Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO.[NH2:4][N:5]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[C:6]1[C:12]#[N:13].C(O)(=O)C.[CH:18](N)=[NH:19].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[NH2:13][C:12]1[C:6]2=[CH:7][C:8]([C:10]#[N:11])=[CH:9][N:5]2[N:4]=[CH:18][N:19]=1
Reactant: N=CN
Reactant: N#Cc1cc(C#N)n(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1cc2c(N)ncnn2c1
Temperature: 80 °C
Yield: 75.3 %

Procedure:
To a solution of EtOH (50 mL) was added 1-amino-1H-pyrrole-2,4-dicarbonitrile (1.00 g, 7.57 mmol) followed by formamidine acetate (9.46 g, 90.8 mmol) and potassium carbonate (14.6 g, 106.0 mmol). The solution was heated to 80° C. for 2 h. Upon cooling to rt, the reaction mixture was diluted with EtOAc transferred to a separatory funnel and washed with water. The organic layer was collected, dried (MgSO4), filtered, and concentrated to dryness. The crude material was then triturated with EtOH-water. The solid was collected, washed with water, and dried under vacuum to afford 0.91 g of the above compound as a yellow-orange solid (5.70 mmol, yield 75%). 1H-NMR (DMSO-d6) δ 8.37 (d, J=1.8 Hz, 1H), 8.19 (d, J=17.4, 2H), 7.93 (s, 1H), 7.27 (d, J=1.8 Hz, 1H); LCMS RT=1.14 min.
Reaction SMILES: C([O:5][C:6](=[O:40])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:32]2[N:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][N:33]=2)[CH2:19][C:20]2[CH:21]=[N:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.[Cl:48]CCl>>[ClH:48].[CH2:38]([C:35]1[CH:36]=[N:37][C:32]([N:18]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:40])=[O:5])[S:12][CH:13]=2)=[N:33][CH:34]=1)[CH3:39]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(-c3ccccc3)nc2)nc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(-c3ccccc3)nc2)nc1
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-{[4-(2-{(5-Ethylpyrimidin-2-yl)[(6-phenylpyridin-3-yl)methyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (740 mg) obtained in Example 327-1 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1). The obtained compound was dissolved in diethyl ether (10 mL), 4 mol/L hydrochloric acid-ethyl acetate (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration to give the title compound (220 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=3[N:14]([CH3:25])[C:13]2=[O:26])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH3:25][N:14]1[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][C:16]=2[N:12]([CH2:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)[C:13]1=[O:26]
Reactant: COC(=O)[C@H]1CC[C@H](Cn2c(=O)n(C)c3ccc(C(F)(F)F)cc32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)O)CC2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
trans-4-(3-Methyl-2-oxo-6-trifluoromethyl-2,3-dihydro-benzoimidazol-1-ylmethyl)cyclohexanecarboxylic acid methyl ester (0.93 g, 2.44 mmol) were dissolved in THF/H2O (9 ml, 2/1). LiOH (129 mg, 5.4 mmol) was added and the mixture stirred at room temperature over night. The THF was evaporated with the formation of a white solid which was collected by filtration. 0.82 g (yield 94%) of the titled compound were isolated.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][N:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:33])([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH:20]1([N:17]2[CH2:18][CH2:19][N:14]([C:11]3([CH2:23][N:24]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]4=[O:33])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:15][CH2:16]2)[CH2:21][CH2:22]1
Reactant: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
Through a solution of 2-((1-Benzyl-4-(4-cyclopropylpiperazin-1-yl)-piperidin-4-yl)methyl)isoindolin-1-one (0.63 mmol) in ethanol (10 ml) was passed argon gas for 10 min. Then acetic acid (200 μl) and Pd(OH)2 (20% by weight) were added to the reaction mixture. The mixture was stirred at room temperature for 16 h under an atmosphere of H2 by using a hydrogen balloon. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness to give the desired product. Yield: 60%.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[C:25]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1cccc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-(trifluoromethyl)phenyl isocyanate (0.37 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.38 g, 51% yield), mp=66–68° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=+22.0° (c=1, EtOH).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:15][CH2:14][NH:13][C:12]1=[O:28])=[O:9])([CH3:6])([CH3:5])[CH3:4].ClC(Cl)(Cl)S(O[CH2:35][C:36]([F:39])([F:38])[F:37])(=O)=O.ClC(Cl)(Cl)S([O-])(=O)=O>CN(C)C=O>[C:3]([O:7][C:8]([NH:10][CH:11]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:15][CH2:14][N:13]([CH2:35][C:36]([F:39])([F:38])[F:37])[C:12]1=[O:28])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCNC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: O=S(=O)([O-])C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCN(CC(F)(F)F)C1=O
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 180 mg, 4.43 mmol) was added to a solution of benzyl 6-[(tert-butoxycarbonyl)amino]-5-oxo-1,4-diazepane-1-carboxylate (1.34 g, 3.69 mmol) in N,N-dimethylformamide (25 mL) at −35° C. After 15 min, 2,2,2-trifluoroethyl trichloromethanesulfonate (0.911 mL, 5.54 mmol) was added and the reaction was stirred at −35° C. After 2 h, an additional amount of sodium hydride (100 mg, 2.5 mmol) and trichloromethanesulfonate (0.500 mL, 3.04 mmol) were added. After 18 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (hexanes→30% ethyl acetate/hexanes) gave the title compound (690 mg). MS 446 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:26][CH2:27][CH3:28])[C:23]([NH2:25])=O)=[CH:17][CH:16]=1)[CH3:11].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1.O>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:26][CH2:27][CH3:28])[C:23]([NH2:25])=[S:38])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(N)=S

Procedure:
3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropanamide (428 mg, 1.1 mmol) was suspended in toluene and Lawesson's reagent (1.1 eq) added. After 3 h at refluxed the suspension was cooled and poured into water. After extraction with chloroform (×3) the extracts were washed with aqueous ammonia, dried and concentrated. Chromatography (methanol/dichloromethane) gave the product as a white solid m.p.=46°48° C.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Product: ClC1=Nc2ccccc2Sc2ccccc21

Procedure:
A solution of dibenzo[b,f][1,4]thiazepin-11(10H)-one, prepared as described in the previous step, (14.6 g, 64 mmol) in phosphorus oxychloride (20 mL) was heated to reflux for 2 hours. The mixture was concentrated to provide the crude product which was used directly without further purification. ESI-MS (M+1): 246 calc. for C13H8ClNS 245.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: [H][H]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(F)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccc(F)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 34 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-p-fluorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (22 mg in 2 ml ethanol) was added 6 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 45 minutes, the mixture was filtered over Celite, concentrated and purified by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (7.5 mg).
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH3:9][S:10]([NH:13][CH2:14][CH2:15][S:16][C:17]1[N:22]2[CH:23]=[CH:24][N:25]=[C:21]2[CH:20]=[CH:19][CH:18]=1)(=[O:12])=[O:11]>C(O)(=O)C>[CH3:9][S:10]([NH:13][CH2:14][CH2:15][S:16][C:17]1[N:22]2[C:23]([CH2:1][N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[CH:24][N:25]=[C:21]2[CH:20]=[CH:19][CH:18]=1)(=[O:12])=[O:11]
Reactant: C=O
Reactant: C1COCCN1
Reactant: CS(=O)(=O)NCCSc1cccc2nccn12
Solvent: CC(=O)O
Product: CS(=O)(=O)NCCSc1cccc2ncc(CN3CCOCC3)n12
Yield: 71.5 %

Procedure:
To a solution of 37% formalin (178 mg, 2.2 mmoles) in acetic acid (2 ml) was added morpholin (192 μl, 2.2 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. 5-[2-(methylsulfonylamino)ethylthio]imidazo[1,2-a]pyridine (543 mg, 2 mmoles) was added to the reaction mixture, followed by stirring at 60° C. for 2 hours. After the solvent was distilled off, the residue was dissolved in chloroform (50 ml) and washed with 1N NaOH (10 ml). Then, the aqueous layer was extracted with chloroform (30 ml×3) and the combined chloroform layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10→1:5) to obtain 530 mg of the desired product (71.5%, colorless solid).
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][NH2:20])=[CH:13][CH:12]=1.O>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][N:20]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])=[CH:15][CH:16]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: NCCCc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)/C(Cl)=C(/Cl)C(O)=NCCCc1ccc(Cl)cc1
Temperature: 20 °C
Yield: 77.5 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 17.0 g (0.1 mol) of 3-(4-chlorophenyl)-propylamine are stirred in 100 ml of glacial acetic acid under reflux for 4 hours. 50 ml of water are added and the mixture is cooled to 20° C. The product is filtered off with suction and dried. 26.1 g (82% of theory) of dichloromaleic acid N-[3-(4-chlorophenyl)-propyl]-imide of melting point 72°-73° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cnc2[nH]cc(Br)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(F)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
3-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 23.3 mmol) was dissolved in DMF (37.5 mL) and cooled to 0° C. Sodium hydride (1.5 g, 37.2 mmol) was added and the reaction mixture was stirred for 10 minutes and then treated with tosyl chloride (6.6 g, 34.9 mmol). The mixture was stirred for 30 minutes at 0° C. and then at room temperature for another 90 minutes. The reaction mixture was poured into water (100 mL) and the resulting solid was collected, washed with water and hexanes three times and dried in vacuo to afford 8.26 g of 3-bromo-5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 22a: 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.31 (s, 1H), 8.01 (d, J=8.3 Hz, 2H), 7.92 (dd, J=8.4, 2.7 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 2.35 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[F:27][C:28]([F:39])([F:38])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:37]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH2:29][C:28]([F:27])([F:38])[F:39])=[CH:32][CH:33]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
Light brown crystalline solid. MS (ESI): 503.1 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 4-(2,2,2-trifluoro-ethoxy)-phenylamine.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.C([O-])(=O)C.[Na+].[I:16]I.[OH-].[Na+]>C(O)(=O)C.O1CCCC1>[I:16][C:2]1[O:1][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=1
Reactant: II
Reactant: Nc1nccc2occc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1nccc2oc(I)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 68.1 %

Procedure:
Furo[3,2-c]pyridin-4-ylamine (7.8 g) was dissolved in 175 mL of glacial acetic acid and sodium acetate (14.3 g) added in portions (exothermic!). Subsequently a solution of iodine (44.2 g) in 150 mL of tetrahydrofuran was added dropwise and the resulting mixture allowed to stir for 4 d at ambient temperature. The mixture was poured on ice and the pH value adjusted to pH 10 by adding 10 N sodium hydroxide solution, followed by extraction with ethyl acetate. The organic extract was washed several times with sodium thiosulfate solution and brine, dried (Na2SO4) and concentrated. The crude product was purified by silica chromatography (ethyl acetate/isohexane=5/5, 7.5/2.5, 10/0) to give 10.3 g (68%) of the title compound as a brownish solid. M.p. 170-173° C.; EI-MS: 260 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CNC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC(O)C2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.5 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.52 g, 3.1 mmol), azetidin-3-ol hydrochloride (0.5 g, 4.6 mmol) and 4 Å molecular sieves (0.7 g) in DCE (8 mL). The reaction mixture was stirred for 7 h at room temperature. Sodium triacetoxyborohydride (1.3 g, 6.13 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 40:60) to give 3-Hydroxy-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester as yellow oil (0.69 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 4.45-4.35 (m, 1H); 3.96 (dd, J=9.3, 6.7 Hz, 2H); 3.74 (dd, J=9.3, 4.5 Hz, 2H); 3.66 (td, J=8.8, 6.7 Hz, 2H); 3.40-3.37 (m, 1H); 3.20 (td, J=8.8, 4.5 Hz, 2H); 1.43 (s, 9H).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[C:50]([F:56])=[C:51]([CH:53]=[CH:54][CH:55]=2)[NH2:52])[CH:38]=[CH:37][N:36]=1.[CH3:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[S:64](Cl)(=[O:66])=[O:65]>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[C:50]([F:56])=[C:51]([NH:52][S:64]([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=3[CH3:57])(=[O:66])=[O:65])[CH:53]=[CH:54][CH:55]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: Cc1ccccc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (350 mg, 1.003 mmol) and 2-methylbenzenesulfonyl chloride (0.145 mL, 1.00 mmol) the title compound of Step A was obtained as a yellow solid (140 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (s, 1H), 8.35-8.65 (m, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.11-7.50 (m, 6H), 6.73 (d, J=5.2 Hz, 1H), 3.35-3.41 (m, 1H), 2.54 (s, 3H), 1.34 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19]C(=O)CC4C=CC=CC=4)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:5][CH:4]=1.CN1CCOCC1.[C:41]([O:45][C:46]([NH:48][C:49]1[S:50][CH:51]=[C:52]([C:54](=[N:58][O:59][C:60]([C:63]([O:65][CH:66]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[O:64])([CH3:62])[CH3:61])[C:55](O)=[O:56])[N:53]=1)=[O:47])([CH3:44])([CH3:43])[CH3:42].C1C=CC(OP(Cl)(Cl)=O)=CC=1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:55](=[O:56])[C:54]([C:52]4[N:53]=[C:49]([NH:48][C:46]([O:45][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:47])[S:50][CH:51]=4)=[N:58][O:59][C:60]([C:63]([O:65][CH:66]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)[C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[O:64])([CH3:61])[CH3:62])[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:32][CH:33]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=NOC(C)(C)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)C(=NOC(C)(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Yield: 83.1 %

Procedure:
To a suspension of 7β-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (1) p-toluenesulfonate (2.705 g: 5 mMol.) in dichloromethane (50 ml) are added N-methylmorpholin (0.55 ml; 1 Eq.) and 2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetic acid (3.51 g; 1.3 Eq.) at 0° C. and then phenylphosphoric dichloride (0.97 ml; 1.3 Eq.) and N-methylmorpholin (1.65 ml; 3 Eq.) at -40° C., and the mixture is stirred at -40° to -10° C. for 1.5 hours. The reaction mixture is diluted with ethyl acetate, washed with water, diluted hydrochloric acid and water, dried, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene:ethyl acetate) to give 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (2) (3.70 g).