Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CS(O[CH2:28][CH2:29][C:30]1[CH:34]=[CH:33][S:32][CH:31]=1)(=O)=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:28][CH2:29][C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Reactant: CS(=O)(=O)OCCc1ccsc1
Product: CCOC(=O)N1CCC(c2cn(CCc3ccsc3)c3ccc(OC)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 8.7 g (28.6 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 6.9 g (33.4 mmol) of 2-thiophen-3-yl-ethyl methanesulfonate. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 6.7 g (57% of yield) of 4-[5-methoxy-1-(2-thiophen-3-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])[CH:29]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1N1CCCC1=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1CCCC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 1-(2-(aminomethyl)-5-fluorophenyl)pyrrolidin-2-one, derived from reduction of intermediate 111, 4-fluoro-2-(2-oxopyrrolidin-1-yl)benzonitrile. 1HNMR 400 MHz (MeOD) δ ppm: 7.44 (3H, m), 7.33 (3H, m), 7.11 (1H, dd, J=9.2, 3.0 Hz) 7.03 (1H, m), 5.21 (2H, s), 4.43 (2H, s), 4.08 (2H, t, J=5.0 Hz), 3.98 (2H, t, J=5.0 Hz), 3.85 (2H, t, J=7.1 Hz), 2.58 (2H, t, J=8.0 Hz), 2.23 (2H, m), 1.61 (6H, s). LCMS (M+H)+ m/z 521.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=O)[C:16]#[C:17][CH2:18][O:19][CH3:20])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][NH2:30].O>CCO>[CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[C:17]([CH2:18][O:19][CH3:20])[NH:30][N:29]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COCC#CC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: CCO
Solvent: O
Product: COCc1cc([C@H]2CC[C@H](N(Cc3ccccc3)Cc3ccccc3)CC2)n[nH]1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A stirred solution of 13E (150 mg, 0.399 mmol) in EtOH (2 mL) was treated with hydrazine (0.116 mL, 2.397 mmol), and stirred overnight at 75° C. Upon cooling, water was added, the mixture was stirred for 1 h, the resulting white solid was collected by filtration and air dried to yield 13F (125 mg, 80% yield). MS (ES): m/z=390.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.31 (d, 4H, J=7.0 Hz); 7.18-7.25 (m, 4H); 7.14 (t, 2H, J=7.3 Hz); 5.92 (s, 11H); 4.35 (s, 2H); 3.58 (s, 4H); 3.30 (s, 3H); 2.44-2.55 (m, 2H); 1.89-2.01 (m, 4H); 1.23-1.50 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][NH2:21]>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([NH:20][NH2:21])=[O:11])=[CH:14][CH:15]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)NN)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
1,1-Carbonyldiimidazole (1.60 g, 9.89 mmol) was added to a solution of 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)acetic acid (2.57 g, 9.00 mmol) in CH2Cl2 (22.5 mL, 9.00 mmol), and the mixture was stirred for 30 minutes until gas evolution ceased. Hydrazine (0.367 mL, 11.7 mmol) was then added to this solution, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with CH2Cl2 and washed with NaHCO3 (10%). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by reversed-phase chromatography (Biotage SP4, 40+M, C18, 25% to 100% MeCN/H2O). Fractions containing product were poured into a separatory funnel and extracted with ethyl acetate (3×). The combined organic layers were dried and concentrated to give tert-butyl 1-(4-chlorophenyl)-2-hydrazinyl-2-oxoethylcarbamate as a solid (1.95 g, 72%). LCMS (APCI+) M+H+: 299 (5%); M+H+-Boc: 199 (100%); rt=2.78 minutes. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.30 (s, 4H), 5.85 (d, J=6.6 Hz, 1H), 5.21 (s, 1H), 3.87 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: Cc1cccc(Nc2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(N(c2ccccc2)c2ccccn2)n1
Yield: 80.5 %

Procedure:
To a flask were added 18.4 g of 6-methyl-N-phenylpyridin-2-amine, 15.8 g of 2-bromopyridine, 11.5 g of sodium tert-butoxide, and 250 ml toluene. The mixture was purged thoroughly with nitrogen and 270 mg of 1,1′-bis(diphenylphosphino)ferrocene and 110 mg of palladium acetate were added. The reaction mixture was heated to 90 C for 6 hours, and then cooled to 22 C. After quenching with 100 ml water, the product was extracted with 75 ml ethyl acetate. The product was extracted with 50 ml of 1M hydrochloric acid, and then basified with sodium hydroxide. The mixture was cooled to 5 C, and the crude product was filtered and washed with water. The product was dissolved in 100 ml hot 2-propanol and treated with 0.4 g activated carbon. After hot filtration through a bed of celite, 150 ml of water was added slowly and the mixture was seeded to induce crystallization. After cooling to 5 C, the product was filtered and washed with 50 ml of 33% 2-propanol in water. The product was dried resulting in 21 g of a light tan solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: Nc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A mixture of 9.90 parts of 2-amino-3-nitrobenzoic acid and 32.4 parts of thionyl chloride was stirred for 15 min at reflux temperature under argon. The excess of thionyl chloride was evaporated, yielding 10.8 parts (100%) of 2-amino-3-nitrobenzoyl chloride (interm. 39).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](Cl)(Cl)=[O:13]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]=[C:12]=[O:13]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N=C=O
Temperature: 0 °C
Yield: 88 %

Procedure:
2-Methyl-4-nitroaniline (35.0 g, 230 mmol) was dissolved in ethyl acetate (400 ml) and cooled to 0° C. Phosgene (180 ml, 20% in toluene) was added drop wise over 30 min, precipitation of a white salt followed instantly. After the last addition the temperature was allowed to slowly rise to room temperature, and then the reaction mixture was brought to reflux (˜100° C.). It was refluxed for 2 h 30 min, after which 200 ml of solvent was distilled off before the temperature was lowered to 80° C. and phosgene (140 ml, 20% in toluene) was added drop wise. After the last addition the reaction solution was refluxed for 3 hours, allowed to cool to room temperature and concentrated to dryness. The brown/yellow material was dissolved in diethyl ether (250 ml), filtered and concentrated to give a pale brown powder (36 g, 88%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][N:1]6[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]6)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: NC(=O)C1CCNCC1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: NC(=O)C1CCN(Cc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)CC1

Procedure:
The title compound was prepared from piperidine-4-carboxylic acid amide and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 198-205° C.; LC-MS: 483 (MH+); HPLC RT: 3.56 minutes.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][CH:12]([C:24]2(O)[CH2:27][CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:6][CH2:5]1.CN1CCCN(C(=O)C(C2(O)CCC2)C2C=CC([O:45]C(F)(F)F)=CC=2)CC1>>[ClH:1].[ClH:1].[CH3:3][N:4]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][CH:12]([CH:24]2[CH2:25][CH2:26][CH:27]2[OH:45])[C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=2)[CH2:6][CH2:5]1
Reactant: CN1CCCN(CC(c2ccc(OC(F)(F)F)cc2)C2(O)CCC2)CC1
Reactant: CN1CCCN(C(=O)C(c2ccc(OC(F)(F)F)cc2)C2(O)CCC2)CC1
Agent: Cl
Product: CN1CCCN(CC(c2ccc(OC(F)(F)F)cc2)C2CCC2O)CC1

Procedure:
In an analogous manner to Example 1, step 2 1-{2-(4-methyl-1,4-diazepan-1-yl)-1-[4-(trifluoromethoxy)phenyl]ethyl)cyclobutanol dihydrochloride was prepared from 1-{2-(4-methyl-1,4-diazepan-1-yl)-1-[4-(trifluoromethoxy)phenyl]-2-oxo-ethyl)cyclobutanol.
Reaction SMILES: N[C:2]1[C:11](C)=[C:10]2[C:5]([C:6](C)=[CH:7][C:8](C)(C)[NH:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(=O)CC(OCC)=[O:21]>>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:21]
Reactant: CC1=CC(C)(C)Nc2c1ccc(N)c2C
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: O=c1ccc2ccccc2[nH]1
Yield: 105.4 %

Procedure:
This compound was prepared in a manner similar to that described for Compound 102 (EXAMPLE 2) with 7-amino-1,2-dihydro-2,2,4,8-tetramethylquinoline (100 mg, 0.49 mmol) and ethyl 4,4,4-trifluoroacetoacetate (107 mL, 0.73 mmol, 1.5 equiv), affording 75 mg (47%) of the desired 2-quinolone as a fluorescent-yellow solid. Data for 1,2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono[5,6-f]quinoline: 1H NMR (400 MHz, CDCl3) 9.23 (br s, 1H, CONH), 7.37 (s, 1H, 5-H), 6.67 (s, 1H, 7-H), 5.45 (s, 1H, 3-H), 4.14 [br s, 1H, (CH3)2CNH], 2.12 (s, 3H, 10-CH3), 2.04 (d, 3H, J=1.1 Hz, 4-CH3), 1.37 [s, 6H, 2-(CH3)2].
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1.[C:23](Cl)(=[O:25])[CH3:24]>C(OCC)(=O)C>[C:23]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1)(=[O:25])[CH3:24]
Reactant: Nc1c(C(=O)c2cccc(C(=O)O)c2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)c2cccc(C(=O)O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-(3-carboxybenzoyl)-6-chloroindole (Example 131) and acetyl chloride. m.p.: >290° C. (ethyl acetate) 1H-NMR (DMSO-d6) δ: 11.85 (1H, s), 9.90 (1H, s), 8.39 (1H, br s), 8.20 (1H, d, J=7.7 Hz), 7.77 (1H, d, J=7.7 Hz), 7.65 (1H, d, J=8.8 Hz), 7.54-7.43 (2H, m), 7.09 (1H, dd, J=1.8, 8.4 Hz), 1.67 (3H, s)
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=O.[Cl-].[NH4+]>C1COCC1>[OH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Agent: O=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CCO)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
30.47 ml (30.47 mmol) of 1 M borane-THF complex solution are slowly added dropwise to a solution of 3.6 g (15.24 mmol) of [4-(tert-butoxycarbonyl)phenyl]acetic acid in 100 ml of THF at −10° C. with exclusion of oxygen. The mixture is stirred at 0° C. for 4 hours. Subsequently, ammonium chloride solution is added and the mixture is extracted with diethyl ether. The combined organic phases are washed with sodium chloride solution, dried over sodium sulphate and evaporated. 3.2 g (14.4 mmol, 92% yield) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]2[NH:6][C:7](=[O:32])[C@H:8]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:9]([CH2:12][C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:35]([N:42]=[C:43]=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C>[CH2:35]([NH:42][C:43](=[O:44])[NH:1][C:2]1[CH:34]=[CH:33][C:5]2[NH:6][C:7](=[O:32])[C@H:8]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:9]([CH2:12][C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)NC(CC(=O)O)c1ccccc1)[C@@H](CCC(=O)O)C(=O)N2
Solvent: CN(C)C=O
Product: O=C(O)CC[C@H]1C(=O)Nc2ccc(NC(=O)NCc3ccccc3)cc2C(=O)N1CC(=O)NC(CC(=O)O)c1ccccc1
Temperature: 45 °C

Procedure:
To a solution of 3-(R,S)-{2-[7-amino-3-(S)-(2-carboxy-ethyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid (0.15 mmol, 70 mg) in DMF (2.5 ml) was added benzylisocyanate (46 μl, 037 mmol). The mixture was shaken at 45° C. over night. Then the solution was evaporated and the crude product was purified by RP-HPLC to give 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(2-carboxy-ethyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid (14 mg): MS (ISN) 600 (M−H)−.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]1[CH2:15][N:14]([C:16]2[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[C:13](=[O:26])[NH:12]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[OH:8][CH2:9][CH2:10][C@H:11]1[CH2:15][N:14]([C:16]2[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[C:13](=[O:26])[NH:12]1
Reactant: O=C1N[C@@H](CCOCc2ccccc2)CN1c1ccc(C(F)(F)F)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1N[C@@H](CCO)CN1c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
Palladium hydroxide (120 mg) was added to a solution of (4S)-4-[2-(benzyloxy)ethyl]-1-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-2-one (1.12 g) in methanol (25 mL), the system was purged with hydrogen gas, and the mixture was stirred at room temperature for 3 hr. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate to afford (4S)-4-(2-hydroxyethyl)-1-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-2-one (235 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].F[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].CC(C)([O-])C.[K+].O>CN(C=O)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]([CH:15]=1)[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1
Reactant: Nc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoroaniline (1.813 mL, 18.86 mmol) and 2,4-difluoro-1-nitrobenzene (1.723 mL, 15.71 mmol) in DMF (26.2 mL) was added potassium tert-butoxide (3.53 g, 31.4 mmol) under argon gas. The solution was stirred overnight at rt poured into water and extracted with DCM. The combined organic extracts were purified by column chromatography on a silica gel column using 5 to 10% gradient of EtOAc in hexane as eluent to give an orange solid that was triturated in EtOAc:hexane (1:1) and filtered to give 5-fluoro-N-(3-fluorophenyl)-2-nitroaniline as an orange solid: LC-MS (ESI), m/z 251.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][CH2:6][CH:7](O)[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25]1(=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[NH:26]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][CH2:6][CH:7]([N:26]1[C:27](=[O:34])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]1=[O:35])[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(NCC(O)COc1ccc(F)c(F)c1)OCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C(NCC(COc1ccc(F)c(F)c1)N1C(=O)c2ccccc2C1=O)OCc1ccccc1

Procedure:
2.2 g of rac-benzyl [3-(3,4-difluorophenoxy)-2-hydroxypropyl]carbamate (Example 135A, 6.5 mmol, 1 equivalent) were reacted with 1.2 g of 1H-isoindole-1,3(2H)-dione (phthalimide, 7.8 mmol, 1.2 equivalents) and worked up analogously to Example 137A. This gave 1.78 g (54% of theory; purity 93%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:53]([C:56]1[CH:66]=[CH:65][C:59]([CH2:60][O:61][C:62](Cl)=[O:63])=[CH:58][CH:57]=1)([O-:55])=[O:54]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][C@H:13]2[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:62]([O:61][CH2:60][C:59]3[CH:58]=[CH:57][C:56]([N+:53]([O-:55])=[O:54])=[CH:66][CH:65]=3)=[O:63])[CH2:40][CH2:39]2)=[O:11])=[CH:44][CH:45]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(piperazin-1-yl)methyl-4-(triphenylmethylthio)-pyrrolidine (2.51 g) and triethylamine (0.73 ml) in dichloromethane (25 ml) was added 4-nitrobenzyloxycarbonyl chloride (0.91 g) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonyl)-piperazin-1-yl]methyl-4-(triphenylmethylthio)pyrrolidine (2.77 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.C(OC([NH:45][C:46]([CH3:51])([CH3:50])[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:45][C:46]([CH3:51])([CH3:50])[C:47]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1)=[O:48]
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)C(C)(C)N)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 94, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid to give the title compound. LC/MS (M+H)+: 620. Ret. time: 1.35 min. (Condition G); analytical HPLC Ret. time: 6.55 min (Condition Q).
Reaction SMILES: [CH2:1]([O:4][NH:5][CH:6]1[CH2:11][NH:10][C@@H:9]([C:12]([NH2:14])=[O:13])[C:8]([CH:15]2[CH2:17][CH2:16]2)=[CH:7]1)[CH:2]=[CH2:3].[CH2:18]([O:21]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:4][N:5]1[C:18](=[O:21])[N:10]2[CH2:11][C@H:6]1[CH:7]=[C:8]([CH:15]1[CH2:16][CH2:17]1)[C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCONC1C=C(C2CC2)[C@H](C(N)=O)NC1
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Product: C=CCON1C(=O)N2C[C@H]1C=C(C1CC1)[C@H]2C(N)=O

Procedure:
The title compound was prepared from (R)-5-(allyloxyamino)-3-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 244, 0.316 g, 1.33 mmol) following the procedure described for Intermediate 16. The desired product was obtained as a colorless oil (0.261 g, 74%).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].C[OH:8].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]#[CH:19])=[CH:12][CH:11]=1>O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH2:17][C:18]#[CH:19])=[O:8])=[CH:12][CH:11]=1
Reactant: C#CCSc1ccc(C)cc1
Reactant: CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: C#CCS(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In 250 mL of water, was subsequently added and dissolved 68.7 g (321 mmol) of sodium periodate. A methanol solution (250 mL) of 49.6 g (306 mmol) of 4-methyl-1-prop-2-ynylthiobenzene [general formula (XI)] was dropped and stirred at room temperature for 2.5 hours. After 2.5 hours, the mixture was filtered, and the solids were washed with 100 mL of ethyl acetate. The filtrate was vacuum concentrated, and 200 mL of water was added. The resulting mixture was extracted with ethyl acetate (150 mL) three times. The obtained organic layers were washed with 150 mL of water, dried with magnesium sulfate and vacuum concentrated to provide 50.6 g (crude yield 93%) of 4-methyl-1-(prop-2-ynylsulfinyl)benzene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>O1CCOCC1.O>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([O:1][C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: OCCc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Oc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Hydroxyphenyl)ethanol (400 mg, 2.90 mmol) was dissolved in a mixture of 4 ml of dioxane and 4 ml of water, and sodium hydrogencarbonate (2.43 g, 29 mmol) was added followed by acetic anhydride (2.96 g, 29 mmol) with ice cooling. The mixture was stirred overnight at room temperature and then partitioned between 2 N hydrochloric acid and EA. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the crude title compound which was used without further purification.