Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([O:8]C)=[O:7])[CH2:3][Zn]I.[NH:17](C(OCC1C=CC=CC=1)=O)[CH2:18][CH2:19][C:20](Cl)=[O:21]>>[O:21]=[C:20]([CH2:19][CH2:18][NH2:17])[CH2:3][C@@H:2]([C:6]([OH:8])=[O:7])[NH2:1]
Reactant: COC(=O)[C@H](C[Zn]I)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)CCNC(=O)OCc1ccccc1
Product: NCCC(=O)C[C@H](N)C(=O)O

Procedure:
Boc-L-Ala(ZnI)-OMe is reacted with Z-beta-Ala-Cl under conditions described in J. Org Chem 57, 1992, pp 3397-3404 to give a protected 4-keto-L-lysine which is then dissolved in DCM and treated with DAST to yield protected 4,4-difluoro-L-lysine. The epsilon carbobenzoxy protecting group is then removed under catalytic hydrogenolysis conditions. The resulting compound is reacted with methyl acetimidate hydrochloride to yield the epsilon amidine which was then reacted with 2 N HCl to give the title compound.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[CH2:8]([N:10]1[C:15]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19]([CH3:20])[C:14]=2[CH:13]=[C:12]([C:23]#[N:24])[C:11]1=N)[CH3:9]>>[CH2:8]([N:10]1[C:15]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19]([CH3:20])[C:14]=2[CH:13]=[C:12]([C:23]#[N:24])[C:11]1=[O:3])[CH3:9]
Reactant: CCn1c(=N)c(C#N)cc2c(C)nc(SC)nc21
Reactant: CC(=O)OC(C)=O
Product: CCn1c(=O)c(C#N)cc2c(C)nc(SC)nc21
Temperature: 100 °C

Procedure:
Acetic anhydride (10.0 mL) was added to a flask charged with 8-ethyl-7-imino-4-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.506 g, 1.95 mmol) and heated to 100° C. After one h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The acetylated residue was then treated with 6 N HCl (40 mL) and heated to 95° C. for one hour then transferred to a large flask. A saturated solution of NaHCO3 (500 mL) was added slowly at 0° C. until a ˜pH 8.0 was achieved. The aqueous phase was washed thrice with ethyl acetate (100 mL) and the organic layers combined, then washed with brine and dried over Na2SO4. The drying agent was filtered and concentrated in vacuo to afford crude 8-ethyl-4-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile which was used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[CH2:8][C:9]4([CH2:13][CH2:12][CH2:11]4)[O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:23].C(N(CC)CC)C.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][CH2:38][CH2:39][NH2:40]>CS(C)=O>[NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[CH2:8][C:9]4([CH2:13][CH2:12][CH2:11]4)[O:10][C:5]([C:6]=23)=[C:4]([NH:40][CH2:39][CH2:38][NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)[C:3]=1[F:23]
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3CC1(CCC1)O2
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3CC1(CCC1)O2
Temperature: 0 °C
Yield: 81.7 %

Procedure:
A solution of 8′-amino-9′,10′-difluoro-7′-oxospiro[cyclobutane-1,2′(3′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (200 mg, 0.621 mmol), triethylamine (0.130 mL, 0.933 mmol) and N-2-pyridyl-1,2-ethanediamine (128 mg, 0.933 mmol) in DMSO (4 mL) was stirred at 100° C. for 3 hours. The reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol, and then dried to yield the title compound (223 mg, 82%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.30-1.50 (2H, m), 1.53-1.73 (1H, m), 3.01-3.12 (2H, m), 3.19-3.30 (2H, m), 3.94 (2H, s), 5.65 (1H, brs), 6.01-6.12 (2H, m), 6.29 (1H, t, J=5.5 Hz), 6.43 (2H, brs), 6.90-7.01 (1H, m), 7.52-7.60 (1H, m), 8.13 (1H, s), 14.90 (1H, s). HRESIMS (+):440.17258 (Calcd for C22H23FN5O4, 440.17341).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].C(N(CC)CC)C>ClCCl>[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:3][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:11][CH:10]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26]
Reactant: COC(=O)C(N)c1ccc(OCCN2CCCC2)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a 0° solution of methyl amino{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate dihydrochloride (1.67 g; 4.55 mmol) in dichloromethane (10 mL) was added 4-but-2-ynyloxy-benzenesufonyl chloride followed by triethyl amine was dropped in. The mixture was stirred at room temperature overnight and then diluted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified using column chromatography on silica gel eluting with ethyl acetate to obtain 2.52 g of methyl ({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate as an oil. Yield 92.6%. Electrospray Mass Spec 487.1 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]([CH:34]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]1)([C:11]1[S:12][C:13]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[N:17]=2)=[CH:14][N:15]=1)[CH3:10]>ClCCl>[CH3:22][C:20]1[CH:19]=[C:18]([NH:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][N:25]=2)[N:17]=[C:16]([C:13]2[S:12][C:11]([C:9]([CH:34]3[CH2:38][CH2:37][NH:36][CH2:35]3)([OH:8])[CH3:10])=[N:15][CH:14]=2)[CH:21]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C(C)(O)C3CCN(C(=O)OC(C)(C)C)C3)s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C(C)(O)C3CCNC3)s2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (0.4 mL, 5.19 mmol) was added to a solution of tert-butyl 3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxylate (100 mg, 0.182 mmol) in dichloromethane (0.8 mL). The mixture was stirred at room temperature for 16 hours then concentrated under reduced pressure. The residue was purified on reverse phase HPLC (Sunfire prep C18 OBD 5 uM, acetonitrile/water+0.1% TFA) to afford 1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-1-(pyrrolidin-3-yl)ethanol as a 1:1 mix of diastereomers. MS ESI calc'd. for C21H22F3N5OS [M+H]+ 450. found 450. 1H NMR (500 MHz, CD3OD) δ 8.55 (d, J=5.6 Hz, 1H), 8.37 (d, 11-1, two singlets from two diastereomers), 8.12 (s, 1H), 7.46 (s, 1H), 7.37 (d, J=5.5 Hz, 1H), 7.05 (s, 1H), 3.58-2.95 (m, 5H, two sets of peaks from two diastereomers), 2.45 (s, 3H), 2.30-1.79 (m, 2H, two sets of peaks from two diastereomers), 1.69 (d, 3H, two singlets from two diastereomers). rhSyk activity=+++.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:27]=[C:28]([CH:45]=[C:46]([F:48])[CH:47]=1)[O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[C:46]([F:48])[CH:47]=[C:26]([F:25])[CH:27]=4)=[CH:35][CH:34]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cc(F)cc(F)c3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (400 mg, 0.90 mmol, 1.00 equiv), 2-[4-(3,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (360 mg, 1.08 mmol, 1.20 equiv), sodium carbonate (190 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 80° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 340 mg (72%) of tert-butyl (3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.Cl.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[CH3:26]>>[CH:14]1[C:5]2[CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:3](=[CH:2][C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([NH2:19])[CH:21]=3)[C:4]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(B(O)O)cc1N
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Agent: Cl
Product: Cc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1N
Yield: 74.9 %

Procedure:
Following the procedure essentially as described for Example 219, below, and using 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (300 mg, 1.05 mmol) and (3-amino-4-methylphenyl)boronic acid hydrochloride (217 mg, 1.16 mmol), yields 245 mg (75%) 5-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-2-methyl-phenylamine as a brown oil. Then, following procedures essentially as described in Example 90, below, and using 5-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-2-methyl-phenylamine (100 mg, 0.321 mmol), affords 35 mg (28%) of the title compound as a colorless oil. MS (ES) 407 (M+NH4), 388 (M−H); HPLC shows 98% purity.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:20](O)[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]12[CH2:20][CH:3]([CH2:4][CH2:5]1)[CH:2]=[C:12]2[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CC3CCC2C3)C1
Temperature: 95 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (594 mg, 1.81 mmol), bicyclo[2.2.1]-2-hepten-2-ylboronic acid (250 mg, 1.81 mmol), ethanol (2 ml), 2N aqueous sodium carbonate solution (10 ml), and tetrakis(triphenylphosphine)palladium(0) (253 mg, 0.219 mmol) in toluene (20 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (282 mg, 45.6%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:35]N1C(C)(C)C(=O)N(Br)C1=O>ClC1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][Br:35])[N:17]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1cccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cccc(CBr)n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To 102.8 g (334 mmol) of t-butyl t-butoxycarbonyl-(6-methyl-pyridin-2-yl)-carbamate were added 10.95 g (20 mol %) of 2,2′-azobisisobutyronitrile and 1,330 ml of chlorobenzene. To the resulting mixture was added 95.31 g of 1,3-dibromo-5,5-dimethylhydantoin, and the temperature of the mixture was then raised to 90° C. at a rate of 2° C./minute and held at the temperature for one hour. Subsequently, the reaction mixture was cooled to 20° C., the precipitate was filtered off, and the volume of chlorobenzene was reduced by half by distillation. The thus obtained residue was cooled to 10° C. or lower, and then 46.03 g (43 ml) of diisopropylethylamine and 43.08 g (58 ml) of diethyl phosphite were added thereto, followed by aging the mixture at room temperature for 16.5 hours. Following confirmation by performing thin-layer chromatography that the raw materials had disappeared, the reaction mixture was washed with 300 ml of 3 N hydrochloric acid, and then further washed with 500 ml of a saturated saline solution. The resulting solution was then dried over anhydrous magnesium sulfate and filtered, yielding a solution of 2-bis(t-butoxycarbonyl)amino-6-bromomethyl-pyridine.
Reaction SMILES: [C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[N+:23]([O-])=O)[CH:18]=[O:19])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CO>C1COCC1.[Pd]>[NH2:23][C:22]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[CH2:14][S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12]
Reactant: O=Cc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2cccc3ccccc23)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(C=O)cc1CS(=O)(=O)c1cccc2ccccc12
Yield: 94.9 %

Procedure:
A mixture of 3-(naphthalene-1-sulfonylmethyl)-4-nitro-benzaldehyde (2.5 g, 7.22 mmoles) and 10% Pd/C in THF (10 mL), and methanol (20 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 lb/in2 overnight. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum to afford the title compound as an off-white solid (2.4 g, 6.85 mmoles).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[C:6]2[C:7]([N:9]([C:12]3([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]3=[O:19])[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[H][H]>CC(C)=O.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:23]=[CH:22][CH:21]=[C:6]2[C:7]([N:9]([C:12]3([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]3=[O:19])[C:10](=[O:11])[C:5]=12)=[O:8]
Reactant: [H][H]
Reactant: CC1(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CCC(=O)NC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Temperature: 25 °C
Yield: 82 %

Procedure:
3-(3-Nitrophthalimido)-3-methylpiperidine-2,6-dione (0.5 g, 1.57 mmol) was dissolved in acetone (250 mL) with gentle heat and then cooled to room temperature. To this solution was added 10% Pd/C (0.1 g) under nitrogen. The mixture was hydrogenated in a Parr apparatus at 50 psi of hydrogen for 4 hours. The mixture then was filtered through Celite and the pad washed with acetone (50 mL). The filtrate was concentrated in vacuo to yield a yellow solid. The solid was slurried in ethyl acetate (10 mL) for 30 minutes. The slurry then was filtered and dried (60° C., <1 mm) to afford 0.37 g (82%) of 3-(3-aminophthalimido)-3-methylpiperidine-2,6-dione as a yellow solid: mp 268–269° C.; 1H NMR (DMSO-d6) δ 10.98 (s, 1H), 7.44 (dd, J=7.1 and 7.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.94 (d, J=6.9 Hz, 1H), 6.52 (s, 2H) (m, 3H), 2.08–1.99 (m, 1H), 1.87 (s, 3H); 13C NMR (DMSO-d6) δ 172.48, 172.18, 169.51, 168.06, 146.55, 135.38, 131.80, 121.51, 110.56, 108.30, 58.29, 29.25, 28.63, 21.00; HPLC, Water Nova-Pak/C18 column, 4 micron, 1mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4(aq), 5.62 min (99.18%). Anal. Calcd For C14H13N3O4: C, 58.53; H, 4.56; N, 14.63. Found: C, 58.60; H, 4.41; N, 14.36.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][CH:21]=[C:22]([Cl:24])[CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:14]=1[C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:16]
Reactant: Cn1c(=O)oc(=O)c2ccc(Cl)cc21
Reactant: Oc1n[nH]c2ccccc12
Product: CNc1cc(Cl)ccc1C(=O)n1nc(O)c2ccccc21
Yield: 53.5 %

Procedure:
1H-Indazol-3-ol was reacted with N-methyl-4-chloroisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 53.5% yield; m.p. 209°-211° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:10]=1[C:19]([CH3:23])([CH3:22])[CH:20]=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:11][C:10]=1[C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)CO)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of compound 8 (9.21 g, 0.030 mol) in MeOH (150 mL) was added slowly NaBH4 (2.3 g, 0.061 mol) at 0° C. After the mixture was stirred at 20° C. for 3 hours, 12 mL of 6 N HCl was added, and the mixture was stirred for an additional 30 minutes. The solution was then concentrated to about one-quarter of the original volume and extracted with EtOAc. The organic layer was separated and washed with water and brine, dried with Na2SO4, filtered, and then concentrated in vacuo to afford compound 9 as a white solid. NMR (DMSO-d6; 400 MHz) δ 7.47 (m), δ 7.42 (m), δ 7.34 (m), δ 7.28 (m), δ 7.16 (m), δ 6.94 (m), δ 5.08 (s), δ 4.45 (t), δ 3.64 (d), δ 1.28 (s), δ 1.25 (s).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[C:18]#[C:19][C:20]1[CH:25]=[CH:24][N:23](NC)[CH2:22][N:21]=1.[CH3:28][N:29]1C(=O)CCC1>>[CH3:28][NH:29][C:22]1[N:21]=[C:20]([C:19]2[NH:7][C:8]3[C:9]([CH:18]=2)=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=3)[CH:25]=[CH:24][N:23]=1
Reactant: CN1CCCC1=O
Reactant: CNN1C=CC(C#Cc2cc(C(=O)OC)ccc2N)=NC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CNc1nccc(-c2cc3cc(C(=O)OC)ccc3[nH]2)n1
Reaction time: 24 h

Procedure:
73 mg (0.7 mmol) of potassium tert-butoxide were dissolved in 1 ml of NMP and admixed with a solution of 140 mg (0.5 mmol) of methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)ethynylbenzoate in 1 ml of NMP. Subsequently, stirring was continued at RT for 24 h. Aqueous workup afforded 115 mg of methyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate (HPLC: 92.3 area %).
Reaction SMILES: [O:1]1[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:2]1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH:28]([CH2:31][OH:32])[O:29][CH3:30]>>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH:28]([O:29][CH3:30])[CH2:31][O:32][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCC1=CO1
Reactant: COC(CO)COC1CCCCO1
Product: CCCCCCCCCCCCCCCCC(O)COCC(COC1CCCCO1)OC
Yield: 54.2 %

Procedure:
The above 1,2-epoxyoctadecane (23) (5.5 g, 20.5 mmoles) was reacted with 7.8 g (41 mmoles) of 2-methylglycerol monotetrahydropyranyl ether in the same manner as Example 1-2 to give 5.1 g (55%) of the desired compound (24) as a colorless wax.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].CC(C)([O-])C.[K+].Cl[CH2:18][C:19]([NH2:21])=[O:20]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH2:18][C:19]([NH2:21])=[O:20]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: NC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: NC(=O)COc1ccc(C=O)cc1Cl
Yield: 32.3 %

Procedure:
To a solution of 3-chloro-4-hydroxybenzaldehyde (10 g) in methanol (100 ml) was added 1.0 M potassium t-butoxide (64 ml). To the mixture was added 2-chloroacetamide (5.96 g) and the mixture heated under reflux overnight. The mixture was evaporated to the residue triturated with water (500 ml) and the solid collected to give the subtitle compound (4.4 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:24]/[O:25][CH3:26])/[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][OH:18])[CH2:15][S:16][C@H:11]12)=[O:8].[N-:27]=[C:28]=[O:29].C([O-])(O)=O.[Na+].CCOCC>O1CCOCC1>[CH3:26][O:25]/[N:24]=[C:6](\[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][O:18][C:28]([NH2:27])=[O:29])[CH2:15][S:16][C@H:11]12)=[O:8])/[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=C=O
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.12 h

Procedure:
A solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4carboxylic acid (3.8 g) in dioxan (35 ml) was added to the above isocyanate reagent in one portion and the resulting solution was stirred at ca 22° for 7 minutes. The reaction mixture was poured into 3% aqueous NaHCO3 solution (170 ml) and the pH was adjusted to 5 by the addition of more aqueous NaHCO3 solution. After heating to 40° for 2 hours and allowing to cool to 22° over 14 hours, the reaction mixture was washed (at pH 5.9) with ethyl acetate (2×200 ml), the aqueous layer was separated, layered with ethyl acetate (200 ml), and acidified with concentrated hydrochloric acid to pH 1.9. The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (200 ml). The organic extracts were combined, washed with brine (2×400 ml), dried (MgSO4) and evaporated to give a white solid which, on trituration with ether (100 ml) afforded the title compound (3.18 g, 75% m.p. (MSO2) 175°; [α]D +42° (c 1.02, DMSO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)Cl)=[CH:4][CH:3]=1.[K].[OH:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CN(C)C=O.[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:4][CH:3]=1
Reactant: On1cncn1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: Fc1ccc(C(On2cncn2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg of potassium iodide and 2.9 g of di-(4-fluorophenyl)-chloromethane were added to 1.5 g of the potassium salt of 1-hydroxy-1,2,4-triazole in 100 ml of dimethylformamide and the mixture was stirred for 2 hours at room temperature. The solvent was evaporated off under reduced pressure, after which the residue was taken up with 50 ml of methyl tert-butyl ether and the solution was extracted twice by shaking with water. The organic phase was evaporated down to give 3.3 g of a pale yellow oil, which was chromatographed over a short silica gel column using dichloromethane. The yield was 2.0 g of a pale oil.