Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][CH3:11].C([Li])CCC.[I:17]I.OS([O-])=O.[Na+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([I:17])=[C:4]([F:9])[C:3]=1[O:10][CH3:11]
Reactant: COc1c(F)cc(F)cc1Cl
Reactant: II
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(Cl)cc(F)c(I)c1F
Temperature: -72.5 °C
Reaction time: 1.25 h
Yield: 92.6 %

Procedure:
2-Chloro-4,6-difluoroanisole (2.0 g, 11 mmol) was dissolved in 20 mL anhydrous THF and cooled to −70 to −75° C. 2.5M n-Butyl lithium in hexanes (6.7 mL, 17 mmol) was added dropwise. After stirring for 75 minutes at −75° C., the mixture was treated dropwise with a solution of iodine (5.1 g, 20 mmol) in 10 mL THF. After stirring for 20 minutes, the reaction solution was allowed to warm to 25° C. over 40 minutes. The reaction mixture was diluted with Et2O (50 mL) and stirred with dilute NaHSO3 solution to destroy excess iodine. The separated aqueous phase was extracted with 20 mL Et2O. The combined ether phases were washed with saturated NaCl, dried, and evaporated to give 1-chloro-3,5-difluoro-4-iodo-2-methoxybenzene (3.1 g, 91% yield): mp 62-64° C.; GC-MS (m/z=304).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH2:13](I)[CH2:14][CH3:15].O>CN(C=O)C>[CH3:3][C:4]1[C:11]([O:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: Cc1c(O)cccc1C=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cccc(C=O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
Sodium hydride (1.15 g, 50% in oil) was added to a stirred solution of 2-methyl-3-hydroxybenzaldehyde (3.00 g) in dry DMF (30 ml). The mixture was stirred for 1 h at room temperature under nitrogen, then n-propyl iodide (4.49 g) was added portionwise over 20 min, followed by stirring for 1 h. The mixture was poured into water and extracted with diethyl ether, and the combined extracts dried (MgSO4) and evaporated to dryness. Purification by chromatography (SiO2 ; hexane/ethyl acetate) gave 2-methyl-3-n-propyloxybenzaldehyde (1.38 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH:13]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:20][C:21]#[N:22]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[C:20](=[CH:13]/[C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:12][N:11]=2)/[C:21]#[N:22])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: O=Cc1cc(-c2ccc(F)cc2)on1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc(-c3ccc(F)cc3)on2)cc1OC
Yield: 41 %

Procedure:
5-(4-Fluorophenyl)-isoxazole-3-carboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (185 mg) through Method A (production step 2), to thereby yield the target product (yield: 150 mg, 41%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38](Br)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH3:38])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Product: CCCCCCCCCCCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.96 g) and dodecyl bromide (0.719 mL) as starting materials, 5-benzyloxy-N-[(1-dodecylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.29 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-[(1-dodecylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.54 g) was obtained. MS (ESI) m/z: 559 [MH]+
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2/[CH:14]=[CH:15]/[C:16](=[O:18])[CH3:17])[CH:6]=[CH:5][CH:4]=1.C[C:20](C)(C([O-])=O)[C:21]([O-])=[O:22].C[O-].[Na+]>CO>[OH:22][C:21]1[CH2:20][CH:14]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH2:15][C:16](=[O:18])[CH:17]=1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: COc1cccc(-c2ccsc2/C=C/C(C)=O)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2ccsc2C2CC(=O)C=C(O)C2)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 200 mL recovery flask was added (E)-4-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)but-3-en-2-one (30D, 4.81 g, 18.6 mmol, 1.0 eq.), MeOH (100 mL), and dimethylmalonate (30E, 2.13 mL, 18.6 mmol, 1.0 eq.). NaOMe (30% wt in MeOH, 3.66 mL, 19.5 mmol, 1.05 eq.) was added and the reaction mixture was stirred overnight at reflux. LC/MS analysis showed the desired intermediate and the mixture was concentrated and then taken up in 1N aqueous NaOH (100 mL) and refluxed for 1 h. The reaction was then cooled to 0° C. in an ice bath and acidified with 1N HCl until acidic. The reaction mixture was then stirred at 80° C. for 1 h. After cooling to room temperature, EtOAc (200 mL) was added and the organic phase was washed with saturated aqueous NaCl (100 mL). The combined aqueous phases were extracted with EtOAc (100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give a foamy brown solid 30F that was taken on to the next step without further purification. (4.9 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 (m, 3H) 3.79 (s, 3H) 4.54-4.70 (m, 1H) 5.30 (s, 1H) 6.73 (d, J=8.08 Hz, 1H) 7.31 (d, J=7.33 Hz, 1H) 7.39-7.54 (m, 2H) 7.76 (t, J=7.83 Hz, 1H). ESI-MS: m/z 302.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([Cl:11])[C:5]=2[O:4][C:3]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([Cl:11])[C:5]=2[O:4][C:3]=1[C:16]([O:18][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17]
Reactant: CCCc1cc(Cl)c2oc(C(=O)O)c(C)c2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Cl)c2oc(C(=O)OCc3ccccc3)c(C)c2c1O
Yield: 29.3 %

Procedure:
A mixture of 3-methyl-4-hydroxy-5-propyl-7-chloro-benzofuran-2-carboxylic acid (0.5 gm; 1.9 mmole), potassium carbonate (0.26 gm; 1.9 mmole) and benzyl bromide (0.22 ml; 1.9 mmole) in acetone (100 ml) was refluxed for a period of 2 hours. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 15% ethyl acetate in hexane to yield 200 mg (30%) of benzyl 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran-2-carboxylate, m.p. 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1oc2ccc(F)cc2c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a mixture of 1-(5-fluoro-2-hydroxyphenyl)ethanone (100 g), methyl bromoacetate (67.6 mL) and N,N-dimethylformamide (500 mL) was added potassium carbonate (135 g), and the mixture was stirred at 50° C. for 2 hr. The insoluble material was filtered off, 1,8-diazabicyclo[5.4.0]undec-7-ene (97.1 mL) was added, and the mixture was stirred at 120° C. for 30 min. 1N Hydrochloric acid was added to the reaction mixture at 0° C., and the resulting precipitate was collected by filtration to give the title object compound (77.9 g, 58%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH3:16])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Li+]>CO.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH3:16])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCCOc1cc(C#N)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1cc(C#N)cc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of methyl 3-cyano-5-propoxybenzoate (1.5 g, 6.8 mmol) in methanol-tetrahydrofuran (1:2, 30 mL) was treated with 0.5 M lithium hydroxide (16 mL, 8.2 mmol). The reaction was stirred at 70° C. for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH˜4) by the addition of 2N hydrogen chloride. The precipitate was collected and dried to afford 1.2 g (86%) of 3-cyano-5-propoxybenzoic acid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(OC)c(C(C)=O)c1
Reaction time: 3 h
Yield: 94.8 %

Procedure:
19.3 g of AlCl3 are placed in 200 ml of CCl4 at +5° C. under nitrogen and 11.36 g of acetyl chloride are added, followed by portionwise addition of 20 g of 1,4-dimethoxybenzene. After stirring for 3 hours at +5° C., the mixture is poured into dilute ice-cold HCl solution. The organic phase is separated out and dried over MgSO4 and evaporated, and the residue is then chromatographed on silica, eluting with a DCM/heptane mixture (50/50; v/v) to give 24.71 g of the expected product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C@@H:13]12[C:21](=[O:22])[O:20][CH2:19][C@@H:18]1[CH2:17][CH2:16][CH2:15][CH2:14]2.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([C@@:13]12[C:21](=[O:22])[O:20][CH2:19][C@@H:18]1[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OC[C@@H]2CCCC[C@H]12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1OC[C@@H]2CCCC[C@]12Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Under argon, a solution of diisopropylamine (3.85 ml, 27.5 mmol) in 20 ml of dry THF is cooled to 0° C. and slowly admixed with butyllithium (11 ml, 27.5 mmol, 2.5M in hexane). With ice-cooling. This solution is stirred for 15 min and then cooled to −78° C. and a solution of cis-8-oxabicyclo[4.3.0]nonan-9-one (3.5 g, 25 mmol) in 10 ml of THF is added dropwise. The mixture is stirred at −78° C. for another 30 min and then mixed with benzyl bromide (3.27 ml, 27 mmol). The mixture is then slowly warmed to room temperature and stirred for another 16 h. The solvent is removed and the residue is taken up in 20 ml of dichloromethane and washed 2× with in each case 20 ml of 2 M HCl. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by column chromatography (mobile phase: cyclohexane:ethyl acetate 10:1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][S:9][CH3:10])(=[O:4])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:16]>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][S:9]([CH3:10])=[O:16])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCSC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=CC(=O)OCCCS(C)=O
Temperature: 0 °C
Yield: 65.8 %

Procedure:
To an ice-cold solution of 3-methylthio-1-propyl acrylate (18) (5.95 g, 37.1 mmol) in CH2Cl2 (80 mL), m-chloroperoxybenzoic acid (76.5 wt % 8.37 g, 37.1 mmol) was added in portions over a period of 1.5 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the solvent was evaporated under reduced pressure. The resulting sticky white solid was washed with water (2×100 mL) and filtered. The water washings were evaporated under reduced pressure to yield the crude product as a yellow oil. The crude product was purified by column chromatography (silica gel, ether, 20 wt % acetone/ether, 70 wt % acetone/ether) to afford colorless oil compound 23, namely methyl 3-(acryloyloxy)propyl sulfoxide (4.3 g, 66 wt %).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>CN(C=O)C>[CH3:19][S:16]([N:11]1[C:12]2[C:7](=[CH:6][C:5]([O:4][CH3:3])=[CH:14][CH:13]=2)[CH2:8][CH2:9][C:10]1=[O:15])(=[O:18])=[O:17]
Reactant: COc1ccc2c(c1)CCC(=O)N2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(=O)N2S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was placed 87 mg (2.17 mmol) of 60% sodium hydride in mineral oil and 15 ml of dimethylformaminde (DMF). The mixture was cooled to 0° C. and was treated with 350 mg (1.97 mmol) of 6-Methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline (Preparation 2) in the minimum amount of DMF. The reaction mixture was stirred for 0.5 hours at 0° C. and was then treated with 226 mg (1.97 mmol) mesyl chloride. The mixture was slowly allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched by the addition of 30 ml of saturated aqueous sodium bicarbonate solution and the mixture was extracted with methylene chloride (3×30 ml). The combined organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude oil was purified by silica gel chromatography eluting with 1/1 ethyl acetate/hexane to afford a light yellow oil in 35% yield (177 mg). Mass spectrum APCI m/e 256 (p+1).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)=[CH:3][CH:2]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:25]2[C:24](=[O:26])[C:23]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]3[C:21]2=[O:31])=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCCCCOc1ccc(-c2ccccc2)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCOc1ccc(-c2ccccc2)cc1

Procedure:
A solution of 1-(4-biphenyloxy)-6-chlorohexane (10.0 g) and potassium phthalimide (9.0 g) in dimethylformamide (100 ml) was heated at 140° C. for 4 hours. The cooled solution was poured into water (900 ml) and filtered to yield N-[6-(4-biphenyloxy) hexyl]phthalimide. (b) In a similar manner, but using the appropriate corresponding optionally substituted 1-(3- or 4-biphenyloxy)-ω-chloroalkane, obtained as described in Preparation 4, the following compounds of Formula C were prepared:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:12]1[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]2[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (5-(2-methoxy-ethoxy)-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M222) (340 mg, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (196 mg, 72%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([N:14]1[CH2:39][CH2:38][CH2:37][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN1CCOCC1.[N:54]1([C:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[O:70])[CH2:68][CH2:67][CH2:66][C@H:55]1[C:56](ON1C(=O)CCC1=O)=[O:57]>Cl.CCOC(C)=O>[N:54]1([C:69]([O:71][CH2:72][C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)=[O:70])[CH2:68][CH2:67][CH2:66][C@H:55]1[C:56]([NH:1][C@H:2]([C:12]([N:14]1[CH2:39][CH2:38][CH2:37][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:57]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O
Reactant: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)NCC(N)=O)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 1.0 g of Boc-Ser(Bzl)-Pro-Arg(NO2)-Gly-NH2, 10 ml of 4N HCl-AcOEt, 0.34 ml of NMM and 0.54 g of Z-Pro-OSu in the same manner as in Example 26-(4).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NN1CCCCC1
Product: O=C(NN1CCCCC1)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 1-amino-piperidine (CAN 2213-43-6; 76.9 mg, 0.51 mmol) as starting materials, and isolated (17 mg, 12.57%) as white solid; (UV peak area, ESI) 100%, 316.6 (M+H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(N(CC)CC)C.[C:38]([O:42][C:43]([NH:45][C@H:46]([C:48](O)=[O:49])[CH3:47])=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(OCC)(=O)C>[C:38]([O:42][C:43]([NH:45][C@@H:46]([CH3:47])[C:48]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:49])=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)C1Cc2ccccc2N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OCc1ccccc1
Temperature: 30 °C

Procedure:
200 g of benzyl 2,3-dihydro-1H-indole-2-carboxylate para-toluenesulphonate, 66 ml of triethylamine and 1 litre of ethyl acetate are introduced into a stirred reactor, followed, after stirring for 10 minutes at ambient temperature, by 89 g of N-[tert-butyloxycarbonyl]-(S)-alanine and 151 g of O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium tetrafluoroborate. The heterogeneous mixture is then heated at 30° C. for 3 hours whilst stirring well and is then cooled to 0° C. and filtered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:15])([CH3:14])[NH:12][C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:37]I>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH3:15])([CH3:14])[N:12]([CH3:37])[C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)NC2(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)N(C)C2(C)C)cc1
Reaction time: 4 h
Yield: 30.8 %

Procedure:
To a solution of 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (150 mg, 0.35 mmol) in DMF (10 mL) were added NaH (15 mg, 0.7 mmol) and CH3I (100 mg, 0.7 mmol) at 0° C. under an inert atmosphere. The mixture was then stirred for 4 h, diluted with cold water and filtered. The resulting residue was dried to afford 4-(4-methoxyphenyl)-1,5,5-trimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (50 mg, 37%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.04 (d, J=7.2 Hz, 1 H), 8.02-7.98 (m, 2 H), 7.81-7.78 (m, 1 H), 7.62-7.58 (m, 2 H), 7.31-7.28 (m, 2 H), 7.19-7.16 (m, 2 H), 6.99-6.84 (m, 4 H), 5.36 (s, 2 H), 3.89 (s, 3 H), 2.96 (s, 3 H), 1.24 (s, 6 H). MS: M+H: m/z=465.2; M+Na: m/z=487.2. HPLC: 92%, (Condition-I).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl.Cl[CH2:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH3:20]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH3:20]
Reactant: Nc1cccc(O)c1
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC1CCOc1cccc(N)c1

Procedure:
3-aminophenol (0.74 g, 6.8 mmol) in DMF (10 ml) was added dropwise to 95% NaH (0.49 g, 20.4 mmol) in 10 ml DMF at 0° C., under nitrogen. The reaction was stirred until H2(g) evolution ceased. 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (1.25 g, 6.8 mmol) was then added portionwise. The mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with 1N NaOH (50 ml) and the desired product extracted into ether (3×50 ml). The combined ether layers were washed (2×50 ml) with water, dried over MgSO4, and evaporated to dryness in vacuo. The residue was purified on silica gel by flash chromatography using 2% TEA in ethyl acetate to give an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.[C:15]([CH2:17][CH2:18][NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)#[N:16]>>[Cl:34][C:33]1[C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([NH:19][CH2:18][CH2:17][C:15]#[N:16])=[O:36])=[N:29][C:30]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:31][CH:32]=1
Reactant: CC1(C)CCCOc2c(N)cccc21
Reactant: N#CCCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CC1(C)CCCOc2c(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCC#N)n3)cccc21

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and N-(2-cyano-ethyl)-2-(2,5-dichloro-pyrimidin-4-ylamino)-benzamide in an analogous manner to Example 179. Product was isolated as a golden brown solid (50 mg, 50%). LCMS (m/e) 491 (M+H); 1H NMR (400 MHz, CDCl3) δ 10.78 (s, 1H), 8.69 (d, 1H, J=8.6 Hz), 8.25 (d, 1H, J=7.8 Hz), 8.12 (s, 1H), 7.80 (s, 1H), 7.53 (m, 2H), 7.12 (t, 1H, J=7.8 Hz), 6.95 (m, 2H), 6.74 (m, 1H), 4.01 (t, 2H, J=5 Hz), 3.73 (dd, 2H, J=6, 12 Hz), 2.76 (t, 2H, J=6 Hz), 2.08 (m, 2H), 1.69 (t, 2H, J=6 Hz), 1.40 (s, 6H).