Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][OH:24].C(P(CCCC)CCCC)CCC.[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1O.C([O-])(O)=O.[Na+]>C1COCC1>[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[O:24][CH2:23][C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(CO)oc2cccc(OCCCNCc3cccnc3)c12
Reactant: Oc1ccc(F)cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(COc2ccc(F)cc2F)oc2cccc(OCCCNCc3cccnc3)c12
Temperature: 25 °C
Yield: 40.1 %

Procedure:
To a solution of the compound in Example 11 (65 mg), tributylphosphine (61 mg) and 2,4-difluorophenol (26 mg) in THF (1 ml) was added bispiperidine azodicarboxyl amide (76 mg) in THF (0.5 ml) at −45° C. under argon atmosphere, and the mixture was slowly warmed up to room temperature over 18 hoursi period. The mixture was poured into sat. NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel (dichloromethane/methanol) to give a yellow oil (35 mg, 40%). ESIMS: m/z 439 (MH+); 1H-NMR (CDCl3): δ 2.07 (2H, tt, J=6.9 Hz, 5.9 Hz, CH2), 2.27 (3H, s, CH3), 2.89 (2H, t, J=6.9 Hz, NCH2), 3.83 (2H, s, NCH2), 4.13 (2H, t, J=5.9 Hz, OCH2), 5.10 (2H, s, OCH2), 6.59 (1H, d, J=7.9 Hz, Ar—H), 6.71-7.23 (6H, m, 6×Ar—H), 7.66 (1H, dd, J=1.7 Hz, 7.9 Hz, Ar—H), 8.49 (1H, d, J=4.9 Hz, Ar—H), 8.56 (1H, s, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:25]1([CH3:33])[CH:30]=[CH:29][CH:28]=[C:27]([Mg]Br)[CH:26]=1>O1CCCC1>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([C:5]([C:27]2[CH:26]=[C:25]([CH3:33])[CH:30]=[CH:29][CH:28]=2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cccc([Mg]Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2cccc(Cl)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloro-2-nitrobenzoic acid (2.5 g, 12.40 mmol) in tetrahydrofuran (50 mL) was treated with oxalyl chloride (1.194 mL, 13.64 mmol) followed by DMF (0.096 mL, 1.240 mmol). The reaction mixture was stirred at room temperature for 2 hrs. After cooling to 0° C., a 1M solution of m-tolylmagnesium bromide (24.81 mL, 24.81 mmol) was added. After 1 hr another portion of m-tolylmagnesium bromide (24.81 mL, 24.81 mmol) was added. After 1 hour, the reaction mixture was partitioned between ethyl acetate (200 mL) and 1N HCl (150 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=ethyl acetate/heptane, REDISEP® SiO2 120 g) to provided Intermediate A-18A (0.700 g, 21%). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J=8.1, 1.1 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.71 (dd, J=7.7, 1.1 Hz, 1H), 7.66-7.54 (m, 3H), 7.52-7.46 (m, 1H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=2)=[CH:5][C:4]=1[NH2:19].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=2)=[CH:5][C:4]=1[NH:19][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1noc(C=Cc2ccc(OC)c(N)c2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1noc(C=Cc2ccc(OC)c(NS(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methoxy-5-[2-(3-propyl-[1,2,4]oxadiazol-5-yl)-vinyl]-phenylamine (compound of Example 8; 0.08 g, 3.08 mmol) was dissolved in dichloromethane (10 mL) followed by addition of pyridine (0.047 mL, 0.60 mmol) and methanesulfonyl chloride (0.034 mL, 0.45 mmol) at room temperature. After stirring for 8 h, dichloromethane was evaporated and the reaction mixture was cooled to room temperature. The crude residue obtained was purified by column chromatography (silica gel, petroleum ether) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:15])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Cl:15]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(CO)c1OC
Solvent: ClCCl
Product: COc1cccc(CCl)c1OC
Yield: 99.4 %

Procedure:
In 30 ml of methylene chloride was dissolved 3.36 g (20 mmol.) of 2,3-dimethoxybenzyl alcohol. Under chilling with ice, to the solution was dropwise added a solution of 1.6 ml (22 mmol.) of thionyl chloride in 5 ml of methylene chloride for 10 min. The mixture was stirred at the same temperature and then placed under reduced pressure to distill off the solvent, to give 3.71 g of 2,3-dimethoxybenzyl chloride as a brown oil, yield 99.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13](=[O:20])[CH2:14][C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[CH:21](OCC)(OCC)[O:22][CH2:23][CH3:24]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13](=[O:20])[C:14](=[CH:21][O:22][CH2:23][CH3:24])[C:15]([CH:17]1[CH2:18][CH2:19]1)=[O:16]
Reactant: CS(=O)(=O)Oc1ccc(C(=O)CC(=O)C2CC2)c(Cl)c1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(OS(C)(=O)=O)cc1Cl)C(=O)C1CC1
Yield: 102 %

Procedure:
A mixture of 1-[2-chloro-4-(methylsulphonyloxy)phenyl]-3-cyclopropylpropan-1.3-dione (4.75 g) and triethyl orthoformate (4.5 g) in acetic anhydride was stirred and heated at reflux for 3 hours. The mixture was cooled and evaporated to dryness. Toluene was added and the mixture as re-evaporated to give 1-[2-chloro-4-(methylsulphonyloxy)phenyI]-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (5.7 g) as a brown oil which was not further purified.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br>CN1C(=O)CCC1.CCOCC>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:12]#[N:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1
Reactant: BrCCOCCBr
Reactant: COc1ccc(CC#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COc1ccc(C2(C#N)CCOCC2)cc1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
A mixture of NaH (3.1 g, 76 mmol) in 100 mL NMP stirred at 0° C., was treated dropwise with the mixture of 2-(4-methoxyphenyl)acetonitrile (4.5 g, 31 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (7.1 g, 31 mmol) in 30 mL ether. The mixture was allowed to warm to room temperature and stirred for 5 hours, M+Na=240. The mixture was carefully quenched with 100 mL H2O, and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5.2 g of the product as a pale yellow oil. MS (m/z)=240 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH2:8].[Cl:14]C1C(Cl)=CC=CC=1O.ClC1C=CC=C(Cl)C=1O>>[Cl:1][C:2]1[C:12]([Cl:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: NCCCOc1c(Cl)cccc1Cl
Reactant: Oc1cccc(Cl)c1Cl
Agent: Oc1c(Cl)cccc1Cl
Product: NCCCOc1cccc(Cl)c1Cl
Yield: 88 %

Procedure:
Intermediate 12 (55 mg, 0.250 mmol, 88% yield) was prepared as a white powder following the procedure described for Intermediate 9 using 2,3-dichlorophenol and 2,6-dichlorophenol as starting materials. LC-MS (ESI) 221 (M+H), RT=1.48 min (Method B).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:12](=O)[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:12]([N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH3:13]
Reactant: C1=CNc2ccccc2C=C1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1C=CC=Cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
To a solution of the secondary benzazepine (0.98 g, 3.9 mmol) from step E above in dichloromethane (50 mL) were added acetaldehyde (0.44 mL, 7.7 mmol), sodium triacetoxyborohydride (1.8 g, 8.3 mmol), acetic acid (0.2 mL), and 3 Å molecular sieves (1.0 g). The reaction solution was stirred at room temperature for 24 h and then it was diluted with dichloromethane, washed with aqueous 1 N sodium carbonate, dried over sodium sulfate and concentrated in vacuo. The crude product obtained was purified by flash column chromatography (dichloromethane to 95:4.5:0.5 dichloromethane/methanol/concentrated ammonium hydroxide) to give the desired N-ethyl benzazepine (0.53 g, 48%) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.34 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.17 (d, J=7.5 Hz, 2H), 6.75 J=2.5 Hz, 1H), 6.68-6.40 (br, 2H), 4.27 (d, J=8.5 Hz, 1H), 3.94 (d, J=13.5 Hz, 1H), 3.81 (d, J=14.5 Hz, 1H), 3.77 (s, 3H), 3.27-3.16 (br, 1H), 3.06-3.01 (m, 1H), 2.55-2.45 (m, 2H), 2.32-2.24 (m, 1H), 2.13-2.04 (br, 1H), 1.11 (t, J=7.0 Hz, 3H); ESI MS m/z 282 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([OH:43])=O)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C([N+:50]([O-])=O)=CC=C(O)C=1.C1CCC(N=C=NC2CCCCC2)CC1.N>CCOC(C)=O.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH2:50])=[O:43])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)O)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(N)=O)cc1
Reaction time: 8 h
Yield: 0.4 %

Procedure:
A solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(2-thiophenesulfonyl)-L-phenylalanyl]-L-lysine (650 mg, 1.0 mmol, example 24) dissolved in EtOAc (10 mL) was treated with p-nitrophenol (139 mg, 1.0 mmol) and DCC (206 mg, 1.0 mmol) and was left in a refrigerator overnight. Afterwards, the precipitate was filtered off through celite and the solvent evaporated. The crude intermediate was used without further purification in the next step. A portion of the intermediate (25 mg, 0.03 mmol) was added to a solution of ammonia in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 2.6 mg, 11% of the desired material.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)(=[O:27])=[O:26])=[O:18])[C:13](O)=[O:14])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C1C[N:41]([P+](Br)(N2CCCC2)N2CCCC2)[CH2:40]C1.F[P-](F)(F)(F)(F)F.CN.C1COCC1>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)(=[O:26])=[O:27])=[O:18])[C:13](=[O:14])[NH:41][CH3:40])=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)O)cc1
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.3 %

Procedure:
To a room temperature solution of (S)-3-(4-isopropoxy-phenyl)-2-{[(S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-propionic acid (319 mg, 0.588 mmol) (prepared according to the method described for the preparation of compound 17e), PyBroP (301 mg, 0.645 mmol), and methylene chloride (8 mL) was added methylamine (3.0 mL of a 2M THF solution) in one portion. The reaction mixture was shaken at room temperature in a sealed vessel for 2.5 h. The reaction mixture was then diluted with methylene chloride, washed with 0.5 N HCl and water successively, dried over MgSO4, filtered, and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate. Homogenous fractions with Rf=0.32 (silica gel, ethyl acetate) material were combined and concentrated to afford 197 mg (60%) of the title compound as a white foam. LC/MS: RT 3.38 min, Area % 100, m/e 556 (M+H). 1H NMR (400 MHz, d6-DMSO) δ8.01 d (J=8 Hz; Tyr NH), 7.99 brd (J=7.5 Hz; H-6 of ArSO2), 7.94 brs (H-2 of ArSO2), 7.84 q (J=4.5 Hz; CONHMe), 7.72 brd (J=8 Hz; H-4 of ArSO2), 7.59 dd (J=8, 7.5 Hz; H-5 of ArSO2), 7.11 m (2H, AA′-part of AA′MM′; H-2/H-6 of C6H4), 6.82 m (2H, MM′-part of AA′MM′; H-3/H-5 of C6H4), 4.56 brd (J=5 Hz; Pip H-2), 4.53 qq (J=6 Hz, 6; OiPr), 4.21 ddd (J=9, 8, 5.5 Hz; Tyr Ha), 3.65 dm (J=12.5; Pip H-6 eq), 3.17 ddd (J=13, 12.5, 3; Pip H-6ax), 2.84 dd (J=13.5, 5.5; Tyr Hb), 2.66 dd (J=13.5, 9; Tyr H′b), 2.53 d (3H, J=4.5; CONHMe), 1.95 brd (J=13.5; Pip H-3 eq), 1.49 dm (J=12.5 Hz; Pip H-Seq), 1.40 m (Pip H-4 eq), 1.36 m (Pip H-3ax), 1.21 d (3H, J=6 Hz; OiPr), 1.19 d (3H, J=6 Hz; OiPr), 1.16 m (Pip H-5ax), 1.06 m (Pip H-4ax).
Reaction SMILES: [CH3:1][N:2]1[CH2:5][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21]C4CCCCO4)=[O:19])[CH:11]=3)[O:6]2)[CH2:3]1.Cl>C(Cl)Cl.CCOCC>[CH3:1][N:2]1[CH2:5][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]([NH:20][OH:21])=[O:19])[CH:11]=3)[O:6]2)[CH2:3]1
Reactant: CN1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CC2(CC(=O)c3cc(/C=C/C(=O)NO)ccc3O2)C1
Yield: 84.3 %

Procedure:
(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (320 mg, 0.86 mmol) in DCM (4 ml) was treated with 1 M HCl in Et2O (4 ml) as described in Example 31, Step C, giving (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (209 mg, hydrochloride salt) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)=[O:6].Cl.[NH2:21][C@H:22]([C:27]([NH2:29])=[O:28])[CH2:23][CH2:24][S:25][CH3:26].C(N(CC)CC)C>CCO>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][C:10]2([NH:29][C:27](=[O:28])[C@H:22]([CH2:23][CH2:24][S:25][CH3:26])[NH:21]2)[CH2:9][CH2:8]1)=[O:6]
Reactant: COc1ccc(C(=O)N2CCC(=O)CC2)c(OC)c1
Reactant: CSCC[C@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(C(=O)N2CCC3(CC2)NC(=O)[C@H](CCSC)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(2,4-dimethoxybenzoyl)piperidin-4-one (1.4 g, 5.1 mmol), (S)-methioninamide hydrochloride (950 mg, 5.1 mmol) and triethylamine (520 mg, 5.1 mmol) in EtOH (40 ml) was heated under reflux for 2.5 h and stirred at RT for a further 16 h. After removal of the solvent, water (25 ml) and CH2Cl2 (25 ml) were added to the residue and it was rendered basic using conc. sodium hydroxide solution. The aqueous phase was extracted with CH2Cl2 (3×20 ml) and the combined organic phases were dried over Na2SO4. After removal of the solvent and drying in vacuo, the product 8-(2,4-dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 1.9 g (95%).
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([OH:13])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([N:17]=[C:18]=[O:19])[CH2:15][CH3:16].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([C:8]1[N:12]([C:18](=[O:19])[NH:17][CH2:14][CH2:15][CH3:16])[C:11](=[O:13])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN=C=O
Reactant: Oc1nc(Cc2ccccc2)no1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCNC(=O)n1c(Cc2ccccc2)noc1=O
Temperature: 0 °C

Procedure:
8.8 parts of 3-benzyl-5-hydroxy-1,2,4-oxadiazole is stirred for 1 hour at room temperature with 4.3 parts of n-propyl isocyanate and 2 parts of triethylamine in 50 parts of dioxane. The reaction mixture is then poured into ice water, and the precipitated solid is suction filtered and recrystallized from alcohol. There is obtained 8.5 parts (65% of theory) of the desired product; m.p.: 74° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(C)=O>CN(C=O)C>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([Br:3])[CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cc(OCc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
NaH (761 mg, 19.83 mmol) was added portion wise to 2-bromo-4-hydroxypyridine (3 g, 17.24 mmol) in DMF (50 mL) at 0° C. under Ar(g). Then the reaction mixture was stirred at it for 10 min after which it was again cooled down at 0° C. and benzyl bromide (2.15 mL, 18.10 mmol) was added. The reaction was stirred at it for 4 h, after which it was poured onto brine (200 mL) and EtOAc (200 mL) was added. The phases were separated and the organic phase was dried over MgSO4, filtered and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 to 80:20) to furnish I as a white solid (2.331 g, 51%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[S:10][C:11](Cl)=[CH:12][C:13]=1[S:14]([N:17]1[CH2:22][C@H:21]2[CH2:23][CH2:24][C@@H:18]1[C@H:19]([C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=1)=[O:26])[CH2:20]2)(=[O:16])=[O:15].[H][H]>[OH-].[Pd+2].[OH-].[C].CO>[CH:35]([O:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:25]([C@H:19]2[C@H:18]3[CH2:24][CH2:23][C@H:21]([CH2:22][N:17]3[S:14]([C:13]3[CH:12]=[CH:11][S:10][CH:9]=3)(=[O:15])=[O:16])[CH2:20]2)=[O:26])=[CH:29][CH:30]=1)([CH3:37])[CH3:36]
Reactant: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(S(=O)(=O)c2cc(Cl)sc2Cl)C3)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(S(=O)(=O)c2ccsc2)C3)cc1

Procedure:
Triethylamine (0.065 mL, 0.42 mmol) and 20% palladium hydroxide-carbon catalyst (8 mg) were added to a methanol (2 mL) solution of the compound (35 mg, 0.0695 mmol) synthesized in Example 25, and the mixture was stirred for 5 hours in a hydrogen (4 atm) atmosphere. The reaction mixture was then celite filtered, and the filtrate was concentrated. The resulting residue was then purified using silica gel column chromatography to obtain the target (9.9 mg, 33%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.[C:19]([NH:21][C:22]([NH2:24])=[NH:23])#[N:20]>C(OCCOCCO)C>[NH2:24][C:22]1[N:21]=[C:19]([NH2:20])[C:11]2[CH2:12][CH:7]([O:6][C:5]3[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=3)[CH2:8][CH2:9][C:10]=2[N:23]=1
Reactant: N#CNC(=N)N
Reactant: O=C1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Solvent: CCOCCOCCO
Product: Nc1nc(N)c2c(n1)CCC(Oc1cccc(C(F)(F)F)c1)C2

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.4 grams (0.013 mole) of 4-(3-trifluoromethylphenoxy)cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2ethoxyethoxy)ethanol, yielding 2,4-diamino-6-(3-trifluoromethylphenoxy)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][CH3:5].[C:6]([C:10]1[N:14]=[C:13]([SH:15])[NH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]>CC[O-].[Na+]>[C:6]([C:10]1[N:14]=[C:13]([S:15][CH2:2][CH2:3][S:4][CH3:5])[NH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CSCCCl
Reactant: CC(C)(C)c1n[nH]c(S)n1
Agent: CC[O-]
Agent: [Na+]
Product: CSCCSc1nc(C(C)(C)C)n[nH]1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
15 g of 2-chloroethyl-methylsulfide are added dropwise to a solution of 15.7 g of 3-tert-butyl-5-mercapto-1,2,4-triazole in ethanolic sodium ethylate (2.3 g of sodium in 300 ml of ethanol). The reaction mixture is stirred for 2 hours at 80° C., then cooled and filtered. The solvent is removed in vacuo and the residue is taken up in 300 ml of chloroform and extracted with 100 ml of water. The solvent is removed by distillation and the crude product is washed with cold petroleum ether, yielding 3-tert-butyl-5-(2-methylthioethylthio)-1,2,4-triazole of the formula ##STR5## with a melting point of 114°-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:20])[N:16]([CH2:18][CH3:19])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:20])[N:16]([CH2:18][CH3:19])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCn1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2C)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-ethyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=439.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23].[Li]CCCC.[C:31]1([C:37]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[C:31]1([C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]([F:14])([F:13])[F:15])[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:5]3[C:22]([F:23])([F:24])[F:25])([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[OH:38])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Reactant: O=C(c1ccccc1)c1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1cccnc1)c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(C(F)(F)F)c2c1
Reaction time: 4 h

Procedure:
A ˜−70° C. solution of 6-bromo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (66.8 mg, 0.159 mmol, Intermediate 8, step c) in THF (0.9 mL) was treated dropwise with n-BuLi (0.12 mL, 1.59 M, 0.191 mmol) via syringe under argon over 1 min. After stirring for less than 1 min, the dark homogeneous solution was treated with a solution of phenyl(pyridin-3-yl)methanone (32.0 mg, 0.175 mmol, Aldrich) in THF (0.6 mL) over 2 min, and the resulting dark amber solution was stirred at ˜−70° C. while the cold bath was allowed to expire over 4 hours. The amber solution was then partitioned with 5 M NH4Cl (2 mL) and EtOAc (5 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by C18 HPLC (20% to 100% CH3CN, with 0.1% TFA throughout) to provide, after lyophilization, the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4) δ 8.87 (s, 1H), 8.78 (d, J=5.38 Hz, 1H), 8.47 (d, J=8.07 Hz, 1H), 8.27-8.39 (m, 2H), 7.92-8.05 (m, 2H), 7.26-7.54 (m, 10H); MS m/e 568.0 [M+H]+.