Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.[Cl:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[ClH:27].[N:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:31][CH:32]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: ClCCc1ccncc1
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCc3ccncc3)cc12

Procedure:
6-(2-Pyridin-4-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 30% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and 4-(2-Chloro-ethyl)-pyridine.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8](I)[CH:7]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[OH:14][C:9]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][C:6]([CH:2]=[O:3])=[CH:11][C:10]=1[O:12][CH3:13]
Reactant: COc1cc(C2OCCO2)cc(I)c1O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(C=O)cc(-c2ccccc2)c1O
Yield: 77.6 %

Procedure:
Under N2, tetrakis-triphenylphosphinepalladium(0) was added to a mixture of the above dioxolane (10 g, 31 mmoles), benzeneboronic acid (4.5 g, 37 mmoles), toluene (67 mL), 2 M aqueous sodium carbonate (33 mL) and methanol (20 mL). The resulting mixture was heated at reflux under N2 for 16 hours. After cooling the mixture was diluted with water (150 mL) and washed with heptane (400 mL). The aqueous phase was made acidic with 3N hydrochloric acid and extracted with ethyl acetate (3×300 mL). The combined organic extracts were dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography over silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:2) to afford 5.49 g (77%) of 4-hydroxy-3-methoxy-5-phenylbenzaldehyde. M.p. 107-108° C. 1,2-Dibromoethane (41 mL, 0.48 moles) was added to a mixture of the above 4-hydroxy-3-methoxy-5-phenylbenzaldehyde (5.49 g, 24 mmoles) and potassium carbonate (17 g, 123 mmoles) in DMF (80 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (200 mL), dried over MgSO4 and evaporated in vacuo to afford 8.1 g (100%) of 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde as an oil.
Reaction SMILES: Cl.[C:2]([S:21][CH2:22][CH2:23][NH2:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:25]([S:28]([C:31]1[CH:39]=[CH:38][C:37]([NH:40][S:41]([C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)(=[O:43])=[O:42])=[C:36]2[C:32]=1[CH:33]=[C:34]([C:49](O)=[O:50])[NH:35]2)(=[O:30])=[O:29])[CH2:26][CH3:27].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH2:25]([S:28]([C:31]1[CH:39]=[CH:38][C:37]([NH:40][S:41]([C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)(=[O:43])=[O:42])=[C:36]2[C:32]=1[CH:33]=[C:34]([C:49]([NH:24][CH2:23][CH2:22][S:21][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:50])[NH:35]2)(=[O:29])=[O:30])[CH2:26][CH3:27]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCS(=O)(=O)c1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)c1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a mixture of 2-(tritylthio)ethylamine hydrochloride (0.42 g), triethylamine (0.17 mL) and N,N-dimethylformamide (15 mL) were added 4-(propylsulfonyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.42 g), 1H-1,2,3-benzotriazol-1-ol (0.20 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.25 g) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (690 mg, yield 97%) as pale-yellow prism crystals. melting point 200-201° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Mg]Br>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]([OH:13])[CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1sc2ccccc2c1-c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenylbenzo[b]thiophene-2-carbaldehyde (430 mg, 1.87 mmol) in THF (10 mL) at −78° C. and under a nitrogen atmosphere was added 3.0M methylmagnesium bromide in diethyl ether (1.24 mL) and stirring continued for 30 min. The reaction mixture was quenched with a saturated solution of NH4Cl (20 mL) and slowly warmed to RT. The mixture was extracted with EtOAc (×2) and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo affording the title compound as a white solid (472 mg, quantitative). 1H NMR (CDCl3, 400 MHz): δ 7.88-7.84 (1H, m), 7.52-7.28 (8H, m), 5.21 (1H, q, J=6.35 Hz), 2.03 (1H, s), 1.59 (3H, d, J=6.63 Hz)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:13]#[N:14].[Na+].[Cl-].[NH4+:17]>N.CO.ClCCl>[NH2:17][C:10]([CH3:12])([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]#[N:14]
Reactant: [C-]#N
Reactant: [NH4+]
Reactant: CC(=O)COCc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(N)(C#N)COCc1ccccc1

Procedure:
5.07 g (27.79 mmol) of 1-(benzyloxy)acetone were initially charged in 55.6 ml of 2 N aqueous ammonia in methanol, 1.53 g (31.12 mmol) of sodium cyanide and 3.71 g (31.12 mmol) of ammonium chloride were added and the mixture was heated under reflux for 2 h. Another 27.4 ml of 2 N aqueous ammonia in methanol were then added, and the reaction mixture was stirred under reflux for 2 h. The reaction solution was cooled and diluted with 90 ml of dichloromethane. The solid obtained was filtered off and the filtrate was concentrated. The residue was purified using silica gel (mobile phase: cyclohexane/ethyl acetate gradient: from 4/1 to 1/1). This gave 4.94 g of the target compound (90% pure, 84% of theory).
Reaction SMILES: [CH2:1]([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][CH:17]([C:15]([C:7]3[S:6][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)=[CH2:1])[CH2:18][CH2:19]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1nc2ccccc2s1)C1CCN(CCc2ccc(OC)cc2)CC1
Reaction time: 2 h

Procedure:
Dissolve methyltriphenylphosphonium bromide (2.50 g, 6.99 mmol) in anhydrous tetrahydrofuran (50 mL). Add n-butyllithium (2.8 mL of a 2.5M solution in hexane, 6.99 mmol) and cool to -10° C. Add, by dropwise addition, a solution of [2-benzothiazolyl][1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methanone (2. 66 g, 6.99 mmol) in anhydrous tetrahydrofuran (50 mL). Stir for 2 hours then quench with water. Separate the organic phase and extract the aqueous phase with ethyl ether. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (50% ethyl ether/hexane) to give the title compound as a white powder; mp 84°-85° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]2)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)CC2C=CC(OC)=CC=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44]>O1CCCC1>[CH2:43]([NH:45][C:46](=[O:47])[O:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[C:5]([C:16]#[N:17])[CH:4]=[C:3]([NH:18][C:19]3[N:24]=[C:23]([NH:25][CH:35]4[CH2:37][CH2:36]4)[C:22]4=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]4[N:20]=3)[C:2]=2[Cl:1])[CH2:9]1)[CH3:44]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(CO)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)OCC1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCO1
Temperature: 50 °C

Procedure:
To a vial was charged with 2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 1) (30 mg, 0.051 mmol) in tetrahydrofuran (256 μl) was added ethyl isocyanate (4.86 μl, 0.061 mmol). The vial was capped and heated at 50° C. over the weekend. Reaction temperature was raised to 70° C. for 6 h to get full conversion. Solvent was removed in vacuo and the crude residue was taken forward as is.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12])=[CH:5][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[Si:27]([O:26][CH2:25][CH2:24][N:7]([C:6]1[C:2]([Cl:1])=[N:3][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=1)[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CSCC(C)C(=O)Nc1cn(-c2cccnc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC(C)C(=O)N(CCO[Si](C)(C)C(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamide (0.150 g, 0.483 mmol) in N,N-dimethylformamide (2.413 ml) was cooled to 0° C. Sodium hydride (0.039 g, 0.965 mmol, 60% dispersion) was added at and the reaction was stirred at 0° C. for 30 minutes. (2-Bromoethoxy)(tert-butyl)dimethylsilane (0.231 g, 0.965 mmol) was added, the ice bath was removed, and the reaction was stirred at room temperature for 2 hours. The reaction was heated at 65° C. for 1.5 hours and then cooled to room temperature. Brine was added and the mixture was extracted with dichloromethane. The combined organic phases were concentrated and chromatographed (0-100% ethyl acetate/hexanes) to give N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamide (0.120 g, 0.243 mmol, 50.4%) as an orange oil: IR (thin film) 1669 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J=2.5 Hz, 1H), 8.55 (dd, J=4.7, 1.4 Hz, 1H), 8.05 (s, 1H), 7.98 (ddd, J=8.3, 2.6, 1.4 Hz, 1H), 7.41 (ddd, J=8.4, 4.8, 0.5 Hz, 1H), 4.35-3.06 (m, 4H), 2.86-2.73 (m, 1H), 2.73-2.59 (m, 1H), 2.41 (dd, J=12.8, 5.7 Hz, 1H), 1.94 (s, 3H), 1.11 (d, J=6.7 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 3H), −0.01 (s, 3H); ESIMS m/z 470 ([M+H]+).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:18][CH2:17][CH:7]2[N:8]([CH3:16])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[CH:6]2[CH2:5]1.S(Cl)([Cl:21])=O>>[Cl:21][CH2:2][CH2:3][N:4]1[CH2:18][CH2:17][CH:7]2[N:8]([CH3:16])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[CH:6]2[CH2:5]1
Reactant: Cc1ccc2c(c1)C1CN(CCO)CCC1N2C
Reactant: O=S(Cl)Cl
Product: Cc1ccc2c(c1)C1CN(CCCl)CCC1N2C
Yield: 77.1 %

Procedure:
In the same manner as described in Example 7, 2-(β-hydroxyethyl)-5,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido-[4,3-b]indole (3.5 g) is reacted with thionyl chloride (5.0 g) to give 2-(β-chloroethyl)-5,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (2.9 g) as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[S:23]1[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24]1>N1C=CC=CC=1>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[NH:7][C:5]1[S:6][C:2]([NH:1][C:28]([C:25]2[CH:26]=[CH:27][S:23][CH:24]=2)=[O:29])=[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:4]=1
Reactant: O=C(Cl)c1ccsc1
Reactant: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of ethyl 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxylate (100 mg, 0.32 mmol) in pyridine (3 mL) was added 3-thiophene carbonyl chloride (61 mg, 0.42 mmol) at 0° C. The mixture was allowed to warm to rt and stirred overnight. The reaction was quenched with ice-water, and the mixture was extracted with EtOAc. The organic layer was washed with water, and dried over Na2SO4. The solvent was evaporated, and the resulting solids were collected and washed with EtOAc to give 55 mg (40% yield) of the titled compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.C(N(CC)CC)C.[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(Cl)Cl>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[O:4][CH:3]([CH2:2][NH:1][C:28]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:29])[CH2:12][CH2:11]2
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1cccc2c1OC(CN)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1OC(CNC(=O)C1CCCCC1)CC2
Reaction time: 8 h

Procedure:
A mixture of 9.5 g (49 mmol) of 2-aminomethyl-8-methoxychroman and 4.9 ml (49 mmol) of triethylamine in 50 ml of anhydrous methylene chloride is added dropwise to a solution of 7.2 g (49 mmol) of cyclohexanecarbonyl chloride in 75 ml of anhydrous methylene chloride, while stirring and cooling with ice. After the mixture has been left to stand overnight, it is poured onto ice. Separation of the phases, extraction of the aqueous phase with methylene chloride, washing with saturated sodium chloride solution and drying of the combined organic phases over anhydrous sodium sulphate gives, after evaporation under a water pump vacuum, 14.5 g of crude amide, which is recrystallised from 160 ml of ethyl acetate. IR (KBr): 3307, 2931, 1642, 1485 and 1256 cm
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1/[CH:21]=[CH:22]/[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>O1CCCC1>[Cl:8][CH2:9][C:10]([N:26]1[CH2:27][CH2:28][CH:23](/[CH:22]=[CH:21]/[C:15]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:13])[CH2:24][CH2:25]1)=[O:11]
Reactant: Cc1cccc(C)c1/C=C/C1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1/C=C/C1CCN(C(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under ice cooling, 6.77 ml of triethylamine and 3.87 ml of chloroacetyl chloride were added to a solution of 9.96 g of 4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidine in 150 ml of tetrahydrofuran. After stirring at ambient temperature for 20 minutes, 200 ml of water was added to the mixture. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether. The combined organic layer was and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate). The collected crystals were washed with diisopropyl ether-hexane and dried under reduced pressure to give 10.69 g of 1-(chloroacetyl)-4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)C.O>[Fe].C(O)(=O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][C@@H:24]1[CH2:28][CH2:27][O:26][CH2:25]1)[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@@H]1CCOC1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@@H]1CCOC1
Temperature: 25 °C

Procedure:
A mixture of 12.80 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((R)-tetrahydrofuran-3-yloxy)quinazoline, 200 ml of ethanol, 100 ml of water, and 17.20 ml of glacial acetic acid is heated to reflux temperature. Then a total of 7.00 g of iron powder is added in batches. The reaction mixture is refluxed for about four hours and then cooled to ambient temperature overnight. For working up, the reaction mixture is evaporated using the rotary evaporator. The residue is taken up in methylene chloride/methanol (9:1), mixed with 20 ml of concentrated ammonia solution and filtered through a layer of silica gel. It is washed with copious amounts of methylene chloride/methanol (9:1) and the combined filtrates are evaporated down. The residue is stirred with diethylether and suction filtered. Yield: 8.59 g (73% of theory); mass spectrum (ESI−): m/z=373, 375 [M−H]−; Rf value: 0.27 (silica gel, ethyl acetate/methanol=9:1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[CH:24][CH:23]=[CH:22]5)=[CH:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.NC1C=CC=CC=1.ClC1C=C(C=CC=1)N>>[C:4]1([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[CH:24][CH:23]=[CH:22]5)=[CH:16][N:17]=3)[N:14]=2)[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Nc2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)c1
Solvent: Nc1ccccc1
Solvent: Nc1cccc(Cl)c1
Product: c1ccc(Nc2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1

Procedure:
The title compound was prepared in analogy to the compound of Example 121 using aniline as starting material instead of 3-chloroaniline and with a preparative LCMS purification instead of a flash chromatography (tR 4.30 min (conditions 4), MH+=352.3, 1H-NMR in DMSO-d6: 8.91 (m, 1H); 8.36 (m, 1H); 8.17 (d, 1H); 8.08 (s, 1H); 8.03 (d, 1H); 7.96 (m, 1H); 7.79 (m, 1H); 7.58 (dd, 1H); 7.50 (m, 2H); 7.35 (d, 1H); 7.25 (t, 2H); 7.01 (t, 1H); 4.59 (s, 2H)).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:15]([O:17]CC)=[O:16])=[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=12)=[O:5])C.[OH-].[Na+]>>[C:15]([C:8]1[S:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=12)([OH:17])=[O:16]
Reactant: CCOC(=O)c1sc(C(=O)OCC)c2c1OCCO2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1sc(C(=O)O)c2c1OCCO2

Procedure:
The 2,5-diethoxycarbonyl-3,4-ethylenedioxythiophene and NaOH are mixed in the microwave reactor. The microwave reactor is heated by the 2.45 GHz microwave at a power of 500-1200 W to perform hydrolysis reaction for no more than 20 minutes to obtain 2,5-dicarboxy-3,4-ethylenedioxythiophene. The reaction is shown in the chemical formula (D).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH3:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:24])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29].CO>CN(C)C=O>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH3:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:24])[C:11]1=[CH:27][N:28]([CH3:30])[CH3:29])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)CC2=O)c(=O)[nH]c1=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)C(=CN(C)C)C2=O)c(=O)[nH]c1=O
Temperature: 50 °C
Yield: 56.3 %

Procedure:
5'-O-(t-Butyldimethylsilyl)-2',3'-dideoxy-5-methyl-2'-oxo-uridine (3.854 g, 10.9 mmol) from Step 3 was dissolved in 50 mL of dry dimethylformamide (DMF) and 1.74 mL (1.56 g, 13.1 mmol) of N,N-dimethylformamide dimethylacetal was added. The reaction mixture was heated in an oil bath at 50° C. for 40 min. The solvent was evaporated in vacuo and the residue purified on a silica gel column, the product eluting with 5% methanol in methylene chloride to give 2.512 g (56.3% yield) of the title compound, [α]D23 =-84.2° (c, 1.44, MeOH). DCI MS M/Z: (M+H)+ 410.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[C:28]1([O:34][CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OC(=O)C)C.CO>FC(F)(F)C(O)=O>[CH3:35][O:34][C:28]1[CH:33]=[CH:32][C:31]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@H:9]3[S:8][CH:7]=2)=[CH:30][CH:29]=1
Reactant: COc1ccccc1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)cc1

Procedure:
A mixture of 5 g of 3-acetoxymethyl-7(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and 10 ml of absolute anisole is dissolved in 40 ml of trifluoracetic acid and the clear solution is evaporated to dryness under a water pump vacuum and with repeated addition of toluene. The residue is dissolved in acetone, and the solution is mixed with about 30 g of silica gel and evaporated to dryness. The residue is suspended in methylene chloride and the suspension is applied to a column (diameter: 35 mm) of 150 g of silica gel. Elution is carried out with methylene chloride and mixtures of methylene chloride and acetic acid ethyl ester (fractions of 400 ml). Unreacted anisole is eluted with 2 fractions of pure methylene chloride. 3-(4-Methoxybenzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid mixed with 3-(2-methoxy-benzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid, is obtained by elution with 6:1 to 1:1 mixtures of methylene chloride and acetic acid ethyl ester. Additional, impure material is obtained with acetic acid ethyl ester and with acetic acid ethyl ester containing 5% of methanol. The pure product is crystallised from a mixture of acetic acid ethyl ester and cyclohexane and melts at 181.5°-182°C (uncorrected); [α]D20 = +379° ± 1° (c = 0.989 in dioxane); thin layer chromatogram (silica gel G): Rf = 0.61 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.72 (system acetic acid ethyl ester/pyridine/acetic acid/water, 62:21:6:11) and Rf = 0.63 (system n-butanol/pyridine/acetic acid/water, 38:24:8:30); ultraviolet absorption spectrum (in 95% strength ethanol), λmax = 224 mμ(ε = 19200), and shoulder at about 255 mμ (ε = 7200) and at about 279 mμ (ε = 3000); infrared absorption spectrum (in mineral oil): characteristic bands at 3.02μ, 3.19μ (shoulder), 3.30μ, 5.67μ, 5.77μ, 6.05μ, 6.23μ, 6.54μ, 6.61μ, 6.69μ, 7.07μ, 7.49μ, 7.99μ, 8.24μ, 8.52μ, 9.71μ, 13.31μ, 14.41μ and 15.05μ. Further recrystallisation from a mixture of acetone, methylene chloride and cyclohexane results in enrichment of 3-(4-methoxy-benzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid, with the melting point rising to 188°C.