Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][O:64][C:65]([CH:67]1[CH2:71][CH2:70][CH2:69][NH:68]1)=[O:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][CH:67]1[C:65]([O:64][CH3:63])=[O:66])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: COC(=O)C1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-methoxycarbonyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(c2nc3ccccc3[nH]2)CC1
Temperature: 90 °C
Yield: 13.7 %

Procedure:
A solution of crude 10 g of 4-(2-amino-phenylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester was dissolved in 200 mL glacial AcOH and heated to 90° C. for 1.5 h. The reaction mixture was evaporated to dryness, redissolved in 20 mL MeOH and concentrated in vacuo. Purification by CC with EtOAc/Hept (9:1) to EtOAc yielded 1.3 g of the desired compound as beige solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][P:8]([CH:12]([NH:17]C(OCC1C=CC=CC=1)=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6](=[O:28])[CH2:7][P:8]([CH:12]([NH2:17])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:10][CH3:11])=[O:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)C(CC(C)C)NC(=O)OCc1ccccc1
Solvent: CO
Product: COP(=O)(CC(=O)OC(C)(C)C)C(N)CC(C)C
Yield: 100 %

Procedure:
[1-(Benzyloxycarbonyl)amino-3-methybutyl(methoxy)phosphinyl]acetic acid tert-butyl ester, prepared by the literature procedure: Bartlett, P. A.; Kezer, W. B.; J. Am. Chem. Soc. , 106, 4282 (1984), (357 mg, 0.86 mmol) was dissolved in MeOH (11 mL) and hydrogenolyzed under H2 using 10% Pd/C (84 mg) for approximately one hour. The catalyst was removed by filtration and the solvent removed under reduced pressure to give the title product as an oil (230 mg, 100%). The 300 MHz 1H NMR spectrum was found to be consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[H-].[Na+].I[CH3:27].O>CN(C)C=O>[CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]([CH3:27])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CI
Reactant: CCON=C(C)c1ccc(S(=O)(=O)NCc2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCON=C(C)c1ccc(S(=O)(=O)N(C)Cc2ccncc2)cc1
Temperature: 22.5 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
0.4 g (1.2 mmol) of the compound from Example 2 was added to a slurry of 0.04 g (1.32 mmol) of NaH (95% pure) in 50 ml of dimethylformamide (DMF), and the mixture was then stirred at 20-25° C. for 10 min. A solution of 0.17 g (1.2 mmol) of iodomethane in 10 ml of DMF was then added dropwise, and the combined reaction solution was stirred at 20-25° C. for about 18 hours, poured into water and then extracted with MtBE. The the organic phases were washed with water and then dried. Removal of the solvent gave 0.3 g of the title compound as a viscous oil.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH3:8])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:9][C:10]1[C:17]([CH3:18])=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[Li+].[Li+]>>[F:9][C:10]1[C:17]([CH3:18])=[C:16]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH3:8])[C@@H:2]2[CH3:1])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: Cc1c(F)ccc(C#N)c1F
Reactant: C[C@@H]1NCC[C@]1(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1c(N2CC[C@](C)(O)[C@@H]2C)ccc(C#N)c1F

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (228 mg), 2,4-difluoro-3-methylbenzonitrile (321 mg) and lithium carbonate (206 mg), the title compound was obtained as a colorless solid (yield: 194 mg, yield: 56%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[Br:9][C:10]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C(Cl)Cl.CC#N>[Br:9][C:10]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]1[N:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: NNc1ccccn1
Reactant: Cc1cccc(C(=O)O)c1Br
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cccc(-c2nnc3ccccn23)c1Br
Temperature: 80 °C

Procedure:
A solution of 2-hydrazinopyridine, 97% (0.254 g, 2.325 mmol), 2-bromo-3-methylbenzoic acid (0.50 g, 2.325 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 1.452 g, 2.79 mmol), and DIEA (0.812 mL, 4.65 mmol) in DCM (6 mL) was stirred at RT until starting material was completely consumed (˜3 h). The mixture was concentrated and chromatographed on silica gel using 0-5% MeOH/DCM to afford a light yellow foam which was dissolved in CH3CN followed by the addition of Lawesson's reagent (0.470 g, 1.163 mmol) and heated at 80° C. for 17 h. The mixture was concentrated and chromatographed on silica gel using 25% EtOAc/hexanes and 0-5% MeOH/DCM to afford a yellow oil as 3-(2-bromo-3-methylphenyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[C:4]([OH:6])=O.C(N(CC)CC)C.[Cl:22][C:23]1[CH:34]=[C:27]2[C:28](OC(=O)[NH:32][C:26]2=[CH:25][CH:24]=1)=[O:29]>C(#N)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[NH:32][C:4](=[O:6])[CH:3]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[NH:2][C:28](=[O:29])[C:27]=2[CH:34]=1
Reactant: NC(Cc1ccccc1Cl)C(=O)O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C1NC(Cc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
2-Amino-3-(2-chlorophenyl)propanoic acid hydrochloride (3.0 g, 12.7 mmol) was suspended in acetonitrile (50 mL) and water (5 mL), triethylamine (3.57 mL, 25.4 mmol) was added which caused a precipitate to form and inefficient stirring. Water (10 mL) was added until all solids were dissolved. 5-Chloroisatoic anhydride (2.51 g, 12.7 mmol) was added in portions, waiting until each portion dissolved before adding the next. Successive portions required longer periods of time, up to 15 minutes for the last portions. After the last portion was added, the suspension was sonicated for several minutes then stirred at ambient temperature overnight. The clear solution was concentrated in vacuo then azeotroped twice with acetone. The residue was redissolved in acetic acid (30 mL) and heated to 130° C. for 6 hours. The mixture was concentrated in vacuo to an oil, diluted with ethyl acetate (150 mL), washed with water (3×50 mL) then brine, dried with sodium sulfate, filtered and concentrated to a brown solid. This solid was resuspended in ethyl acetate (20 mL) and hexanes (10 mL) then slurried at ambient temperature for 30 minutes. Filtration provided 7-chloro-3-(2-chlorobenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (2.4 g, 56%). 1H-NMR (300 MHz, DMSO-d6) δ 2.97 (m, 1H), 3.23 (m, 1H), 4.00 (m, 1H), 7.12 (d, 1H, J=8.79 Hz), 7.27 (m, 2H), 7.40 (m, 2H), 7.58 (dd, 1H, J1=8.79 Hz, J2=2.64 Hz), 7.67 (d, 1H, J=2.64 Hz), 8.73 (d, 1H, J=6.15 Hz), 10.59 (s, 1H); ESI m/z 335.0, 337.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:34]1C=C(S(Cl)(=O)=O)C=C[CH:39]=1>>[CH2:34]([O:29][C:28](=[O:30])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:16][CH:17]=2)=[O:22])=[CH:32][CH:31]=1)[CH3:39]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCC3)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCC3)cc1

Procedure:
4-{[1-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=453.2 (M−H), was prepared in analogy to example 57, steps 1 to 6. Step 5 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:42]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:42])[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Br)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
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: [K+]
Solvent: C1COCCO1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (82.5 mg, 0.13 mmol) in 1,4-dioxane (1 mL) was added trimethylboroxin (39 mg, 0.31 mmol), Pd(PPh3)4 (15 mg, 10 mol %) and potassium carbonate (35 mg, 0.25 mmol). The resulting reaction mixture was purged with nitrogen and sealed in a microwave vessel. The vessel was subject to microwave irradiation at 130° C. for 15 min. The crude mixture was diluted with brine and extracted with EtOAc. The combined organic extracts were dried over Na2SO4. The titled compound was obtained as a glassy material after two preparative TLC plates developed respectively by 20% EtOAc in hexanes and dichloromethane. LC-MS: 584.08 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamers δ 7.84 (s, 1 H), 7.65-7.70 (m, 2 H), 7.29 (s, 0.5), 7.18-7.22 (m, 1.5 H), 7.10-7.15 (m, 1 H), 7.01 (d, J=8.0 Hz, 0.5 H), 6.98 (d, J=8.5 Hz, 0.5 H), 6.66 (d, J=5.0 Hz, 0.5 H), 6.64 (d, J=5.5 Hz, 0.5 H), 5.54 (d, J=8.5 Hz, 0.5H), 5.31 (d, J=8.0 Hz, 0.5H), 4.82 (d, J=15.5 Hz, 1 H), 4.02 (d, J=15 Hz, 0.5 H), 3.71-3.82 (m, 5 H), 3.15-3.24 (m, 1 H), 2.42 (s, 1.5 H), 2.41 (s, 1.5 H), 1.13-1.27 (m, 6 H), 0.48 (d, J=6.5 Hz, 1.5 H), 0.31 (d, J=6.5 Hz, 1.5 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH3:11].C[Si](C)(C)[O:14][K].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:10])=[O:14])=[CH:4][C:3]=1[CH3:11]
Reactant: C[Si](C)(C)O[K]
Reactant: Cc1cc(CC#N)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(CC(N)=O)ccc1F
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
4-Fluoro-3-methylphenylacetonitrile (1.1 g) was dissolved in toluene (35 ml), and trimethylsiloxypotassium (3.7 g) was added. After stirring at 110° C. for 2.5 hours, saturated sodium bicarbonate water was added, followed by separation with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain 863 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[C:20]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1)(=[O:22])[CH3:21].C(O)(=O)C>O1CCCC1>[OH:29][CH:28]([C:27]1[CH:30]=[CH:31][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:25][C:26]=1[N+:32]([O-:34])=[O:33])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C#CC(=O)OCC
Reactant: CC(=O)Nc1ccc(C=O)c([N+](=O)[O-])c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#CC(O)c1ccc(NC(C)=O)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
To a solution of diisopropylamine (1.1 ml, 7.70 mmol) in tetrahydrofuran (12 ml) was added, at -78° C. under an argon atmosphere, 1.5 N butyllithium (4.8 ml, 7.22 mmol). The mixture was stirred for 30 min. Ethyl propiolate (0.9 ml, 8.66 mmol) and a solution of 4-acetylamino-2-nitrobenzaldehyde (1.0 g, 4.81 mmol) in tetrahydrofuran (6 ml) were added in that order, and the mixture was further stirred at -78° C. for one hr. A solution of acetic acid (0.9 ml, 14.91 mmol) in tetrahydrofuran (3 ml) was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution, and saturated brine in that order. It was then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(4-acetylamino-2-nitrophenyl)-2-butynoate (1.613 g) as an oil. Ethyl 4-hydroxy-4-(4-acetylamino-2-nitrophenyl)-2-butynoate thus prepared was dissolved in toluene (14 ml), 4-methoxybenzylazide (2.35 g, 14.4 mmol) was added to the solution, and the mixture was stirred at 10° C. for 18 hr. The reaction mixture was cooled to room temperature, and the resultant crystal as a precipitate was collected by suction filtration to give a 3:1 mixture (1.09 g, 48%) of ethyl 4-hydroxy-(4-acetylamino-2-nitrophenyl)methyl-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (a-1) and ethyl 5-hydroxy-(4-acetylamino-2-nitrophenyl)methyl-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (a-2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1.[C:13]([CH2:17][C:18](Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][C:18](=[O:19])[CH2:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([CH3:12])[CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Solvent: O
Solvent: CC#N
Product: Cc1cc(Br)cc([N+](=O)[O-])c1NC(=O)CC(C)(C)C
Temperature: 140 °C
Yield: 88.5 %

Procedure:
4-Bromo-2-methyl-6-nitro-phenylamine (2.22 g) and tert-butylacetyl chloride (1.30 g) were mixed in acetonitrile (3 mL) and heated to 140° C. for 40 minutes in a sealed microwave process vial. Water (5 mL) was added and the product was collected by filtration and washed with water and heptane to furnish 2.80 g (86% yield) of the title compound as a yellow solid. LC-MS (m/z) 329 (MH+); tR=3.07, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.01 (s, 9H), 2.21 (s, 2H), 2.29 (s, 3H), 7.87 (d, 1H), 7.95 (d, 1H), 9.77 (s, 1H).
Reaction SMILES: O1CCCCC1OC1CCCCO1.[NH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH4-].[Na+]>C(O)C>[CH2:24]([NH:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1cccc(O)c1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CCNCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 17.6 g. (79.6 mMol) tetrahydropyran-2-yl ether of 3-(2-aminoethyl)-phenol, 150 ml. ethanol and 8.9 g. (83.5 mMol) benzaldehyde is stirred for 1 hour at ambient temperature, 3.5 g. (92 mMol) sodium borohydride are added thereto at 0° C. with vigorous stirring and the reaction allowed to continue for 1 hour at 0° C. and for 1 hour at ambient temperature. The reaction mixture is then evaporated in a vacuum and the residue mixed with diethyl ether and water. After shaking up, the ethereal phase is separated off, dried with anhydrous sodium sulphate and mixed dropwise with concentrated sulphuric acid. The precipitated sulphate is dissolved in water, some 2N hydrochloric acid is added thereto, followed by heating on a waterbath for 10 minutes and cooling. By the addition of sodium carbonate, the base is liberated. It is extracted with diethyl ether, the ethereal solution is dried with anhydrous sodium sulphate and evaporated. Yield 15.0 g. (83% of theory); m.p. 86°-88° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[Cl:37][CH2:38][C:39](Cl)=[O:40]>O>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]([C:39](=[O:40])[CH2:38][Cl:37])[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:21][CH:22]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCl)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1 g (2.3 mmol) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [compound (A)] is dissolved in 170 ml of abs. DMF under argon. 110 mg (4.6 mmol) of sodium hydride are added, and the mixture is stirred at RT for 20 min. Then 3.5 g (31 mmol) of chloroacetyl chloride are added, keeping the reaction temperature at RT. After 30 min, 25 ml of water are added while cooling, and the mixture is left to stand at RT for two days. The solvent is then removed in vacuo, during which the temperature should not rise above +25° C. The residue is taken up in 500 ml of dichloromethane and extracted five times with 200 ml of water. The organic phase is dried over magnesium sulphate, filtered and concentrated to a volume of about 50 ml. While stirring, 200 ml of diethyl ether are added, and the precipitate (mostly unreacted starting material) is then filtered off. The mother liquor is concentrated and the residue is purified by flash chromatography on silica gel with toluene/ethanol 10:1 as eluent. The appropriate fractions are combined, and the solvent is removed. The residue is lyophilized from dioxane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][CH:22]1[O:27][CH:26]([CH3:28])[CH2:25][N:24]([CH2:29][C:30]([N:33]2[CH:37]=[C:36]([NH2:38])[N:35]=[CH:34]2)([CH3:32])[CH3:31])[CH2:23]1>>[CH3:28][CH:26]1[O:27][CH:22]([CH3:21])[CH2:23][N:24]([CH2:29][C:30]([N:33]2[CH:37]=[C:36]([NH:38][C:15](=[O:17])[CH:14]([NH:13][CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=4)[CH2:8]3)[CH2:18][CH2:19][CH3:20])[N:35]=[CH:34]2)([CH3:32])[CH3:31])[CH2:25]1
Reactant: CC1CN(CC(C)(C)n2cnc(N)c2)CC(C)O1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CC(C)OC(C)C2)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-[2-(2,6-Dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-ylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.1, 19.5, 25.9, 28.2, 28.9, 29.7, 36.6, 38.8, 53.0, 58.9, 61.0, 61.3, 68.5, 72.1, 74.4, 76.9, 77.3, 77.6, 100.8, 101.1, 101.3, 104.7, 110.7, 110.9, 117.9, 131.2, 137.3, 139.8, 159.8, 162.3, 172.3; MS m/z 518.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[C:27]([CH3:32])=[N:28][CH:29]=[N:30][CH:31]=1)=[O:24].[CH3:33][NH2:34].C1COCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:34][CH3:33])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[C:27]([CH3:32])=[N:28][CH:29]=[N:30][CH:31]=1)=[O:24]
Reactant: CN
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cncnc4C)c3)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cncnc4C)c3)c(=O)n(C)c2n1
Yield: 38 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(4-methylpyrimidin-5-yl)urea (300 mg, 0.664 mmol) and 2.0 N methylamine in THF (2.3 mL, 4.53 mmol) were combined to afford 1-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(4-methylpyrimidin-5-yl)urea (75 mg, 38% yield). 1H NMR (300 MHz, DMSO-d6), δ 2.45 (s, 3H), 2.88 (s, 3 H), 3.50-3.57 (m, 3 H), 7.23-7.29 (m, 2 H), 7.67-7.79 (m, 1 H), 7.82 (s, 1 H), 8.39-8.42 (m, 1 H), 8.60 (s, 3 H), 8.68 (s, 2 H), 9.13 (m, 1 H); MS (ESI) m/z: 435.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+].[CH2:37]=O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH3:37])[CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O

Procedure:
(Method C) 4-(6-Chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone (90 mg) was dissolved in a 37% aqueous solution of formaldehyde (2.9 ml) and formic acid (1.4 ml) and refluxed for 15 hours. The reaction mixture was cooled, made alkaline by adding a 1N aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and concentrated. The residue obtained was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (38 mg) as colorless crystals.