Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10](CO)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[C:28]([Br:32])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:28][Br:32])[C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CBr)c1-c1ccccc1C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a stirred solution at −10° C. under N2 of N-[4-hydroxymethyl-2-(2-methylphenyl)benzoyl]methionine methyl ester (200 mg, 0.517 mmol ), prepared as in Example 403F, and carbon tetrabromide (189 mg, 0.568 mmol) in CH2Cl2 (5 mL) was added triphenylphosphine (163 mg, 0.620 mmol). Reaction stirred one hour at −10° C., and then, solvents concentrated in vacuo to produce a colorless glass. The residue could not be stored, and so, was used directly in the reaction in Example 1188B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:38]1([CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:15])[NH:47][CH2:46][CH2:45][CH:44]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
219 mg (0.61 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 138 mg (0.72 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 201 mg (0.95 mmol) of 3,3-diphenylpropylamine and 20 mg (0.16 mmol) of 4-dimethylaminopyridine were stirred in 10 ml of dichloromethane at room temperature overnight. 2 N hydrochloric acid was added to the reaction mixture. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[N:11][OH:12])[CH:5]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(Br)c1
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(-c2ccc(S(C)(=O)=O)cc2)c1

Procedure:
In analogy to example 22, from 3-(3-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 11) and (4-methylsulfonylphenyl)boronic acid was prepared the title compound as a mixture of E and Z isomers (3:1) as a yellow oil, MS (ESI+): m/z=471.1 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)OCc2ccccc2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and benzyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-benzyloxycarbonyloxy-2(1H)-primidinone as the residue.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][O:7][CH:6]2[CH:9]([O:12][CH2:13][CH2:14][O:15]CC3C=CC=CC=3)[CH2:10][O:11][CH:5]12)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]1[CH:5]2[O:11][CH2:10][CH:9]([O:12][CH2:13][CH2:14][OH:15])[CH:6]2[O:7][CH2:8]1
Reactant: [N-]=[N+]=NC1COC2C(OCCOCc3ccccc3)COC12
Agent: [Pd]
Solvent: CO
Product: NC1COC2C(OCCO)COC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-azido-6-(2-(benzyloxy)ethoxy)hexahydrofuro[3,2-b]furan (crude product) in MeOH (20 mL) was added Pd/C (10%, 0.31 g). The mixture was stirred at room temperature under a H2 atmosphere overnight. The mixture was filtered and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the crude product as brown liquid. The residue was used in the next reaction without further purification.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH:26]([N:29]1[CH:33]=[N:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)C.O>[CH:26]([N:29]1[CH:33]=[N:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH:36][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[S:3])([CH3:28])[CH3:27]
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: CC(C)n1cnnc1-c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)n1cnnc1-c1ccccc1NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 20.7 %

Procedure:
3-(4-Isothiocyanatophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (WO 2011/017513) (0.088 g, 0.24 mmol), 2-(4-isopropyl-4H-1,2,4-triazol-3-yl)aniline (0.080 g, 0.40 mmol), and cesium carbonate (0.16 g, 0.50 mmol) in isopropyl alcohol (1.2 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated. The residue was loaded onto Celite® cartridge and purified by flash chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent to provide the title compound as a yellow solid (0.028 g, 20%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19](=[O:20])[CH:18]=[C:17]([CH3:21])[NH:16][C:15]=3[CH3:22])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:27][C:18]1[C:19](=[O:20])[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:25])[F:26])=[CH:24][CH:23]=3)=[CH:9][CH:10]=2)=[C:15]([CH3:22])[NH:16][C:17]=1[CH3:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(C)[nH]1
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(C)c(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(=O)c1Br
Yield: 43.4 %

Procedure:
To a stirred suspension of 3-(4-(4-trifluoromethylphenoxy)phenyl)-2,6-dimethyl pyridin-4(1H)-one (4.12 g) in chloroform (50 ml) at room temperature was added N-bromosuccinimide (2.25 g). After 2 hr the mixture was filtered and the solid washed with chlorofrom and dried in vacuo. Recrystallisation from DMF afforded the title compound (2.18 g), m.p. 304°-305°, NMR δH (d6 -DMSO) 7.70 (2H, dd, J 5, 0.5 Hz), 7.0-7.3 (6H, m), 2.42 (3H, s), 2.1 (3H, s).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3n3ccnc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1cc(F)c(O[C@H]2CCCC[C@H]2n2ccnc2)cc1F
Yield: 93.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2S*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (315 mg, 0.538 mmol) prepared in Example 32a, triethylsilane (0.40 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL), to yield the title compound (220 mg, 94%) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[Cl:40][C:41]1[CH:42]=[C:43]([S:48](Cl)(=[O:50])=[O:49])[CH:44]=[C:45]([Cl:47])[CH:46]=1>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:48]([C:43]1[CH:42]=[C:41]([Cl:40])[CH:46]=[C:45]([Cl:47])[CH:44]=1)(=[O:50])=[O:49])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3cc(Cl)cc(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 60 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 5, Example 1)was added 3,5-dichlorobenzenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 60% yield.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[O:9][C:10](=O)[NH:11][C:6]=2[CH:5]=1.[CH2:16](Br)[CH:17]=C.O>CN(C)C=O>[CH2:10]([NH:11][C:6]1[C:7](=[CH:14][CH:15]=[C:4]([F:3])[CH:5]=1)[C:8]([OH:9])=[O:13])[CH:16]=[CH2:17]
Reactant: C=CCBr
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNc1cc(F)ccc1C(=O)O
Reaction time: 1 h

Procedure:
Sodium hydride (0.41 g of 80% suspension in oil) was added to a solution of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (2.5 g) in dimethylformamide (30 ml). The mixture was cooled to keep the temperature below 30° and then stirred for 1 hour until a clear solution was obtained. A solution of allyl bromide (1.2 ml) in dimethylformamide (30 ml) was added dropwise with cooling and the mixture stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The extract was washed with water, dried and evaporated and the residue added to aqueous sodium carbonate (10%; 20 ml) and stirred for 3 hours, acidified with hydrochloric acid to pH 3, filtered and the solid washed with water and dried to give N-allyl-4-fluoroanthranilic acid, mp 136°-139°. (Compound 21).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[H][H]>[Pt].CN1CCOCC1>[OH:9][NH:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: [H][H]
Agent: [Pt]
Solvent: CN1CCOCC1
Product: ONc1cccnc1Cl
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
A mixture of 18.3 g (115 mmol) of 2-chloro-3-nitropyridine and 300 ml of N-methylmorpholine was hydrogenated at room temperature and a hydrogen pressure of approximately 1.1 bar in the presence of 3 g of 5% platinum/charcoal (55.5% of water [Degussa]). After approximately 1.5 hours, the hydrogen uptake had ceased. The catalyst was removed by filtration through kieselguhr. The filtrate obtained was freed from solvent at approximately 45° C. under reduced pressure. Any remaining N-methylmorpholine was distilled off with 200 ml of Solvesso (Esso) under reduced pressure using a 20 cm column. The crystallizate which remained was taken up in 200 ml of n-hexane, filtered off with suction and washed with n-hexane. 15.9 g (96%) of the title compound were obtained as brown crystals.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[S:7][C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)=[CH:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26]>>[CH:19]([N:18]1[C:14]([C:8]2[S:7][C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:32]5[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][C:10]=3[CH:9]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(-c3cccc(S(C)(=O)=O)c3)cc1OCC2

Procedure:
Following the procedure for 114, 5 5-(8-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole was reacted with 3-methylsulfonylphenylboronic acid to give 146. MS(ESI+) 466.1.
Reaction SMILES: N=C=N.[CH3:4][N:5]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)[CH2:6][CH2:7][NH2:8].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24]([NH:8][CH2:7][CH2:6][N:5]([CH3:4])[C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: CN(CCN)c1nccn1C
Reactant: O=C(O)C#Cc1cccc(Cl)c1
Agent: N=C=N
Solvent: ClCCl
Product: CN(CCNC(=O)C#Cc1cccc(Cl)c1)c1nccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
2.3 g (≅2.8 mmol) PS carbodiimide was added to a solution of 215 mg (1.4 mmol) N1-methyl-N1-(1-methyl-1H-imidazol-2-yl)ethane-1,2-diamine and 378 mg (2.1 mmol) 3-(3-chloro-phenyl)propiolic acid in DCM (30 ml) and the reaction solution was shaken for 16 h at RT. The resin was subsequently filtered off, washed with DCM and ethanol and the filtrate concentrated in a vacuum. CC (DCE/EtOH 5:1) was performed with the residue, whereby 241 mg (0.8 mmol, 54%) 3-(3-chlorophenyl)-N-(2-(methyl(1-methyl-1H-imidazol-2-yl)amino)ethyl)-propiolamide was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:6][CH2:7]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]([C:8]([CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12.C(N(CC)CC)C.C>ClCCl.C(=O)(O)[O-].[Na+]>[O:1]([C:8]([CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([NH:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12)=[O:12])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(C(=O)Oc1ccccc1)c1ccccc1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
α-(Phenoxycarbonyl)phenylacetyl chloride (0.02 M) in dichloromethane (50 ml.) was added to 7-amino-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylic acid (6.56 g., 0.02 M) and triethylamine (6.0 ml.) in dichloromethane (100 ml.). The resulting solution was stirred at room temperature for three hours then the solvent was removed in vacuo, the residue dissolved in water (200 ml.) and washed with ethyl acetate (2×100 ml.). The aqueous solution was covered with ethyl acetate (50 ml.) acidified to pH 1.5 with 1 N hydrochloric acid, filtered, the organic phase was collected and the aqueous phase extracted with more ethyl acetate (50 ml.). The combined extracts were washed with water (2×100 ml.) and saturated sodium chloride (50 ml.) dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo to give an oily residue which was triturated with anhydrous ether to give a pale brown solid (5.0 g.). This solid was dissolved in dilute sodium bicarbonate solution (100 ml.), treated with decolourising charcoal, filtered, acidified to pH 1.5 and the precipitated cephalosporin free acid collected and dried in vacuo.
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[O:3][CH2:4][CH:5]([OH:7])[CH3:6].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[NH4+]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:14][C:11]([CH3:13])([O:10][C:8](=[O:9])[N:2]([CH3:1])[O:3][CH2:4][CH:5]([CH3:6])[O:7][C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:12]
Reactant: CC(O)CON(C)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(CON(C)C(=O)OC(C)(C)C)OC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
To a solution of N-methyl-N-boc-(2-hydroxypropyl)hydroxylamine (227 mg, 1.11 mmol) in dichloromethane (4 mL) were added DMAP (41 mg, 0.333 mmol) and succinic anhydride (167 mg, 1.67 mmol). The resulting mixture was stirred for 20 h at room temperature. The reaction mixture was poured into a saturated solution of ammonium chloride (15 mL) and extracted with DCM (3×40 mL). The combined organic layer was washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by silica flash column chromatography using 40% EtOAc/hexane as eluent to give the product as a white solid (227 mg, 0.744 mmol, 67%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.14 (d, 3H, J=6.4 Hz), 1.45 (s, 9H), 2.51-2.57 (m, 4H), 2.91 (s, 3H), 3.77-3.79 (m, 2H), 5.04-5.11 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[O:32])=[C:26]([F:41])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([OH:21])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[O:32])=[C:26]([F:41])[CH:25]=1)#[N:7]
Reactant: C1CCNC1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CO1
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC(O)CN1CCCC1
Temperature: 50 °C

Procedure:
After adding tetrahydrofuran (1 ml) and pyrrolidine (0.1 ml) to N-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea (100 mg), the mixture was heated at 50° C. for 30 minutes. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (45 mg) as light yellow crystals.
Reaction SMILES: [C:1]([NH:8][CH2:9][C@H:10]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:11]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:34].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[C:1]([NH:8][CH2:9][C@H:10]1[O:16][C@H:13]([C:14]([OH:34])=[O:15])[C@@H:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:11]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1O[C@H](C(=O)O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
The product from step 5 was dissolved in dry DMF and cooled to 0° C. Pyridinium dichromate (PDC, 4 molar equiv) was added portion wise and the reaction mixture was stirred at room temperature for 12 h. It was then diluted with EtOAc, washed with saturated aqueous CuSO4, brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by silica gel column chromatography gave the required N-Boc-6-amino-2,5-anhydro-3,4-di-O-benzyl-6-deoxy-D-mannonic acid in 77% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH2:13][O:14][CH3:15])=[O:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:38]([NH2:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:40])[CH3:39].Cl>CN(C=O)C.O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:47][C:38]([CH3:40])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:39])=[O:9])=[CH:5][C:4]=1[O:12][CH2:13][O:14][CH3:15])=[O:2]
Reactant: COCOc1cc(C(=O)O)ccc1C=O
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
4-Formyl-3-methoxymethoxybenzoic acid (2.57 g, 12.2 mmol) was dissolved in DMF (50 mL), and the solution was added with EDCI (4.68 g, 24.4 mmol), HOBT monohydrate (1.65 g, 12.2 mmol) and cumylamine (4.03 mL, 24.4 mmol), followed by stirring at room temperature for 4 hours. The reaction mixture was added with water (10 mL) and 1 mol/L hydrochloric acid (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate=95/5 to 80/20 to 70/30) to obtain 4-formyl-3-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (3.12 g, yield 78%).