CO>[NH2:27][C:25]1[S:26][CH:21]=[C:20]([C:4](=[N:3][O:2][CH3:1])[C:5]([NH:7][CH:8]2[C:18](=[O:19])[N:10]3[C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH2:13][S:14][C@H:9]23)=[O:6])[N:24]=1
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 30 °C
Reaction time: 5 h
Yield: 118.7 %

Procedure:
7-(2-Methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 10 g.) was added to a solution of thiourea (2.81 g.) and sodium acetate (2.22 g.) in methanol (50 ml) and stirred at 30° C. for 5 hours. To the resultant solution was added diisopropyl ether (200 ml.) and stirred at 30 minutes. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 11.2 g.).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].[CH:9]1[C:19]2[CH:18]=[CH:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH:14]([C:24]3[C:25](=[O:38])[NH:26][C:27](=[O:37])[N:28]([C:30]4[N:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=4)[CH:29]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH:20]1[C:16]2[CH:17]=[CH:18][C:19]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]([C:24]3[C:25](=[O:38])[NH:26][C:27](=[O:37])[N:28]([C:30]4[N:31]=[N:32][C:33]([S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[CH:34][CH:35]=4)[CH:29]=3)[C:15]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)nn2)cc1C1c2ccccc2C=Cc2ccccc21
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1ccc(-n2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl thioglycolate (0.97 ml) was added dropwise to a stirred suspension of sodium hydride (0.434 g, 60% dispersion in oil) in dimethylformamide (30 ml). The mixture was stirred at room temperature for 1 hour. 13 ml of this solution was added to a solution of the product from step (i) (0.9 g) in dimethylformamide (20 ml). The mixture was stirred for 2 hours then quenched with aqueous arnmonium chloride and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.0 g.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=3[O:17][CH3:18])[N:8]=2)[CH2:3][CH2:2]1.[CH3:19][O:20]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH:1]1([C:4]2[NH:5][CH:6]=[C:7]([C:9]3[C:10]([O:17][CH3:18])=[CH:11][C:12]([O:15][CH3:16])=[C:13]([CH:14]=3)[CH:19]=[O:20])[N:8]=2)[CH2:3][CH2:2]1
Reactant: COC(Cl)Cl
Reactant: COc1ccc(-c2c[nH]c(C3CC3)n2)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1cc(OC)c(-c2c[nH]c(C3CC3)n2)cc1C=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Ex-105B: To a solution of 2-cyclopropyl-4-(2,4-dimethoxy-phenyl)-1H-imidazole (0.51 g, 2.09 mmol) was added dichloromethyl methyl ether (0.28 mL, 3.13 mmol) followed by addition of titanium tetrachloride (1.0M in dichloromethane, 8.4 mL, 8.4 mmol) dropwise at 0° C. The solution was allowed to warm up to ambient temperature and stir for 4.5 hours. The reaction mixture was then poured into ice. The aqueous layer was adjusted to pH 12 and extracted with dichloromethane. The combined solution of dichloromethane was washed with saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated to afford 5-(2-cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-benzaldehyde which was used without further purification. 1H NMR (DMSO-d6) δ 13.95 (bs, 1H), 10.22 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 6.88 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 2.25 (m, 1H), 1.20 (m, 4H). MS m/z=245 ([M+H]+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=[CH:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:4][CH:3]=1.I[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].ClC1C=CC=CC=1Cl>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([N:1]([C:2]2[CH:23]=[CH:22][C:5]([CH3:6])=[CH:4][CH:3]=2)[C:2]2[CH:23]=[CH:22][C:5]([CH:6]=[C:7]3[C:8]4[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=4[CH:10]=[CH:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=4)=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(I)cc1
Reactant: Nc1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=C3c4ccccc4C=Cc4ccccc43)cc2)cc1
Reaction time: 7 h
Yield: 75 %

Procedure:
7.90 g (26.7 m moles) of the previously obtained 5-(4-amino-benzylidene)-5H-dibenzo[a,d]cycloheptene, 22.0 g (101 m mole) of p-iodotoluene, 11.0 g (79.6 m moles) of anhydrous potassium carbonate and 2.2 g of copper powder were added to 30 ml of o-dichlorobenzene, and the resulting mixture was stirred and refluxed over an oil bath kept at about 190° C. for 7 hours. After the end of reaction, the reaction mixture was subjected to filtration by suction, and the filtrate was washed successively with an aqueous 3-5% sodium thiosulfate solution and an aqueous saturated NaCl solution. The organic layer was dried over anhydrous sodium sulfate and then the solvent was removed therefrom under reduced pressure. The residue was admixed with about 60 ml of acetone, and the precipitated crystal was recovered therefrom by filtration, and recrystallized from ethyl acetate-n-hexane solvent mixture, whereby 9.52 g of 5-[4(di-p-tolylamino)benzylidene]-5H-dibenzo[a,d]cycloheptene was obtained (yield: 75.0%). The melting point was 168.0°-169.0° C. Elemental analysis as C36H29N was as follows:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([S:12][C@H:13]1[N:16]([CH:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])O)[C:15](=[O:32])[C@@H:14]1[C@H:33]([O:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37])[CH3:34])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:57])=O>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]([S:12][C@H:13]1[N:16]([CH:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[Cl:57])[C:15](=[O:32])[C@@H:14]1[C@H:33]([O:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37])[CH3:34])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CO[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of 0.27 g of 4(R)-t-butyldimethylsilyloxyacetylthio-3(S)-[1(R)-p-nitrobenzyloxycarbonyloxyethyl]-1-(1-p-nitrobenzyloxycarbonyl-1-hydroxymethyl)-azetidin-2-one in 3 ml of anhydrous tetrahydrofuran was cooled at 0° C. 0.045 ml of pyridine and 0.03 ml of thionyl chloride were added. After 10 minutes the mixture was filtered.