Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10](Cl)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:5][CH:4]=1.[C:21]([NH:25][NH2:26])(=O)[CH2:22][CH3:23]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:22]([C:21]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:26][N:25]=1)[CH3:23]
Reactant: CCC(=O)NN
Reactant: COc1ccc(N=C(Cl)c2cccc([N+](=O)[O-])c2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1nnc(-c2cccc([N+](=O)[O-])c2)n1-c1ccc(OC)cc1
Yield: 56.8 %

Procedure:
Using the procedure of Step B of Example 4, 15 g of the product of Step A and 8.8 g of propionic acid hydrazide in 200 ml of toluene and 14 ml of triethylamine were reacted to obtain 9.5 g of 3-ethyl-4-(4-methoxyphenyl)-5-(3-nitrophenyl)-4H-1,2,4-triazole melting at 126° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][CH2:19]O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[B-](F)(F)(F)[F:22].CCN([S+](F)F)CC.C([O-])(O)=O.[Na+]>ClCCl>[F:22][CH2:19][CH2:18][C:17]#[C:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[CH:9]2
Reactant: F[B-](F)(F)F
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Agent: CCN(CC)[S+](F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To a solution of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g, 3.7 mmol; Intermediate 17) in dry dichloromethane (25 mL), was added triethylamine-3HF (1.2 g, 7.4 mmol). XtalFluor-E (1.2 g, 5.5 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜20% EtOAc in petroleum ether) affording the title compound (100 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.88 (s, 1H), 7.73 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 4.60 (dt, 2H), 3.88 (m, 1H), 3.78-3.71 (m, 1H), 2.89 (dt, 2H), 2.48-2.34 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.72 (m, 1H), 1.58 (m, 2H); LCMS: 273 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.S(Cl)(Cl)(=O)=O>C1COCC1>[CH2:2]([O:9][NH:10][S:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1)(=[O:21])=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 107.1 %

Procedure:
O-Benzylhydroxylamine hydrochloride (31.3 mmol, 5.0 g), 4-methoxybenzenesulfonyl chloride (34.5 mmol, 7.12 g) and anhydrous THF (50 mL) were combined under nitrogen. The reaction was cooled to 0° C. and dlisopropylethylamine (69.0 mmol, 12.0 mL) was injected. The reaction was allowed to warm to room temperature and continued to stir for 18 hours. An additional 0.25 equivalents of O-Benzylhydroxylamine hydrogen chloride (7.8 mmol, 1.25 g) and 0.75 equivalents of diisopropylethylamine (23.5 mmol, 4.1 mL) were added to encourage complete conversion of the remaining sulfonyl chloride. The reaction stirred for 4 additional hours at room temperature. The reaction solution was concentrated to a solid and partitioned between ethyl acetate and 1N HCl. The organic layer was dried over magnesium sulfate and concentrated under vacuum to yield 9.83 g (76%) of an off-white colored solid. Rf: 0.2 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.84 (2H,d), 7.34 (5H,s) 7.08 (2H,d), 4.92 (2H,s), 3.88 (3H,s).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC1.C1(=O)C2C(CC=CC=2)CCC1.[Br:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH3:35])([CH3:34])[CH2:28][CH2:29][C:30]2=O)=[CH:25][CH:24]=1.[C:36]1([SH:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:34][C:27]1([CH3:35])[C:26]2[C:31](=[CH:32][C:23]([Br:22])=[CH:24][CH:25]=2)[C:30]([S:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:29][CH2:28]1
Reactant: Sc1ccccc1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1=Cc2ccccc2CC1
Agent: O=C1CCCC2CC=CC=C12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CC=C(Sc2ccccc2)c2cc(Br)ccc21

Procedure:
Reaction Scheme 3 provides further examples for the synthesis of compounds within the scope of Formula 5 where the linking group between the dihydronaphthalene moiety and the Y group is --CH=CH--. In the sequence of reactions described here the oxo function of a starting tetrahydronaphthalene-one moiety is modified before a Heck coupling reaction is performed. Specifically, in the example shown in the reaction scheme, 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) is reacted with thiophenol in the presence of titanium tetrachloride and triethylamine in tetrahydrofuran (THF), to provide the intermediate 4,4-dimethyl-7-bromo-1-phenylthio-3,4-dihydronaphthalene (Compound A35). A similar reaction can be performed with ethanethiol as a reagent instead of thiophenol, to yield 2-bromo-5,6-dihydro-5,5-dimethyl-8-ethylthio-naphthalene (Compound A36) and other analogous compounds which are not shown in the reaction scheme. Compound A35 is reacted in the Heck reaction to yield ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-phenylthio-naphthalenyl)ethenyl] benzoate (Compound A16). Compound A16 is saponified to yield the carboxylic acid, (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl] benzoic acid (Compound A18), and is oxidized with m-chloroperoxybenzoic acid (MCPBA) to provide the corresponding phenylsulfonyl compound, ethyl (E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(phenylsulfonyl)-naphthalenyl)ethenyl]benzo ate (Compound A17). Compound A18 can also be oxidized under similar conditions to provide the free carboxylic acid (or salt thereof) of the phenylsulfonyl compound, (E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-phenylsulfonyl-naphthalenyl)ethenyl]benzoic acid (Compound A19). ##STR18##
Reaction SMILES: [CH2:1]([CH:3]([NH:6][OH:7])[CH2:4][CH3:5])[CH3:2].[O:8]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:7][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:16][CH:17]=1)=[O:23]
Reactant: CCC(CC)NO
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)N(O)C(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A solution of N-(1-ethylpropyl)hydroxylamine (1.13 g, 11 mmole, Compound 39, Part B) in tetrahydrofuran (30 mL) was charged with 4-phenoxyphenylisocyanate (2.1 g, 10 mmole) and maintained at ambient temperature overnight. The solvent was removed in vacuo to yield 3.2 g of the crude product as a white solid. Recrystallization from hexanesethyl acetate provided 1.6 g of the desired product as a white crystalline solid, m.p. 124°-125° C. Analysis: Calculated for: C18H22N2O3 : %C, 68.77; %H, 7.05; %N, 8.91; Found: %C, 68.44; %H, 7.09; %N, 8.82.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:12][CH2:11][O:10][B:9]([OH:13])[C:8]=2[CH:14]=1)([O-])=O.CCN(CC)CC.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1COCC1.CCOC(C)=O.[Pd]>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:4]2[CH:5]=[CH:6][C:7]3[CH2:12][CH2:11][O:10][B:9]([OH:13])[C:8]=3[CH:14]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)B(O)OCC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ccc2c(c1)B(O)OCC2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-nitro-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol (694.6 mg, 3.6 mmol) in THF (70 mL) was passed through H-cube equipped with a 10% Pd/C cartridge. The collected light yellow solution was treated with Et3N (0.6 mL, 4.3 mmol, 1.2 eq.) and divided evenly into 12 portions. To a portion of the solution was added 4-chloro-benzenesulfonyl chloride (63.3 mg, 0.29 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with EtOAc (20 mL), washed with 1N HCl (10 mL), H2O (10 mL), brine (10 mL) and concentrated under reduced pressure. The residue was dissolved in minimal amount of THF and then titrated with heptanes to vive a white suspension. The precipitate was collected by filtration, washed with heptanes to give the title compound as a white solid. LCMS (M/Z): 338 (M+H); 1H NMR (DMSO-d6) δ: 10.17 (s, 1H), 8.39 (s, 1H), 7.65-7.70 (m, 2H), 7.56-7.61 (m, 2H), 7.32 (d, J=1.8 Hz, 1H), 7.02-7.08 (m, 2H), 3.96 (t, J=5.9 Hz, 2H), 2.72 (t, J=5.9 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]1[CH2:18][C:17](=[O:19])[C:16]([C:20](=[O:23])[CH2:21][CH3:22])=[C:15]([OH:24])[CH2:14]1.[Cl-].[Cl-].[Cl-].[Al+3].[C:29](Cl)(=[O:31])[CH3:30].Cl>ClCCCl>[C:29]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:13]2[CH2:18][C:17](=[O:19])[C:16]([C:20](=[O:23])[CH2:21][CH3:22])=[C:15]([OH:24])[CH2:14]2)=[C:2]([CH3:1])[C:11]=1[CH3:12])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c(C)cc3ccccc23)CC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCC(=O)C1=C(O)CC(c2c(C)c(C)c(C(C)=O)c3ccccc23)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(2,3-dimethylnaphth-1-yl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (1.7 g; 5.3 mmol) in 1,2-dichloroethane (5 ml) was added to a suspension of aluminium trichloride (2.2 g; 16.75 mmol) in 1,2-dichloroethane (10 ml) at 0° C. The mixture was stirred at 0° C. for 30 min and a solution of acetyl chloride (0.5 g; 6.36 mmol) in 1,2-dichloroethane (5 ml) was added. After stirring at 0° C. for 30 min and at room temperature for 2 hr, the mixture was poured into a cold aqueous 50% hydrochloric acid solution which was then stirred vigorously for 1 hr. The solution was extracted with dichloromethane and the organic phase was washed with water. The dried (MgSO4) organic fraction was evaporated and the residue was purified by preparative thin-layer chromatography with dichloromethane/ethyl acetate (2:1 v/v) elution to give 5-[4-acetyl-2,3-dimethylnaphth- 1-yl]-3-hydroxy-2-propionylcyclohex-2-en-1-one as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1>CS(C)=O.CCOC(C)=O>[CH3:22][C:21]1[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccnc1F
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cccnc1Oc1ccc(N)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-aminophenol (0.87 g, 8.0 mmol) in DMSO (12 mL) was added cesium carbonate (3.1 g, 9.6 mmol) and 2-fluoro-3-picoline (0.89 g, 8.0 mmol). The resulting mixture was heated to 80° C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide 4-(3-methylpyridin-2-yloxy)benzenamine as tan solid. MS (ESI, pos. ion) m/z: 201.2 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]=2[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(COC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a solution of [1-hydroxy-4-methoxymethyl-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.20 g, 0.56 mmol) in THF (6 mL) and H2O (2 mL) was added LiOH (0.110 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography to give [1-hydroxy-4-methoxymethyl-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.150 g, 81%). 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 9.27 (s, 1H), 8.58 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.40 (s, 1H), 7.26 (s, 1H), 5.60 (s, 1H), 4.50 (m, 2H), 3.30 (s, 3H), 3.10 (m, 1H), 2.17 (m, 1H). MS (ESI) m/z: 329 [M−1]−. HPLC purity: 97.28% (220 nm), 96.84% (Maxplot).
Reaction SMILES: P(Cl)(Cl)(O[P:4]([O-:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O)=O.[ClH:17].[CH2:18]([O:25][C:26](=[O:30])[C@H:27]([CH3:29])[NH2:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CCN(CC)CC>C(Cl)Cl>[Cl:17][P:4]([NH:28][C@H:27]([C:26]([O:25][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:30])[CH3:29])([O:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:14]
Reactant: Cl
Reactant: CCCCCCCOC(=O)[C@H](C)N
Reactant: O=P(Cl)(Cl)OP(=O)([O-])Oc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCOC(=O)[C@H](C)NP(=O)(Cl)Oc1ccc(Cl)cc1

Procedure:
Following the procedure described for Step 1 of Example 1, treatment of a DCM (0.098 M) solution of para-chlorophenyl dichlorodiphosphate with L-alanine n-heptyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colourless oil as a 1:1 mixture of diastereomers.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:23][N:22]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: Nc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(NCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 11.7 %

Procedure:
A mixture of 1.0 g of 1-(3-bromopropyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene and 4.0 g of 2-amino-5-(trifluoromethyl)pyridine was stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and subjected to silica gel chromatography, which afforded 0.14 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(5-(trifluoromethyl)-2-pyridylamino)propyloxy)benzene (12% yield), nD25.0 1.5525.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15].[N+]([O-])([O-])=[O:17].[Na+]>O>[OH:17][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15]
Reactant: Nc1ccc2c(c1)C(=O)CC21CCCC1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CC2(CCCC2)c2ccc(O)cc21
Temperature: 0 °C
Yield: 98.9 %

Procedure:
A mixture of 5'-amino-spiro(cyclopentane-1,1'-indan)-3'-one (20.1 g; 0.1 mole) 2 N sulphoric acid (150 ml) and ice (30 g) is diazotised at about +5° C. with a solution of sodium nitrate (11 g) in water (25 ml). The solution is filtrated and poured in boiling mixture of 100 ml of water and 10 ml of conc. sulphuric acid. The boiling is continued until the development of nitrogen gas ceases, after which the mixture is chilled and the solid, dark brown substance is filtered off. After drying there are obtained 20 g of a crude product, which is recrystallized from trichloroethylene. Yield 12 g of a light powder of mp. 145° C. 4 g of the substance can be recovered from the mother liquid by means of extraction with 2 N sodium hydroxide and subsequent precipitation with 2 N hydrochloric acid.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2
Yield: 93.3 %

Procedure:
A solution of intermediate 6, ethyl 3-benzyloxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (0.236 g, 0.714 mmol) in a mixture of ethyl acetate (60 ml) and ethanol (20 ml) was treated with 1 atm of hydrogen at 25° C. over 10% palladium on activated carbon (0.10 g) for 2.5 h to give 0.160 g (94% yield) of the title compound as white needles; mp 172-174° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ ppm: 1.47 (3H, t, J=7.3 Hz, CH3), 4.08 (4H, m, 2×CH2), 4.54 (2H, q, J=7.3 Hz, OCH2), 4.72 (2H, s, OCH2), 10.75 (1H, s, OH). Anal. Calcd for C10H12N2O5: C, 50.00; H, 5.03; N, 11.66. Found: C, 50.01; H, 4.95; N, 11.54.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:5]=2[NH:4][C:3]1=[O:13].[ClH:14]>CO.CCOC(C)=O.O.[Pd]>[ClH:14].[NH2:12][CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3](=[O:13])[NH:4][C:5]=2[CH:10]=1
Reactant: Cn1c(=O)[nH]c2cc(C#N)ccc21
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1c(=O)[nH]c2cc(CN)ccc21
Temperature: 25 °C
Reaction time: 50 h
Yield: 64 %

Procedure:
The suspension of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (1.84 g, 10.6 mmol) in MeOH (30 ml) and 38% HCl aqueous solution (5.0 ml) was treated with 10% Pd—C (500 mg) and the mixture was stirred for 50 hours at room temperature under hydrogen atmosphere (4.0 kgf/cm2). After the filtration to remove Pd—C, the filtrate was evaporated to give the crude residue, which was dissolved in EtOAc/38% HCl aqueous solution/water (30:1:30). After washing the aqueous phase with EtOAc, water was removed under reduced pressure, followed by recrystallization from DCM-MeOH to furnish the title compound as a dark pink colored solid (1.45 g, 64%). 1H NMR (CDCl3): δ 3.27 (3H, s), 3.99 (2H, m), 6.90 (3H, m), 8.42 (2H, brs), 11.1 (1H, s). MS (ESI) m/z 179 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15]O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[ClH:19].[Cl:19][CH2:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nccc(CO)c2cc1OC
Solvent: c1ccccc1
Product: COc1cc2nccc(CCl)c2cc1OC
Product: Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
(6,7-Dimethoxyquinolin-4-yl)methanol (1.11 g, 5.07 mmol) was dissolved in thionyl chloride (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes then warmed to room temperature and stirred for 3.5 hours. The reaction mixture was diluted with benzene (20 ml) then concentrated under vacuum. The remaining solid was triturated with benzene then dried under high vacuum to afford 1.35 g of 4-(chloromethyl)-6,7-dimethoxyquinoline hydrochloride as a yellow solid. MS (ESI, pos. ion) m/z: 238.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:17][CH2:16][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1C(=O)N1CCOCC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C(c1cc(F)ccc1CBr)N1CCOCC1
Yield: 38.3 %

Procedure:
A mixture of intermediate 41, (5-fluoro-2-methylphenyl)(morpholino)methanone, (2.1 g, 9.5 mmol) and N-bromosuccinimide (2.0 g, 11 mmol) in CCl14 (30 mL) was heated at reflux. To this mixture was added benzoylperoxide (242 mg, 1 mmol) and the mixture heated at reflux for 2 hrs. After cooling, the insoluble materials were filtered and the filtrate purified by column chromatography (SiO2, 0-10% ether in CH2Cl2) to give 1.1 g (Yield 38%) of the title compound as a clear oil: 1H NMR (300 MHz, CDCl3) δ ppm: 3.31 (2H, t, J=4.94 Hz) 3.55-4.02 (6H, m) 4.56 (2H, dd, J=128.81, 9.51 Hz) 6.89 (1H, dd, J=8.23, 2.74 Hz) 6.96-7.12 (1H, m) 7.33-7.49 (1H, m); LC/MS m/z 302 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[C:2]2[NH:1][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2cc(Cl)ccc21
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 38 from 3-amino-5-chloro-2-(3-chlorobenzoyl)-1-ethoxycarbonyl-1H-indole (step 1) and methanesulfonyl chloride.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:30]=[C:31]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C@H:47]([CH2:64][C:65]3[CH:70]=[C:69]([C:71]([F:74])([F:73])[F:72])[C:68]([NH2:75])=[C:67]([Cl:76])[CH:66]=3)[C:48]([N:50]3[CH2:55][CH2:54][CH:53]([N:56]4[CH2:60][CH2:59][CH2:58][C@@H:57]4[C:61]([OH:63])=[O:62])[CH2:52][CH2:51]3)=[O:49])=[O:45])[CH2:40][CH2:39]2)[CH2:36][CH2:35][C:34]2[CH:77]=[CH:78][CH:79]=[CH:80][C:33]=2[NH:32]1.O[CH2:82][C:83]([N:85]([CH3:87])[CH3:86])=[O:84]>CN(C=O)C>[O:30]=[C:31]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C@H:47]([CH2:64][C:65]3[CH:70]=[C:69]([C:71]([F:72])([F:74])[F:73])[C:68]([NH2:75])=[C:67]([Cl:76])[CH:66]=3)[C:48]([N:50]3[CH2:51][CH2:52][CH:53]([N:56]4[CH2:60][CH2:59][CH2:58][C@@H:57]4[C:61]([O:63][CH2:82][C:83](=[O:84])[N:85]([CH3:87])[CH3:86])=[O:62])[CH2:54][CH2:55]3)=[O:49])=[O:45])[CH2:40][CH2:39]2)[CH2:36][CH2:35][C:34]2[CH:77]=[CH:78][CH:79]=[CH:80][C:33]=2[NH:32]1
Reactant: CN(C)C(=O)CO
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@@H]3C(=O)O)CC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)COC(=O)[C@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
25 mg (0.08 mmol) TBTU and 11 μL (0.08 mmol) triethylamine were added to a solution of 50 mg (0.07 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL DMF and stirred for 10 min at RT. 8.1 mg (0.08 mmol) 2-hydroxy-N,N-dimethyl-acetamide were added to the reaction mixture and this was shaken overnight at RT. After filtration through a syringe filter the reaction solution was purified by HPLC without further working up. The fractions containing the product were combined and freeze-dried.