Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][C:7]([NH:9][C@@H:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:11]([O:13]CC)=[O:12])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[Li+].[OH-].Cl>C1COCC1.CCO>[CH2:1]([O:6][C:7]([NH:9][C@@H:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:11]([OH:13])=[O:12])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCCC[C@H](NC(=O)OCCCC=C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCCCCC[C@H](NC(=O)OCCCC=C)C(=O)O
Yield: 91.7 %

Procedure:
A solution of ethyl (2S)-2-{[(pent-4-en-1-yloxy)carbonyl]amino}non-8-enoate (0.96 g, 3.08 mmol) in THF (20 mL), EtOH (1 mL) and 1 M aqueous LiOH (21.58 mL, 21.58 mmol) was stirred at RT for 2 hours. The reaction mixture was acidified to pH 5 with 1 N aqueous HCl and extracted with ether (3×100 mL). The combined ether layers were washed with water (100 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to give title compound (0.80 g). LRMS (ESI) m/z 284.4 [(M+H)+; calcd for C15H26NO4: 284.2].
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@H:5](COC2C=CN=C(CO)C=2C)[CH2:4][O:3]1.[Na:19].FCC1(CF)O[CH2:26][CH:25]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][S:37]([C:39]3[NH:43][C:42]4[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=4[N:40]=3)=[O:38])[C:31]=2[CH3:48])[CH2:24]O1.O1C2(CCC(CO)CC2)OCC1>>[Na:19].[O:3]1[C:2]2([CH2:18][CH2:26][CH:25]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][S:37]([C:39]4[NH:43][C:42]5[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=5[N:40]=4)=[O:38])[C:31]=3[CH3:48])[CH2:24][CH2:1]2)[O:6][CH2:5][CH2:4]1
Reactant: Cc1c(OC[C@@H]2COC(C)(C)O2)ccnc1CO
Reactant: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: OCC1CCC2(CC1)OCCO2
Agent: [Na]
Product: Cc1c(OCC2CCC3(CC2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (14a) to (14b) of Example 14 and the steps (7d) to (7f) of Example 7 was repeated using the 1,4-dioxaspiro[4.5]dec-8-ylmethanol obtained in the step (82a) above to obtain the title compound (115 mg, the total yield of 5 steps: 7.3%) as a white solid. Note that, in the same process as in the step (14b), after acetic anhydride was added, 2 equivalents of triethylamine relative to pyridine 1-oxide derivative was added to perform the reaction.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:12]=1.C(N(CC)CC)C.[H][H]>[Pd].CO>[N:12]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc2c(n1)CCNCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: c1cnc2c(c1)CCNCC2

Procedure:
Under a hydrogen atmosphere 0.125 g (0.49 mmol) 2-chloro-6,7,8,9-tetrahydro-5H-pyri do[2,3-d]azepine, 30 mg palladium on charcoal (10%) and 0.28 mL triethylamine in 4 mL methanol were hydrogenated at RT under 50 psi hydrogen pressure for 6 h. The catalyst was removed and the filtrate was concentrated to dryness. The residue was used without further purification. Yield: 72 mg (99% of theory). ESI-MS: m/z=149 (M+H)+; Rt(HPLC): 0.52 min (Method J).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:14])[CH2:12][O:11][NH:10][C:9]1=[O:13].[CH3:15][O:16][C:17](=[O:28])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[C:21]([Cl:27])[CH:20]=1>C(#N)C.O1CCOCCOCCOCCOCCOCC1>[Cl:27][C:21]1[CH:20]=[C:19]([NH:18][C:17]([O:16][CH3:15])=[O:28])[CH:24]=[CH:23][C:22]=1[CH2:25][N:10]1[C:9](=[O:13])[C:8]([CH3:14])([CH3:7])[CH2:12][O:11]1
Reactant: CC1(C)CONC1=O
Reactant: COC(=O)Nc1ccc(CBr)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To a stirred suspension of 2.4 grams (0.017 mole) of potassium carbonate and 0.1 gram (0.02 eq.) of 1,4,7,10,13,16-hexaoxacyclooctadecane in 60 ml of acetonitrile, at ambient temperature, was added dropwise a mixture of 2.0 grams (0.017 mole) of 4,4-dimethyl-3-isoxazolidinone and 4.8 grams (0.017 mole) of methyl(4-bromomethyl-3-chlorophenyl)carbamate in 30 ml of acetonitrile. The complete addition required 30 minutes, after which the reaction mixture stirred for 16 hours. The reaction mixture was filtered to collect a solid. The solid was slurried with 300 ml of water and the insoluble material collected by filtration. The filter cake was recrystallized from hexane/ethyl acetate to give 2.4 grams of 2-[2-chloro-4-(methyloxycarbonylamino)phenyl]methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 165°-167° C. (Compound 14)
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl-].[CH:10]([O:23][C:24]([C:26]1[N:31]2[C:32](=[O:48])[CH:33]([NH:34][C:35](=[O:47])[C:36]([C:41]3[N:45]=[C:44]([NH2:46])[S:43][N:42]=3)=[N:37][O:38][CH2:39][CH3:40])[C@H:30]2[S:29][CH2:28][C:27]=1[CH2:49][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.C(OCC)(=O)C>[NH2:46][C:44]1[S:43][N:42]=[C:41]([C:36](=[N:37][O:38][CH2:39][CH3:40])[C:35]([NH:34][CH:33]2[C:32](=[O:48])[N:31]3[C:26]([C:24]([O:23][CH:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:25])=[C:27]([CH:49]=[CH:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)[CH2:28][S:29][C@H:30]23)=[O:47])[N:45]=1
Reactant: O=Cc1cccnc1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1nsc(N)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
Nicotinaldehyde (1.1 g) was added to a solution of {4-benzhydryloxycarbonyl-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-cephem-3-ylmethyl}triphenylphosphonium chloride (syn isomer)(3.0 g) in tetrahydrofuran (30 ml) and water (15 ml) and the solution was adjusted to pH 9.0 with 20% aqueous sodium carbonate. The solution was stirred at ambient temperature for 2 hours under keeping the pH 8.8 to 9.2 with 20% aqueous potassium carbonate. Ethyl acetate and water were added to the resulting solution. The separated organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography using a mixture of acetone and dichloromethane (rate 1:1) as eluent. The eluted fractions were evaporated to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer)(cis-trans mixture)(1.1 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>C(Cl)Cl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)N(C)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 85.4 %

Procedure:
To a solution of 25 mg of amine prepared in Example 11 and 0.05 mL of DIPEA in 0.5 mL of methylene chloride was added 15 mg of dimethylcarbamoyl chloride. After 2 h at 50° C. in a sealed vial, the volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with ethyl acetate to afford 25 mg of title compound. Mass spec (NH3 /CI): 489 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=1[CH2:43]Cl>>[Br:35][C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=1[CH2:43][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: Cc1ccc(CCl)c(Br)c1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)cc2Br)cc1

Procedure:
Analogously to Method D, 1.45 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.80 g of 2-bromo-1-chloromethyl-4-methylbenzene are used to obtain the title compound as a slightly yellowish oil. Rf=0.56 (1:1 EtOAc-heptane); Rt=6.53.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13].[H-].[Na+].[CH3:17]I>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[O:13][CH3:17]
Reactant: CI
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 47.4 %

Procedure:
788 mg (4 mmol) of 2-hydroxy-4-nitro-benzoic acid methyl ester is mixed in 20 ml of absolute dimethylformamide with 177 mg of sodium hydride (60%; 4.4 mmol), and it is heated for 1 hour to 50° C. After cooling to room temperature, it is mixed with 625 mg (4.4 mmol) of methyl iodide and heated for 4 hours to a bath temperature of 80° C. After concentration by evaporation, it is taken up in 50 ml of water and extracted three times with 25 ml each of ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on 5 g of Isolute SI (50 μm) with a gradient from cyclohexane to cyclohexane:ethyl acetate=80:20 as an eluant, and 400 mg (47% of theory) of 2-methoxy-4-nitro-benzoic acid methyl ester is obtained as an oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]=O)[C:9]#[N:10])=[CH:4][CH:3]=1.[CH3:14][NH:15][CH3:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[CH3:14][N:15]([CH3:16])[CH2:12][CH2:11][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: N#CC(CC=O)c1ccc(I)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)CCC(C#N)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4iodophenyl)-4oxobutyronitrile (2.03 g, 7.1 mmol) in ClCH2CH2Cl (50 mL) was added dimethylamine (14.3 mL, 2M in THF, 28.6 mmol, 4 eq) and the mixture was left stirring at room temperature for 1 h. Na(OAc)3BH (6.04 g, 28.6 mmol, 4 eq) was added and the mixture was stirred at room temperature for 16 h. The reaction was quenched by adding aqueous saturated NaHCO3 (50 mL) and the mixture was extracted with EtOAc (50 mL×3). The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (50% EtOAc/hexanes) to give 4dimethylamino-2-(4iodophenyl)-butyronitrile as a dark brown solid, 2.09 g (94%). 1H NMR (300 MHz, CDCl3): δ 7.83 (d, 2H), 7.22 (d, 2H), 4.10 (t, 1H), 2.56 (m, 1H), 2.41 (m, 1H), 2.34 (s, 6H), 2.20 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([N:12]([CH:21]([C:25]2[CH:34]=[CH:33][C:28]3OC[CH2:31][O:32][C:27]=3[CH:26]=2)[C:22]([NH2:24])=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:35]C1C(C(O)=S)=NC(C)=NC=1.COC1C=C(C=CC=1)C=O>>[CH3:35][C:2]1[C:3]([C:10]([N:12]([CH:21]([C:25]2[CH:34]=[CH:33][CH:28]=[C:27]([O:32][CH3:31])[CH:26]=2)[C:22]([NH2:24])=[O:23])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: Cc1ncc(C)c(C(O)=S)n1
Reactant: CSc1ncc(Cl)c(C(=O)N(Cc2ccc(C)cc2)C(C(N)=O)c2ccc3c(c2)OCCO3)n1
Agent: COc1cccc(C=O)c1
Product: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(SC)ncc2C)c1

Procedure:
This was prepared in the same manner as the product from example 242 using 5-methyl-2-methylthiopyrimidine-4-carboxylic acid (preparation 17) and 3-methoxybenzaldehyde as the acid and aldehyde components to give the title compound as a solid, 0.97 g, (72%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:4]=[C:3]([CH3:5])[CH:2]([CH2:11][CH:10]=[CH2:9])[C:1]([O:7][CH3:8])=[O:6]
Reactant: C=CCBr
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCC(C(C)=O)C(=O)OC
Yield: 56.3 %

Procedure:
A mixture of methyl acetoacetate (11.6 g, 100 mmol), allyl bromide (12.1 g, 100 mmol) and potassium carbonate (13.8 g, 100 mmol) in acetone (70 mL) is heated under reflux for 18 hours. The mixture is filtered and the filtrate is evaporated. The residue is chromatographed on silica gel (15:1 hexane:ethyl acetate) to give methyl 3-oxo-2-(1-propen-3-yl)butanoate (8.8 g, 47%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 2.22 (s, 3H), 2.58 (t, 2H), 3.54 (t, 1H), 3.72 (s, 3H), 4.90-5.12(m, 2H), 5.60-5.82 (m, 1H).
Reaction SMILES: N[C@H](C(O)=O)CC1C=CC=CC=1.[N+:13]([C:16]1[CH:27]=[CH:26][C:19]([CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:18][CH:17]=1)([O-])=O.[H][H]>[Na].[Pd]>[NH2:13][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:26][CH:27]=1
Reactant: [H][H]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Pd]
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na]
Product: Nc1ccc(C[C@H](N)C(=O)O)cc1
Temperature: 5 °C

Procedure:
L-Phenylalanine was converted to 4-nitro-L-phenylalanine by a conventional nitration process known in the art. Thereafter, about 100 g of 4-nitro-L-phenylalanine was dissolved in about 600 mL of about 3.5% methanolic sodium hydroxyide solution and hydrogenated by hydrogen gas at a pressure of about 45 psi in the presence of a 5% palladium/carbon catalyst with the pH of the solution being about 11. The temperature of the reaction mixture was maintained from about 20° C. to about 40° C. The reaction mixture was periodically monitored for the completion of reaction by use of HPLC analysis. The reaction mixture was then filtered to remove the palladium/carbon catalyst and neutralized to about pH 7 with acetic acid. The neutralized filtrate was cooled to about 5° C., until 4-amino-L-phenylalanine precipitated out. The precipitate was isolated by filtration, washed with methanol and dried. (Weight 76 g, HPLC Purity 98%.)
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[N:12]=[C:11]([C:13]#[N:14])[C:10]([N:15]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16]2)=[CH:9][CH:8]=1)=O.[N:22]1([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[CH:30][CH:29]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CCO>[OH:20][C@H:17]1[CH2:18][CH2:19][N:15]([C:10]2[C:11]([C:13]#[N:14])=[N:12][C:7]([C:5]3[CH:4]=[CH:3][N:37]=[C:35]([NH:34][C:31]4[CH:30]=[CH:29][C:28]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[CH:33][CH:32]=4)[N:36]=3)=[CH:8][CH:9]=2)[CH2:16]1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Reactant: CN(C)/C=C/C(=O)c1ccc(N2CC[C@H](O)C2)c(C#N)n1
Solvent: CCO
Product: N#Cc1nc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)ccc1N1CC[C@H](O)C1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
Compound 66 (150 mg, 0.524 mmol) and N-(4-morpholin-4-yl-phenyl)-guanidine were dissolved in EtOH (4 mL). The mixture was then stirred at 180° C. in the microwave for 30 minutes. The solvent was evaporated in vacuo and the residue diluted with MeOH (50 mL). The solution was heated to 60° C. on a rotary evaporator with swirling. The solution was cooled to rt and the solvent carefully decanted. The process was repeated twice more. The residual solvent was then evaporated in vacuo. The title compound was afforded as a yellow solid (110 mg, 47%); LCMS, Rt=2.58 min (MeOH-FA method), m/z 444 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[CH2:7]([O:14][C:15]1[C:16](Br)=[N:17][CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>CN(C=O)C>[CH2:7]([O:14][C:15]1[C:16]([O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[N:17][CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)CCO
Reactant: Brc1ncccc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ncccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a mixture of N,N-dimethylaminoethanol (4.16 g, 46.7 mmol) and (3-benzyloxy)-2-bromopyridine (from Step 1; 8.22 g, 31.1 mmol) in dry DMF (50 mL) was sodium tert-butoxide (5.98 g, 62.2 mmol) added in one portion. The reaction mixture was stirred at 80° C. for 1.5 h, the solvent was removed under reduced pressure and the oily residue was taken up between CHCl3/water. The aqueous phase was extracted twice with CHCl3 and the combined organic layers were washed once with brine, dried (MgSO4), and concentrated under reduced pressure. This gave 8.4 g (100%) of the title compound as a light brown oil. Purity 95% (HPLC). HRMS m/z calcd for C16H20N2O2 (M)+ 272.1525. found 272.1537.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.N1CCOCC1.C=O.Cl>CO>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: Cl
Solvent: CO
Solvent: C1COCCN1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (0.50 g, 1.1 mmol) is dissolved in 2 mL of methanol, add morpholine (125 mg, 1.4 mmol) and paraformaldehyde (66 mg, 2.2 mmol) in one portion, reflux for 2 h under nitrogen atmosphere. The reaction mixture is added 10 mL of 5% HCl(aq), extract with toluene, the organic extracts are washed with saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum, the residue is purified by column chromatography to obtain (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH3:11][Sn:12](Cl)([CH3:14])[CH3:13].[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([Sn:12]([CH3:14])([CH3:13])[CH3:11])=[CH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2sccc2c1
Reactant: C[Sn](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc2sc([Sn](C)(C)C)cc2c1
Reaction time: 0.5 h

Procedure:
A solution of 7.411 g of 5-methylbenzo[b]thiophene (Maybridge, Chemical Co. Ltd., 11-78) in 35 ml of ether is added dropwise at 0° to a mixture of 40 ml of 1.5N butylithium in hexane and 40 ml of ether. After 30 minutes, a solution of 9.963 g of trimethyltin chloride in 50 ml of ether is also added dropwise at 0°. After stirring for 1 hour at 0°, 50 ml of 5% ammonium chloride solution are added. The product is obtained by extracting with 100 ml and 150 ml of ether. Distillation at 0.15 mbar and 100-106° yields 5-methyl-2-trimethylstannylbenzo[b]thiophene.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.CN1C(=O)N(C)CC1>[CH2:19]([NH:26][C:27]([NH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=C=NCc1ccccc1
Solvent: C1COCCO1
Solvent: CN1CCN(C)C1=O
Product: O=C(NCc1ccccc1)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With the exclusion of moisture, 261 mg (1.00 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) are dissolved in 2.5 ml of dioxane and 1 ml of DMEU; 138 μl (1.1 mmol) of benzyl isocyanate are added and the reaction mixture is stirred at RT overnight. The dioxane is evaporated off from the reaction mixture in a rotary evaporator. The resulting yellow solution is poured into 75 ml of water and the product that precipitates is filtered off. Stirring in boiling ethyl acetate yields 3-(benzylamino-carbonylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100)=9.5; FAB-MS: (M+H)+=394.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[C:44]2[CH:43]=[C:42](B(O)O)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1>O1CCOCC1.C([O-])(O)=O.[Na+].CCOC(C)=O.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:42]2[S:41][C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([F:35])[C:44]=3[CH:43]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc2c(F)cccc2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
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: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3c(F)cccc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (152 mg, 0.305 mmol), 4-fluorobenzo[b]thiophen-2-ylboronic acid (149 mg, 0.762 mmol) and tetrakis(triphenylphosphine)palladium(0) (352 mg, 0.305 mmol) in dioxane and saturated aqueous NaHCO3 (1:1, 5 mL) was heated to 120° C. via microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, and the solvent was removed in vacuo to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(4-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dispersed in TFA and DCM (1:1, 10 mL) and stirred at room temperature for 60 minutes. The mixture was concentrated and the resulting crude material was reconstituted in MeOH/DCM (10.0 mL) and was purified via preparative HPLC eluting with a gradient of 30-50% ACN (0.035% TFA) and H2O (0.05% TFA). The combined fractions were neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (83 mg, 66%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.31-1.48 (m, 2H), 1.55-1.85 (m, 6H), 3.17 (s, 2H), 4.10 (dd, J=6.35, 2.93 Hz, 2H), 4.45 (s, 2H), 6.79 (d, J=6.35 Hz, 1H), 7.19 (dd, J=10.25, 7.81 Hz, 1H), 7.40 (td, J=8.05, 5.37 Hz, 1H), 7.82 (d, J=8.30 Hz, 1H), 8.56 (s, 1H), 9.56 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H20F2N4OS, 415. found, 415.