Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([C:7]1[CH:8]=[C:9]2[S:15](=[O:17])(=[O:16])[NH:14][C:13](=[O:18])[N:10]2[CH2:11][CH:12]=1)S(C)(=O)=O.[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1>ClCCl>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([O:28][CH3:29])[N:21]=[C:20]([NH:19][C:13](=[O:18])[NH:14][S:15]([C:9]2[C:8]([N:14]([CH3:13])[S:15]([CH3:9])(=[O:17])=[O:16])=[CH:7][CH:12]=[CH:11][N:10]=2)(=[O:16])=[O:17])[N:25]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: CN(C1=CCN2C(=O)NS(=O)(=O)C2=C1)S(C)(=O)=O
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ncccc2N(C)S(C)(=O)=O)n1

Procedure:
2.9 g (10 mmol) of the compound (II-1) (Example 1) and 1.55 g (10 mmol) of 2-amino-4,6-dimethoxypyrimidine are combined in 30 ml of dichloromethane and refluxed for 8 hours. After the solvent has been removed in vacuo, 4.45 g (100% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-[3-(N-methyl-N-methylsulfonylamino)-2-pyridylsulfonyl]-urea of m.p. 168°-173° C. (decomp.) are obtained in a purity of approx. 90%.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][C:3]=1[CH:7]=[CH:8][C:9]([Cl:11])=[O:10].[OH-].[Na+].[H][H]>[Pd]>[CH3:1][C:2]1[N:6]=[CH:5][NH:4][C:3]=1[CH2:7][CH2:8][C:9]([Cl:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1nc[nH]c1C=CC(=O)Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc[nH]c1CCC(=O)Cl
Temperature: 80 °C
Reaction time: 72 h
Yield: 22.3 %

Procedure:
50 mg of palladium-on-charcoal at 10% are added to 500 mg (2.65 mmol) of 3-(5-methyl-3H-imidazol-4-yl)acrylic acid chloride in 10 ml of a 0.5N solution of sodium hydroxide. The reaction mixture is placed under 6 bar of hydrogen pressure and stirred at 80° C. for 72 hours. After having filtered off the catalyst through celite, the residue is acidified to pH 2 with hydrochloric acid, concentrated to dryness and taken up in ethanol. The insoluble material is filtered off and the filtrate is concentrated to dryness. 102 mg of 3-(5-methyl-3H-imidazol-4-yl)propanoic acid chloride are obtained in the form of a white powder with a yield of 16%.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N[C@@H:17](C(O)=O)CC1C2C(=CC=CC=2)NC=1>>[CH2:17]1[C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3][C@@H:2]([C:13]([OH:15])=[O:14])[NH:1]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1

Procedure:
When L-tryptophan is substituted for D-tryptophan in Example 1E, (3S)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid is obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]([OH:17])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+](=[CH2:22])=[N-]>C1COCC1.CCOCC>[CH3:22][O:16][C:15](=[O:17])[C:14]#[C:13][C:5]1[CH:4]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1
Reactant: O=C(O)C#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The 3-[3,5-bis(trifluoromethyl)phenyl]-propynoic acid was dissolved in a mixture of THF and ether and treated with diazomethane until all acid was methylated. All solvent was removed and the resulting oil was purified by chromatography (10% ether/hexane) to give 30.5 g of 3-[3,5-bis(trifluoromethyl)phenyl]-propynoic acid methyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1)=[O:4].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C1COCC1>[CH3:35][O:34][C:32](=[O:33])[CH2:31][NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CN)cs2)c(C(=O)C2CCCC2)c1
Solvent: C1CCOC1
Product: COC(=O)CNCC(=O)NCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Yield: 36.1 %

Procedure:
{[({2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-carbamoyl)-methyl]-amino)-acetic acid methyl ester (44 mg, 88%) was prepared by treating 2-amino-N-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-acetamide (104 mg, 0.25 mmol) with methyl bromoacetate (0.023 mL, 0.25 mmol) in THF (5 mL) at 60° C. for 2 h followed by column purification [silica, DCM:ethyl acetate (80:20 to 20:80)].
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:17]=[C:16]([C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C>[OH-].[Na+].C(O)C.O>[CH:20]1([C:18]([C:16]2[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=2)[C:4]([OH:23])=[O:3])=[O:19])[CH2:22][CH2:21]1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)C2CC2)c1

Procedure:
Stir the crude 5-cyclopropanecarbonyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (0.38 mmol) in 1 N NaOH (1 mL) and ethanol (1 mL) for 3 h at room temperature. Dilute the mixture with water (5 mL) and wash the aqueous solution with diethyl ether (2×3 mL). Acidify with 1 N HCl (1 mL) and extract with ethyl acetate (3×5 mL). Wash the combined organic layer with saturated aqueous sodium chloride, dry (sodium sulfate) and concentrate to give the title compound as a crude residue which is used in the next step without further purification.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:14](SC)[N:13]=[C:12]([S:25][CH3:26])[N:11]=1.[CH3:27][OH:28]>>[CH3:26][S:25][C:12]1[N:13]=[C:14]([O:28][CH3:27])[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=2[Cl:2])[N:11]=1
Reactant: CO
Reactant: CSc1nc(SC)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Na]
Product: COc1nc(SC)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
To a round bottom flask fitted with a magnetic stir bar and small reflux condenser was added 0.25 mL methanol, sodium metal (23 mg, 1.0 mmol). The flask was flushed with nitrogen. When the sodium dissolved, 2,4-bis(methylthio)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]-pyrimidine (Reference Example 4, 215 mg, 0.5 mmol) in 500 μL methanol was added by syringe. The methanol was removed under high vacuum and 2 mL scrupulously dried DMF (15X sieve and 3A sieve, respectively) added to the mixture. The mixture was stirred for 5 h, quenched in aqueous NH4Cl and immediately extracted with ether. Starting material and product were observed by LC. The organic layer was dried over MgSO4 and filtered. The solvent removed under reduced pressure. Flash column chromatography on silica gel (eluted with 98/2 hexanes/ethyl acetate) gave pure product and mixed starting material/product fraction. The title compound eluted by LC at Rt=4.62 min, m/e=313 (M++1). 1H-NMR 500 MHz (CDCl3): δ 2.64 (s, 3H), 4.05 (s, 3M), 7.08 (d, J=8 Hz, 2H), 7.13 (d, J=8 Hz, 1H), 7.19-7.24 (m, 3H), 7.34 (d, J=2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([OH:26])[C:22]([F:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([C:22]([F:25])=[CH:23][CH:24]=2)[O:26][C@H:29]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6 difluoro-phenol (0.700, 1.59 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.572g, 3.17mmol) and triphenylphosphine (0.831g, 3.17 mmol) in dry benzene (10 mL) was added diethylazodicarboxylate (0.50 mL, 3.17 mmol) dropwise at room temperature under a dry nitrogen atmosphere. The reaction mixture was sealed in a pressure bottle and immersed in a pre-heated oil bath at 105° C. and heated for 2.5 hours. After stirring at ambient temperature for 14 hours the reaction mixture was diluted with methylene chloride and combined with silica gel. The solvents were removed and the adsorbate was flash chromatographed (90/10 petroleum ether/ethyl acetate) to give (R)-2-[3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-difluoro-phenoxy ]-3-phenyl-propionic acid, methyl ester as an off white solid (0.73g., 76%). To a solution of this methyl ester (0.66g, 1.09 mmol) in tetrahydrofuran (2 mL) and methanol (7 mL) was added a 1 N aqueous solution of potassium hydroxide (1.64mL, 1.64mmol). After stirring for two hours the solvents were removed and the residue was combined with water (50 mL) and acidified with 10% HCl. The solid was extracted into ether and the layers were shaken well together for several minutes before they were separated. The organic layer was washed with water and concentrated to give the title compound as a white solid (0.613 g, 95%): [a]D25 =-13.81 (9.413 mg/mL chloroform); NMR (400 MHz, DMSO-d6): δ13.21 (s, 1H), 8.30 (d, J=8 Hz, 1 H), 8.08 (d, J=8 Hz, 1 H), 7.82 - 7.78 (m, 1 H), 7.62 - 7.41 (m, 4 H), 7.35 - 7.14 (m, 7 H), 6.74 (dd, J=8, 9 Hz, 1 H), 5.17 - 5.11 (m, 1 H), 3.32 - 3.24 (m, 1 H), 3.19 -3.12(m, 1H), NMR indicates that 0.22 mole eq. of benzene is present; MS (+FAB): (M:+): one bromine pattern observed, 588/590 (78%, 75%); Anal. Calc. for C31H19BrF2O3S.0.22 C6 H6: C, 63.99, H, 3.38, N, 0.00. Found: C, 64.52, H, 3.48. N, 0.06.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[CH2:21][C:20](=[O:22])[CH2:19]1>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3([OH:22])[CH2:21][O:18][CH2:19]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: O=C1COC1
Product: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)COC1

Procedure:
Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and oxetan-3-one (CAS: 6704-31-0). Brown solid. MS (m/e): 282.4 ([M+H]+, 100%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([F:36])[N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([F:36])[N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccnc(F)n2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccnc(F)n2)cc1F
Yield: 101.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(2-fluoropyrimidin-4-yl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (648 mg, 0.13 mmol) prepared in Example 24c, triethylsilane (0.11 mL), trifluoroacetic acid (0.13 g) and dichloromethane (1.3 mL), to yield the title compound (0.06 g, 78%) as a colorless solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:32][C:31]=3[O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[N:27][NH:28][CH:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([O:37][CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:32][C:31]=3[O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[N:27][N:28]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)n2)cc1
Reaction time: 18 h
Yield: 74.7 %

Procedure:
Para toluene sulphonyl chloride (180 mg, )0.95 mmol) was added to a stirred solution of 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 0.9 mmol) in dichloromethane (10 ml) and pyridine (0.9 mmol). Stirring was continued for 18 h, then the solution was partitioned between water (20 ml) and ethyl acetate (2×20 ml). The combined organic phases were dried over magnesium sulphate, and concentrated in vacuo to leave a yellow oil. Purfication on silica (20 g) eluting with hexane, followed by hexane:diethyl ether, 1:1, then diethyl ether gave 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (490 mg, 77%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[NH:5][CH:6]=[C:7]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:15]3[C:14](=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13](=[O:21])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(=CNc1cccc(Br)c1)C(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The crude compound from Step 1 was dissolved in tetrahydrofuran (500 mL), the solution was cooled to 0° C., and sodium hydride (as a 60% dispersion in oil, 9.4 g, 235 mmol) was added in portions. After stirring at 0° for 1 hour, the resulting mixture was allowed to warm up to room temperature. After 2 hours, water (400 mL) was added to the resulting suspension and the insoluble solid was filtered and washed copiously with water. When dry, the solid was stirred in ether (150 ML) at room temperature for 24 hours and filtered to afford the ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate compound as a cream-colored solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH2:11]([N:18]=[C:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C=NCc1ccccc1
Product: NC(=O)CC[C@H](NC(=O)NCc1ccccc1)C(=O)O
Yield: 67.9 %

Procedure:
Preparation from L-(+)-glutamine (5.39 g, 36.9 mmol) and benzyl isocyanate (4.96 g, 36.9 mmol) (final pH value after 24 h stirring: 8-9) gave N2-[(benzylamino)carbonyl]-L-glutamine (7.0 g, 68%, white solid).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH3:27])([CH3:26])[CH2:22][NH:23]4)=[CH:19][CH:18]=3)[C:10]2=[O:28])[CH:5]=[CH:4][N:3]=1.[N:29]([CH:32]1[CH2:37][CH2:36][N:35](C(=O)C(F)(F)F)[CH2:34][CH2:33]1)=[C:30]=[O:31]>C1COCC1>[NH:35]1[CH2:36][CH2:37][CH:32]([NH:29][C:30]([N:23]2[C:24]3[C:20](=[CH:19][CH:18]=[C:17]([N:11]4[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]5[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=5)[C:10]4=[O:28])[CH:25]=3)[C:21]([CH3:27])([CH3:26])[CH2:22]2)=[O:31])[CH2:33][CH2:34]1
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccnc(N)n4)C(C)(C)C3=O)ccc21
Reactant: O=C=NC1CCN(C(=O)C(F)(F)F)CC1
Solvent: C1CCOC1
Product: CC1(C)CN(C(=O)NC2CCNCC2)c2cc(N3C(=O)N(Cc4ccnc(N)n4)C(C)(C)C3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
200 mg (0.53 mmol) of 1-(2-aminopyrimidin-4-ylmethyl)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethylimidazolidine-2,4-dione were dissolved in 3 ml of THF, and a solution of 118 mg (0.53 mmol) of 4-isocyanatotrifluoroacetylpiperidine in 3 ml of THF was added. After stirring at RT for 1 h, the mixture is concentrated and taken up in 3 ml of dioxane and 3 ml of 2 N HCl, and the mixture is heated in a microwave at 120° C. for 15 min. For workup, the mixture was concentrated and the remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). After release of the base by treating with sodium hydrogencarbonate solution, 60 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1.[CH3:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][N:31]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:35][C:33]3[S:34][C:30]([CH3:29])=[N:31][N:32]=3)=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Reactant: Cc1nnc(N)s1
Solvent: Cc1ccccc1
Product: Cc1nnc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)c([N+](=O)[O-])c2)s1

Procedure:
A solution of Example 162b (300 mg, 0.6197 mmol) and 5-Methyl-[1,3,4]thiadiazol-2-ylamine (71 mg, 0.6197 mmol) in toluene (10 mL) was reacted as in Example 162c to give the title compound as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Reactant: CCNCc1nccs1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [CH2:1]([N:5]([CH3:15])[C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([N:5]([CH3:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCCCN(C)Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
In a manner analogous to Example 1 a solution of N-butyl -N-methyl -4 -chlorobenzamide (4.49 g; 0.02 mol) in dry THF (50 ml) was reacted wit h an ice-cooled solution of 1.0M diborane-THF complex (90 ml); 0.09 mol) to give the title compound which was converted to the hydrochloride salt and crystallised from ethyl acetate (1.51 g; 65.7%), mp 136°-138°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:28][C:22]1([CH3:29])[CH2:21][CH:20]([NH:19][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:13]([OH:14])=[C:12]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:11]=2)[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23]1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)CC(NC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC(C)(C)N1

Procedure:
To a stirred solution of 25 grams (0.1 mole) of 3,5-di-t-butyl-4-hydroxybenzoic acid and 15.6 grams (0.1 mole) of 4-amino-2,2,6,6-tetramethylpiperidine in 100 milliliters of dry tetrahydrofuran was added dropwise a solution of 20.6 grams (0.1 mole) of dicyclohexylcarbodiimide in 75 milliliters of dry tetrahydrofuran. The mixture was stirred for several hours and the white solid (dicyclohexyl urea) was filtered off and discarded. Evaporation of the filtrate gave a white solid, which was recrystallized from 1:1 benzenehexane to give N-(2,2,6,6-tetramethyl-4-piperidinyl)-3,5-di-t-butyl-4-hydroxybenzamide; melting point 256°-258° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[Li]CCCC.[I:21]I>C1COCC1.CCOC(C)=O>[I:21][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CC(C)Oc1cc(Br)cc(OC(C)C)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(I)cc(OC(C)C)c1
Temperature: -78 °C
Yield: 79.2 %

Procedure:
To a solution of 1-bromo-3,5-bis(propan-2-yloxy)benzene (46) (2.0 g, 7.3 mmol) in THF (100 mL), cooled to −78° C., a 1.6 M n-BuLi solution in hexanes (9.16 mL, 14.7 mmol) was added dropwise. The temperature was maintained at −78° C. for 30 min, after which a solution of iodine (3.17 g, 29.3 mmol) in THF (15 mL) was added dropwise. The mixture was warmed to −35° C. and maintained at this temperature for 1.5 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave 1-iodo-3,5-bis(propan-2-yloxy)benzene (47) (1.85 g, 79%) as a viscous orange oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@@H:50]1COC(=O)[N:51]1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([C:50]#[N:51])=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 69 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 4-(2-piperazin-1-ylpyrimidin-5-yl)benzonitrile, trifluoroacetic acid salt (0.64 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.75 g), to yield the title compound as a white solid (0.70 g, 69%).