Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([C:10]2([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)C(C)C)(C)C.[Cl:45][C:46]1[C:54]([S:55]([NH:58][CH3:59])(=[O:57])=[O:56])=[CH:53][CH:52]=[C:51]([Cl:60])[C:47]=1[C:48](O)=[O:49].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:45][C:46]1[C:47]([C:48]([N:13]2[CH2:12][CH2:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14]2)=[O:49])=[C:51]([Cl:60])[CH:52]=[CH:53][C:54]=1[S:55]([NH:58][CH3:59])(=[O:57])=[O:56]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of 1-(8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (100 mg, 0.16 mmol, 1 equiv) and N,N-diisopropylethyl amine (117 μL, 0.66 mmol, 4 equiv) in dimethylformamide (2 mL) was added the mixture of 2,6-dichloro-3-[(methylamino)sulfonyl]benzoic acid 880-1 b. After stirring at RT for several min, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (62 mg, 0.16 mmol, 1 equiv) was added and the reaction was stirred for 18 h. The mixture was partitioned between dichloromethane and satd. aq. NaHCO3. The organic layer was dried and concentrated and the residue was purified by SiO2 flash column chromatography (100% EtOAc→10% 2M NH3 in MeOH in EtOAC) to provide 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide (example 880) as a white solid (25 mg, 22% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([CH2:20][CH2:21][NH2:22])([NH:12]C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:23].C(OCC)C>C(O)(C)C>[ClH:23].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([NH2:12])([CH2:20][CH2:21][NH2:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(CCN)(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)N1CCC(N)(CCN)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.01 g (9.56 mmol) of 4-(2-amino-ethyl)-4-tert-butoxycarbonylamino-piperidine-1-carboxylic acid ethyl ester in 19 ml of isopropanol was added 8 ml of a solution of hydrochloric acid (5.6 N) in isopropanol and the resulting solution was stirred at room temperature for 3 h. The mixture was cooled and diethyl ether was added. The resulting precipitate was filtered. The product was dried to give 2.49 g of pure compound as a white solid.
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.[NH:23]1[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[N:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@@H:9]2[CH2:10][C@H:6]([N:23]3[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[N:24]3)[CH:7]=[CH:8]2)=[C:16]([Cl:20])[N:15]=1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: OCc1cn[nH]c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OCc1cnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture comprising carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AA2) (1.00 g, 2.92 mmol), (1H-pyrazol-4-yl)-methanol (preparation shown below) (0.34 g, 3.50 mmol) and triphenyl phosphine (0.115 g, 0.44 mmol) in deoxygenated THF (10 mL) under an inert atmosphere of argon is treated with tris(dibenzylideneacetone)dipalladium(0) (0.13 g, 0.15 mmol) and stirred at 50° C. for 1 hour. The solvent is removed in vacuo and the crude product is purified by chromatography on silica eluting with MeOH/DCM (1:25) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:6]([OH:8])[CH:7]=1.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[O:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(-n2cccc2)c(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1cccn1-2
Yield: 59.6 %

Procedure:
To 5-methyl-2-pyrrol-1-yl-phenol (6.0 g, 33.6 mmol) in dichloromethane (75 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (6.61 g, 33.6 mmol) then trifluoroacetic acid (3.1 mL, 40.3 mmol) and the mixture was stirred at room temperature for 5.5 hours. The solvent was evaporated and the crude residue was purified by column chromatography utilizing a gradient of 0-100% dichloromethane in hexanes to yield tert-butyl 7′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (7.1 g, 59%). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=8.1 Hz, 1H), 7.12-7.09 (m, 1H), 6.88 (s, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.29 (t, J=3.2 Hz, 1H), 6.00-5.98 (m, 1H), 5.30 (s, 1H), 3.97 (s, 2H), 3.26 (t, J=12.2 Hz, 2H), 2.32 (s, 3H), 2.09-2.01 (m, 2H), 1.87 (dt, J=13.3, 4.9 Hz, 2H), 1.48 (s, 9H). ESI-MS m/z calc. 354.4, found 355.5 (M+1)+; Retention time 2.28 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:12][C:4]1[CH:3]=[C:2]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 82.5 °C
Reaction time: 1.25 h

Procedure:
The compound of example 219 (10 g, 0.044 mol), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (13.16 gm, 0.0528 mole) and Pd(dppf)Cl2:CH2Cl2 (1.07 g, 0.00132 mol) were taken in DMF (250 mL) under an argon atmosphere. To this reaction mixture, degassed 2M solution of Na2CO3 (14 g, 0.132 mol, 66.5 mL) was added. The reaction mixture was stirred at 80-85° C. for 1 to 1.5 h. After completion of the reaction, water was added and the product obtained was extracted with ether. The combined ether layer was washed with brine and dried over anhydrous Na2SO4 or MgSO4. The solvent was evaporated and the product was purified by column (silica gel, 20% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:14][NH2:15].[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38]([NH:15][CH2:14][C:13]3[CH:12]=[C:11]([F:10])[CH:18]=[C:17]([F:19])[CH:16]=3)=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cc(F)cc(F)c1
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1cc(F)cc(F)c1
Yield: 45 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 3,5-difluorobenzylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 45% yield: mp 208-209° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.23 (m, 5H), 6.82 (s, 1H), 6.80 (s, 1H), 6.66 (t, J=8.7 Hz, 1H), 6.24 (t, J=5.7 Hz, 1H), 4.51 (d, J=5.7 Hz, 2H), 4.44 (s, 2H), 4.03 (t, J=8.4 Hz, 2H), 3.43 (t, J=8.4 Hz, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 164.6, 162.6, 161.5, 161.4, 157.4, 155.3, 142.3, 135.4, 128.9, 128.2, 128.0, 116.7, 110.3, 102.8, 47.9, 43.0, 42.0, 41.6, 17.2; MS (ES+) m/z 443.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.ClCCl>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCC(NCc2ccc(Cl)cc2)CC1

Procedure:
1-Methyl-4-piperidone (566 mg, 5.0 mmol) was dissolved in 10 ml methanol and placed in 100 ml flask. 4-Chlorobenzylamine (708 mg, 5.0 mmol) was added. Mixture was stirred and Acetic acid (˜0.75 ml) was added until pH˜5. NaCNBH3 (628 mg, 10 mmol) was slowly added. Gas evolution observed. After magnetic stirring for 16 hrs methanol was partly removed on Rotavapor (40° C.). Dichloromethane, 2M NaOH and water were added until pH˜10. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were dried over MgSO4. Concentration on Rotavapor (40° C.) yielded 1.14 g crude 47AKU-27. TLC (10% methanol in dichloromethane): Rf=0.3. HPLC-MS (Method A): M+=239.1 (MS (%)=96).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[S:13][C:6]=12>C(O)(=O)C.[Fe]>[CH3:17][S:14]([C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:2]=2[F:1])[CH:11]=1)(=[O:15])=[O:16]
Reactant: CS(=O)(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 0.08 h
Yield: 48.4 %

Procedure:
To a solution of 236 (45 mg, 0.122 mmol) in acetic acid (4 mL) at 100° C., was added iron powder (34 mg, 0.611 mmol). The reaction mixture was stirred for 5 minutes, filtered through a celite pad and concentrated under reduced pressure to afford title compound 237 (20 mg, 48% yield, crude) as a yellow oil that was used in the next step without further purification. MS (m/z): 339.0 (M+1).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:35]=[CH:36][CH:37]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[CH:21][C:22]3[N:23]([CH:25]=[C:26]([NH:28]C(=O)C(F)(F)F)[N:27]=3)[CH:24]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[OH-].[Na+].O>C(O)C>[NH2:28][C:26]1[N:27]=[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:35]=[CH:36][CH:37]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:17]=[CH:16][CH:15]=3)=[CH:24][N:23]2[CH:25]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C(F)(F)F)cn4c3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)c1
Temperature: 45 °C
Reaction time: 12 h
Yield: 107.9 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]benzamide (400 mg, 0.788 mmol) in ethanol (4.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at 45° C. for 12 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→80/20), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (0.35 g, quantitative) as a colorless solid.
Reaction SMILES: C1[O:30][C:4]([C@@H:6]2[C@:23]3([CH3:24])[C@H:9]([C@H:10]4[C@H:20]([C@H:21]([NH2:25])[CH2:22]3)[C@:18]3([CH3:19])[C@H:13]([CH2:14][C@H:15]([OH:29])[C@@H:16]([O:26][CH2:27][CH3:28])[CH2:17]3)[CH2:12][CH2:11]4)[CH2:8][CH2:7]2)([CH3:5])OC1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Br[CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43]>C(O)C>[CH2:27]([O:26][C@H:16]1[CH2:17][C@@:18]2([CH3:19])[C@@H:13]([CH2:12][CH2:11][C@@H:10]3[C@@H:20]2[C@H:21]([NH:25][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:22][C@@:23]2([CH3:24])[C@H:9]3[CH2:8][CH2:7][C@@H:6]2[C:4](=[O:30])[CH3:5])[CH2:14][C@@H:15]1[OH:29])[CH3:28]
Reactant: CC(C)CCBr
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N)C[C@]2(C)[C@@H](C4(C)OCCO4)CC[C@@H]32)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](NCCC(C)C)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O

Procedure:
11α-amino-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one 20-ethylene acetal (20 g) in ethanol (200 ml) was stirred with K2CO3 (25 g), NaI (1 g) and 1-bromo-3-methylbutane (50 ml) and the mixture was heated at reflux for 24 h. The excess K2CO3 was removed by filtration and washed with ethanol. The filtrate and washings were acidified with 2M-HCl to pH 2, washed with ether and the ether wash in turn washed with M-HCl and water (x3). The aqueous layers were brought to pH 10 with 2M-NaOH and the resulting suspension was extracted with ether (x2). The ether layers were combined, washed with water (x2), dried and evaporated to leave a froth (18.96 g), which was purified by column chromatography eluted with CHCl3 /MeOH (19:1) and crystallised from acetonitrile to give the title compound (9.211 g), m.p. 110.5°-112° C., [α ]D +56°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:31])[C:28](O)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:31])[C:28]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)O
Reactant: C1COCCN1
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N1CCOCC1
Yield: 26 %

Procedure:
Using the same procedure as in Example 44, (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (400 mg, 0.87 mmol) was reacted with morpholine to give the title compound as a white solid (120 mg, 26%); NMR Spectrum 1.58 (d, 3H), 3.46-3.73 (m, 8H), 5.70 (s, 2H), 5.88 (q, 1H), 7.04-7.12 (m, 3H), 7.29 (d, 1H), 7.34-7.37 (m, 2H), 7.72-7.75 (m, 2H), 7.86 (d, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.54 (s, 1H), 11.13 (br s, 1H); Mass spectrum MH+ 527.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[F:18][C:15]1[C:14]2[N:13]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[N:12]=[CH:11][C:10]=2[C:9]([OH:8])=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(OCc3ccccc3)ccc(F)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ncc2c(O)ccc(F)c21
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 419C (1.25 g) and 5% palladium on carbon (0.35 g) in ethanol (20 mL) was treated with a balloon of hydrogen. The reaction mixture was stirred overnight. The solid was filtered off. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S@](C(C)(C)C)=O)[CH3:9])=[C:4]([F:17])[CH:3]=1.[ClH:18].O1CCOCC1>CO>[ClH:18].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([F:17])[CH:3]=1
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(Br)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](N)c1ccc(Br)cc1F
Reaction time: 4 h

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(4-bromo-2-fluoro-phenyl)-ethyl]-amide (4.02 g, 12.5 mmol) in methanol (25 ml) was added a 4M HCl solution in dioxane (6.24 ml, 25.0 mmol) and the mixture was stirred for 4 h. The reaction mixture was then concentrated and diethyl ether was added. The resulting suspension was stirred for 2 h and then filtered to deliver the title compound as white solid (3.11 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=4)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[Li].O>O.CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=4)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2nc(N3CCCC(NC(=O)c4ccc(C(=O)O)cc4)C3)nc3scnc23)cc1OC
Reaction time: 0.15 h
Yield: 18.7 %

Procedure:
A solution of methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidin-3-ylcarbamoyl)benzoate (250 mg, 0.45 mmol) and LiOH.H2O (191 mg, 4.5 mmol) in 2 mL of water, 12 mL of methanol and 30 mL of THF was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was suspended in 30 mL of THF, then treated with 2N HCl to pH=2. The solvent was evaporated and the residue was dissolved in 50 mL of THF, filtered to remove the salts. The filtrate was evaporated and crude purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 28% acetonitrile/72% water (0.1% TFA V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidin-3-ylcarbamoyl)benzoic acid (45 mg, 18.4%) as a solid. 1H NMR (300 MHz, DMSO): δ 13.20 (brs, 1H), 9.63 (s, 1H), 8.85 (s, 1H), 8.04-7.95 (m, 4H), 7.63 (s, 1H), 7.41-7.32 (m, 2H), 6.88-6.85 (m, 1H), 5.34-5.31 (m, 1H), 4.71-4.52 (m, 2H), 3.70 (s, 3H), 3.67 (s, 3H), 3.04-2.97 (m, 2H), 2.04-1.96 (m, 4H). LC-MS: 535 [M+H]+; 532.9 [M−H]−, tR=1.43 min. HPLC: 99.26% at 214 nm, 99.79% at 254 nm, tR=5.37 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@@H:38]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:39][S:40]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])(=[O:42])=[O:41])[C:34]([F:55])=[CH:33][N:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:55][C:34]1[C:35]([NH:37][C@@H:38]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:39][S:40]([CH2:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])(=[O:42])=[O:41])=[N:36][C:31]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[CH:9]=2)=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)C[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CS(=O)(=O)CC(=O)OC(C)(C)C)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 115 °C

Procedure:
A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.76 g, 1.83 mmol), (S)-tert-Butyl 2-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutyl-sulfonyl)ethanoate, 169a, (0.75 g, 1.83 mmol) and K3PO4 (0.93 g, 4.39 mmol) in 2-methyl THF (10 mL) and water (2 mL) was degassed under a stream of nitrogen for 30 minutes. X-Phos (0.06 g, 0.12 mmol) and Pd2(dba)3 (0.03 g, 0.03 mmol) were added and the reaction mixture was heated at 115° C. in a pressure vial for 2.5 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 1.0 g of the desired product as a foamy solid: LCMS Gradient 60-98% ACN/water, 0.9% formic acid, 7 minutes, C4, Retention Time=2.39 minutes (M+H) 564.34.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:50]/[O:51][CH2:52][C:53](=[O:56])[NH:54][CH3:55])/[C:27]([NH:29][C@@H:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[N:43]([NH2:44])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NC1SC=C(/C(=N/OC)/C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(NC(C)C)N=NN=4)CS[C@H]23)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:50]/[O:51][CH2:52][C:53](=[O:56])[NH:54][CH3:55])/[C:27]([NH:29][C@@H:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[N:43]([NH2:44])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CNC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC(C)C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CNC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(N)n1
Yield: 84.7 %

Procedure:
A solution of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(N-methylcarbamoyl)methoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.1 g, 2.59 mmol) in 80% formic acid (8 ml) was treated in a manner similar to that described in Example 6, (d) to yield pale brown powder of 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-(N-methylcarbamoyl)methoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (1.25 g, 85%).