Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]1([CH2:20][C:21](O)=[O:22])[C@@H:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2].CN1CCOCC1.ClC(OCC)=O.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1.C1C=CC=CC=1>[CH2:37]([NH:44][C:21](=[O:22])[CH2:20][C@@:3]1([CH2:1][CH3:2])[C@@H:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC[C@@]1(CC(=O)O)CCCN2CCc3c([nH]c4ccccc34)[C@@H]21
Reactant: NCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: c1ccccc1
Product: CC[C@@]1(CC(=O)NCc2ccccc2)CCCN2CCc3c([nH]c4ccccc34)[C@@H]21
Temperature: -5 °C
Yield: 44 %

Procedure:
3.12 g. (0.01 mole) of (-)-(1S,12bS)-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indol[2,3-a]quinolizin-1-yl-acetic acid are added to a solution containing 2.04 g. (0.02 moles) of N-methylmorpholine (redistilled from sodium) in 20 ml. of dry tetrahydrofuran while stirring under nitrogen, then the solution is cooled to -5° C. and 1.10 g. (0.01 mole) of ethyl chloroformate are rapidly dropped in while stirring vigorously and keeping the inner temperature at or lower than 0° C. The mixture is stirred at 0° C. for 30 minutes, then a mixture containing 1.18 g. (0.011 moles) of benzylamine in 10 ml of dry tetrahydrofuran is dropwise added at a temperature between -5° C. and 0° C. during 10 minutes. The mixture is stirred at 0° C. for 30 minutes and then during an additional stirring for 4 hours the temperature of the mixture is allowed to warm to room temperature. The mixture is evaporated on a rotating evaporator. After shaking thoroughly the residue with 50 ml. of dichloromethane and 20 ml. of water, the phases are separated. The dichloromethane solution is washed with 20 ml. of 5% sodium carbonate solution and then three times with 20 ml of water each, dried over anhydrous magnesium sulphate and evaporated. The residue which is the crude product, is purified by column chromatography on silica gel by using toluene containing 10% of diethylamine as eluant to give 1.89 g. (44% yield) of the title product which can further be purified by recrystallization from benzene, m.p. 179°-180° C.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9]
Reactant: Nc1ccccc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)Nc2ccccc2Cl)c(C(F)F)n1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
80.0 g (0.403 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 257.2 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 3 hours, 221.3 g (0.399 mol, 23% strength) of toluenic 2-chloroaniline solution were metered in and the reaction mixture was stirred for a further 1 hour. After venting and cooling to 20° C. with a ramp of 10° C./h, the mixture was stirred overnight. Subsequently, the mixture was cooled to 0° C., and the solids were filtered off, washed with cold toluene and dried at 80° C. under reduced pressure. The yield (without further processing of the mother liquor) was 105 g (92%).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][NH:5][C:6](=[O:33])[C@@H:7]([NH:18][C:19]([N:21]([CH2:30][CH2:31][OH:32])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1>C(O)C.[C].[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C@H:7]([NH:18][C:19]([N:21]([CH2:30][CH2:31][OH:32])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:20])[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:34])[CH3:1])=[O:33])=[CH:14][CH:13]=1
Reactant: CN(C)CCNC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)N(CCO)CCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCNC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)N(CCO)CCc1ccccc1
Reaction time: 3 h
Yield: 49 %

Procedure:
Under a nitrogen atmosphere, 5% palladium-carbon (92 mg) is added to a solution of (2S)-N-[2-(dimethylamino)ethyl]-2-[3-(2-hydroxyethyl)-3-phenethylureido]-3-(4-nitrophenyl)propionamide (Compound No. 19-1, 921 mg) in ethanol (30 ml). The mixture is stirred under a hydrogen atmosphere for three hours. Palladium-carbon is filtered out with Celite, and the filtrate is concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 418 mg (49%) of the titled compound (Compound No. 24-1) as noncrystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([OH:13])[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27](O)=[CH:26][C:25]=2[CH3:32])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([O:13][C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:19][CH:20]=3)=[C:25]([CH3:32])[CH:26]=2)[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)c1ccc(C(C)O)s1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of (±)-5-(1-hydroxy-ethyl)-thiophene-2-carboxylic acid ethyl ester (0.416 g, 2.08 mmol), 4′-tert-butyl-2,6-dimethyl-biphenyl-4-ol (0.561 g, 2.20 mmol), and PPh3 (0.787 g, 3.00 mmol) is dissolved in toluene (19 mL) and treated with 1,1′-(azodicarbonyl)dipiperidine (ADDP, 0.760 g, 3.01 mmol) and stirred overnight at rt. The mixture is diluted with MeOH until homogeneous and conc. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% giving (±)-5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid ethyl ester (0.604 g, 671%) as a clear syrup.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[S:37][C:38]([CH2:41]O)=[CH:39][N:40]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:41][C:38]3[S:37][C:36]([Cl:35])=[N:40][CH:39]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: OCc1cnc(Cl)s1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2cnc(Cl)s2)cc1
Reaction time: 18 h
Yield: 3 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), (2-chlorothiazol-5-yl)methanol (23.94 mg, 0.160 mmol) and Ph3P-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DEAD (0.025 mL, 0.160 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (1.067 mL, 1.067 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-((2-chlorothiazol-5-yl)methoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (0.9 mg, 1.573 μmol, 2.95% yield). 1H NMR (400 MHz, METHANOL-d4) δ 7.69 (s, 1H), 7.37-7.32 (m, 1H), 7.24-7.17 (m, 2H), 7.16-7.10 (m, 1H), 5.55 (s, 1H), 5.42 (s, 2H), 2.68 (s, 3H), 2.28 (s, 3H), 1.36 (br. s., 3H), 1.31 (br. s., 1H), 1.20 (s, 9H), 0.84 (s, 6H). 4H of piperidine were not resolved. LCMS (M+H)=572.5.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:16]([C:13]1[O:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:18])=[O:2])=[CH:15][CH:14]=1)=[O:17]
Reactant: COC(=O)CCCCCCCc1ccc(C=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=Cc1ccc(CCCCCCCC(=O)O)o1
Yield: 79.9 %

Procedure:
8-(5-Formyl-2-furyl)-octanoic acid methyl ester (5.04 g, 0.02 moles), methanol (30 ml) and 20% aqueous potassium carbonate (55 ml) were stirred and heated under reflux for 40 minutes. The clear solution was concentrated to 2/3 of the volume by distillation from a water bath (50° C) under reduced pressure (100 mm Hg). The residue was washed with ether (30 ml). Ether (50 ml) was added, and the resulting emulsion was acidified to pH 5 with 3N hydrochloric acid. The ethereal layer was separated. The aqueous layer was extracted with ether (30 ml). The combined ethereal extracts were washed with two 50-ml-portions of water and then dried over magnesium sulphate. The dried ethereal solution was evaporated to dryness from a water bath (60° C), at last under 15 mm Hg. The yellow crystalline residue (4.66 g), m.p. 68°-72° C, was crystallized from ethanol-water (1:3). 3.81 g (80%) of the title compound were obtained as pale yellow crystals, m.p. 70°-72° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:17]1[N:25](S(C2C=CC(C)=CC=2)(=O)=O)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:16][N:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][CH2:5][CH2:4][OH:3])=[CH:15][CH:14]=2)[C:10]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:11]1
Reactant: CCOC(=O)COc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(OCCO)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.4 %

Procedure:
A solution of {1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yloxy}-acetic acid ethyl ester [120 mg, Reference Example 15(b)] in dry tetrahydrofuran (5 mL) was treated with lithium aluminium hydride (1.0M solution in tetrahydrofuran, 50 μl) at 0° C. under a nitrogen atmosphere. The mixture was allowed to warm to ambient temperature, then stirred for 3 hours and then carefully poured into water (75 mL). The mixture was extracted three times with ethyl acetate (25 mL). The combined organic extracts were washed with brine (75 mL), then dried over sodium sulfate and then evaporated to give the title compound (45 mg) as a colourless solid, m.p. 209-210° C. MS: 308 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ncc(Br)cc2N)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a stirred mixture of 5-bromo-2-(4-methoxyphenyl)-3-nitropyridine (0.19 g, 0.60 mmol) in EtOAc (10 mL) was added tin(II) chloride dihydrate (0.67 g, 3.00 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 70° C. After 20 h, the reaction was cooled to rt and diluted with ethyl acetate, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The light yellow solid was identified as 5-bromo-2-(4-methoxyphenyl)pyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (1H, d, J=2.0 Hz), 7.57 (2H, d, J=8.8 Hz), 7.35 (1H, d, J=2.0 Hz), 7.01 (2H, d, J=8.8 Hz), 5.36 (2H, s), 3.80 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:22][CH:23]=4)[N:15]=[CH:16][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:21]2[N:20]=[CH:19][C:18]([NH:17][C:14]3[N:15]=[CH:16][C:11]4[S:10][CH:9]=[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:33]([CH:30]6[CH2:32][CH2:31]6)=[O:34])[CH:7]=[CH:6][CH:5]=5)[C:12]=4[N:13]=3)=[CH:23][CH:22]=2)[CH2:25][CH2:26]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)c1
Product: O=C(Nc1cccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)c1)C1CC1
Yield: 91.5 %

Procedure:
N-(3-(2-(6-Morpholinopyridin-3-ylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)cyclopropanecarboxamide (16 mg, 91% yield) was prepared in the same manner as Step 7 of Example 1 using 7-(3-aminophenyl)-N-(6-morpholino pyridin-3-yl)thieno[3,2-d]pyrimidin-2-amine (15 mg, 0.037 mmol) and cyclopropanecarbonyl chloride (5 mg, 0.044 mmol).
Reaction SMILES: OCCNS([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])(=O)=O.ClC1C=CC([NH2:22])=CC=1C1C=CC=CN=1>>[C:11]([NH2:22])(=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:8][CH:9]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)NCCO)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: NC(=O)c1ccccc1

Procedure:
Procedure G was used to couple 3-(2-hydroxyethylsulfamoyl)benzoic acid with 4-chloro-3-(pyridin-2-yl)aniline (42 mg) to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-[(2-hydroxyethyl)amino]sulfonyl]-benzamide. MS (Q1) 432.0 (M)+.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][C@H:5]1[NH2:15])[CH3:2].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[OH-]>C(Cl)Cl.CCOC(C)=O.CO>[CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][C@H:5]1[NH:15][C:25](=[O:26])[CH2:24][NH:23][C:21](=[O:22])[C:20]1[CH:28]=[CH:29][CH:30]=[C:18]([C:17]([F:16])([F:32])[F:31])[CH:19]=1)[CH3:2]
Reactant: CCO[C@@H]1CN(C2CCOCC2)C[C@H]1N
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of rel-(3R,4R)-4-ethoxy-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine (36 mg, 0.168 mmol) in DCM was added {[3-(trifluoromethyl)benzoyl]amino}acetic acid (41.5 mg, 0.168 mmol), HATU (76.7 mg, 0.202 mmol), HOBt (27.2 mg, 0.202 mmol) and DIPEA (0.044 mL, 0.252 mmol) and was stirred at RT overnight. The resulting crude mixture was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford the title compound (38 mg, 51%) as a white solid. 1H-NMR (CDCl3) δ: 1.17 (t, J=6.9 Hz, 3H), 1.40-1.60 (m, 2H), 1.65-1.82 (m, 2H), 2.22-2.40 (m, 2H), 2.63-2.80 (m, 2H), 3.22-3.51 (m, 4H), 3.63-3.80 (m, 2H), 3.89-4.00 (m, 2H), 4.10-4.20 (m, 2H), 4.24-4.37 (m, 1H), 6.45-6.58 (m, 1H), 7.20-7.30 (m, 1H), 7.56 (t, J=8.1 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.08 (s, 1H). MS m/z: 444 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:27])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: CCOC(=O)c1cc(Br)c(-c2cccc(C#N)c2)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2cccc(C#N)c2)o1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under argon, 1.45 g (4.53 mmol) of the compound from Example 8A are provided in 50 ml of 1,2-dimethoxyethane, and 0.79 g (4.53 mmol) of 3-chloro-5-fluorophenylboronic acid, 4.43 g (13.6 mmol) of cesium carbonate, 0.15 g (0.32 mmol) of dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane and 0.03 g (0.14 mmol) of palladium(II) acetate are added. The mixture is stirred at 50° C. overnight. The mixture is concentrated and the crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 20:1). 1.05 g (43% of theory) of the title compound with a purity of 68% are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CCN(C(C)C)C(C)C.[CH3:22][C:23]1[O:24][C:25]([CH3:31])=[CH:26][C:27]=1[C:28](O)=[O:29].O=P(Cl)(Cl)Cl.NCCNCCN.CCN(C(C1C=CC=C(C)C=1)=O)CC.[OH-]>ClCCCl.CC(N(C)C)=O>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:28]([C:27]2[CH:26]=[C:25]([CH3:31])[O:24][C:23]=2[CH3:22])=[O:29])[CH:11]=1
Reactant: Cc1cc(C(=O)O)c(C)o1
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: NCCNCCN
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)Nc2cc(Cl)ccc2C(=O)O)c(C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 2 mL vial, methyl 2-amino-4-chlorobenzoate (7.4 mg, 40 μmol) was dissolved into a mixture of 655 μL DCE and 120 μL DMA, followed by addition of DIPEA (600 μmol, 15 eq.). 2,5-Dimethylfuran-3-carboxylic acid (16.8 mg, 120 μmol, 3 eq.) and POCl3 (18.2 mg, 120 μmol, 3 eq.) were added. The reaction mixture was capped and stirred at room temperature overnight. Another 700 μL of DCE was added to the reaction mixture along with the following resin bound reagents: a resin bound diethylene triamine (PL-DETA, Polymer Labs, 297 μmol, 7.4 eq.) and a hydroxide ion exchange resin (PL-MP Hydroxide, Polymer Labs, 800 μmol, 20 eq.). The vial was recapped and shaken at room temperature overnight. The resin in the reaction mixture was filtered off, rinsed with 300 μL of MeOH and discarded. The combined filtrates were concentrated down in vacuo. The residue was re-dissolved into 1 mL of DMA and 280 μL of 1M aqueous NaOH. The solution was stirred at room temperature overnight. The desired product was isolated directly from this solution via reverse phase C18 preparative HPLC (water/acetonitrile w/0.1% formic acid, 30%-100% eluant gradient) to yield the final product (2.3 mg, 95% purity). MS (EI) for C14H12ClNO4: 294 (M+H).
Reaction SMILES: Cl.O1CCOCC1.[O:8]=[C:9]1[NH:40][CH2:39][CH2:38][C@@:10]21[N:14](C(OC(C)(C)C)=O)[C@H:13]([C:22]1[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH:25]=[CH:24][N:23]=1)[CH2:12][CH2:11]2>>[F:37][C:34]([F:35])([F:36])[C:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH:25]=[CH:24][N:23]=[C:22]([C@@H:13]3[CH2:12][CH2:11][C@@:10]4([CH2:38][CH2:39][NH:40][C:9]4=[O:8])[NH:14]3)[CH:27]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](c2cc(-c3ccc(C(F)(F)F)cc3)ccn2)CC[C@@]12CCNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NCC[C@@]12CC[C@@H](c1cc(-c3ccc(C(F)(F)F)cc3)ccn1)N2
Reaction time: 16 h
Yield: 96.9 %

Procedure:
4 M HCl in dioxane (3 mL, 12 mmol) was added to tert-butyl (2S,5S)-6-oxo-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate (18 mg, 0.0400 mmol) and the reaction mixture stirred for 16 hours. The mixture was concentrated at reduced pressure and then re-dissolved in methanol. The solution was applied to an SCX column which was eluted with methanol, followed by 0.5 M ammonia in methanol. Basic product containing fractions were combined and concentrated to give (2S,5S)-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one as a colourless oil (14 mg);
Reaction SMILES: ClC(Cl)C(O[CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C>O>[CH:32]1[CH:31]=[CH:30][N+:29]([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[C@H:17]([NH:18][C:19]([CH2:20][C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[O:26])[C:16](=[O:27])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])=[CH:34][CH:33]=1
Reactant: c1ccncc1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Solvent: O
Solvent: CC(=O)O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (0.1 g., 2.15 mmole.) was suspended in water (4 ml.), and pyridine (0.352 ml., 4.3 mmole.) was added. The solution was heated at 50° for 1 hour, acidified to pH 4.5 with acetic acid, and washed with ethyl acetate and finally with petrol. The aqueous solution was freed from dissolved organic solvents and applied to a column comprising (from top to bottom) layers of deactivated neutral alumina (8 ml.), Dowex 1 (AcO-) (20 ml.) and Zeokarb 226 (H+) (5 ml.). Elution with water was carried out until the eluate showed no optical rotation; the total eluate was freeze-dried and the residue triturated with methanol to give a white solid (296 mg.), [α]D23 +48.8° (c 0.8, water), λλmax (water) 238nm (E1cm1% = 351), 255 nm (E1cm1% = 324).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([NH2:8])=[O:7])=[CH:2]1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O>>[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[O:7][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccsc1
Product: ClCc1coc(-c2ccsc2)n1
Yield: 50 %

Procedure:
In substantially the same manner as in Reference Example 47, 3-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3-thienyl)oxazole. The yield was 50%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 91-92° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[C:18]1[CH:17]=[CH:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC2CCNCC2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 4-(4-methoxycarbonyl-phenoxy)-piperidine-1-carboxylic acid t-butyl ester (6 g, 17.89 mmol) in DCM (50 mL) was added TFA (25 mL) and stirring was continued for 1.5 hrs at room temperature. The volatiles were removed in vacuo and the residues was crystallised from diethyl ether affording after filtration and drying 5.92 g (95%) of 4-(piperidin-4-yloxy)-benzoic acid methyl ester as a solid TFA salt.