Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].OC1C=CC=CC=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:29]([O:39][C:40](=O)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=O)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]CC.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:41]([C:40]1[O:39][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=2[CH:35]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCC(=O)OC(=O)CCCCCCCC
Agent: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCc1cc2ccccc2o1
Yield: 76.6 %

Procedure:
112 g (249 mM) of (2-hydroxybenzyl)triphenylphosphonium bromide, 83 g (278 mM) of nonanoic anhydride, 104 g (1.03 mM) of triethylamine and 800 ml of toluene were placed in a 3 1-three-necked flask, followed by refluxing for 4.5 hours under stirring. After the reaction, the reaction mixture was left standing at room temperature to precipitate a crystal. The crystal was removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography (eluent:toluene/hexane=1/1) to obtain 44 g of liquid 2-octylbenzofuran (Yield: 76.6%).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]1[CH:23]=CC=C2C([O:26][C:27](=[O:28])[C:19]=12)=O.C1([Mg]Cl)CCCCC1>>[CH:1]1([C:7]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:15](=[O:17])[N:18]([CH3:23])[C:19]=2[C:27]([OH:28])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: O=C(O)c1ncccc1C(=O)C1CCCCC1
Agent: Cl[Mg]C1CCCCC1
Product: Cn1c(C(=O)O)c(C2CCCCC2)c2cccnc2c1=O

Procedure:
Starting from 3-cyclohexylcarbonyl-2-pyridinecarboxylic acid, which was prepared from 2,3-pyridinedicarboxylic anhydride and cyclohexylmagnesium chloride, substantially the same reaction and work-up as in Reference Exampe 1-Process 2-Step 1 to Step 4 were conducted to give the title compound as a pale yellow oil, which was used for the reaction of Example 76.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+].Br[C:36]1[CH:41]=[C:40]([CH3:42])[C:39]([NH:43][C:44](=[O:50])[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[C:38]([CH3:51])[CH:37]=1.[F:52][C:53]([F:65])([F:64])[C:54]1[CH:55]=[N:56][C:57]2[CH2:58][CH2:59][NH:60][CH2:61][C:62]=2[CH:63]=1>C1(C)C=CC=CC=1>[CH3:42][C:40]1[CH:41]=[C:36]([N:60]2[CH2:59][CH2:58][C:57]3[N:56]=[CH:55][C:54]([C:53]([F:52])([F:64])[F:65])=[CH:63][C:62]=3[CH2:61]2)[CH:37]=[C:38]([CH3:51])[C:39]=1[NH:43][C:44](=[O:50])[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47]
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ncc(C(F)(F)F)cc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (4 mg, 0.069 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (7 mg, 0.015 mmol) were added to dry toluene (1 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (36 mg, 0.32 mmol), N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (52 mg, 0.17 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (WO/04069162) (40 mg, 0.15 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% Ethyl acetate:Hexanes) to afford the desired compound as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 1.05 (s, 9H), 2.11 (s, 6H), 2.17 (s, 2H), 3.08 (t, J=5.6 Hz, 2H), 3.64 (t, J=5.9 Hz, 2H), 4.48 (s, 2H), 6.76 (s, 2H), 8.08 (s, 1H), 8.75 (s, 1H), 8.90 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:26]=3[OH:27])[N:23]=[CH:22][CH:21]=[N:20]4)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:36]1C=C(O)C(C2C3C(=CC=CC=3)N(CC3C=CC(OC)=CC=3)C2=O)=CC=1C#N>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:18]=[C:19]5[C:24]([N:23]=[CH:22][CH:21]=[N:20]5)=[CH:25][C:26]=4[O:27][CH2:36]3)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Reactant: O=C1C(c2cc3nccnc3cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3nccnc3cc12

Procedure:
Following the procedure as described in EXAMPLE 2.40 and making non-critical variations using 1-(diphenylmethyl)-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile, 1′-(diphenylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one was obtained (34%): 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J=1.5 Hz, 1H), 8.46 (d, J=1.5 Hz, 1H), 8.07-8.04 (m, 1H), 7.63-6.86 (m, 15H), 6.55-6.52 (m, 1H), 5.10 (ABq, 2H).
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][N:25]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])C2C=CC=CC=2N=N1.O>C1COCC1.[Zn]>[CH2:33]([N:25]([CH2:24][C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)Cn1nnc2ccccc21
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCN(Cc1ccccc1)CC(F)(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a solution of 1H-benzotriazole (2.38 g) in methanol (20 mL) were added ethyl N-benzyl-β-alaninate (4.14 g) and aqueous formaldehyde solution (37%, 2 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give ethyl N-(1H-benzotriazol-1-ylmethyl)-N-benzyl-β-alaninate (5.60 g). To a mixture of zinc powder (1.74 g) in anhydrous THF (16 mL) was added chlorotrimethylsilane (1.58 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added ethyl bromodifluoroacetate (2.97 g) at room temperature, and then a solution of ethyl N-(1H-benzotriazol-1-ylmethyl)-N-benzyl-β-alaninate (4.50 g) in THF (8 mL) was added thereto at room temperature. The reaction mixture was stirred at room temperature for 18 hr, and added to water. The insoluble substance was removed by the filtration, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (3.23 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[C:21]2[CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][C:17](=[O:26])[NH:16][C:15]=2[CH:14]=[CH:13][C:12]=1[O:27][CH3:28]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:21]3[CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][C:17](=[O:26])[NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[O:27][CH3:28])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: COc1ccc2c(c1N)CN(S(C)(=O)=O)CC(=O)N2
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: COc1ccc2c(c1Nc1nc(Cl)ncc1Cl)CN(S(C)(=O)=O)CC(=O)N2
Temperature: 120 °C

Procedure:
A mixture of 2,4,5-Trichloro-pyrimidine (1.5 g, 0.0084 mol), 6-Amino-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.400 g, 0.00140 mol) was heated at 120° C. for 48 hrs. The reaction was triturated with ethyl acetate and then with methanol giving 6-(2,5-Dichloro-pyrimidin-4-ylamino)-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one the product as a gray solid (0.338 g, 51%). Mp 280-300d; LCMS (m/e)-432 (M); 1H-NMR (DMSO, 400 MHz) δ 10.23 (s, 1H), 9.34 (s, 1H), 8.34 (s, 1H), 7.20-7.17 (d, 1H, J=9.10 Hz), 7.14-7.11 (d, 1H, J=8.84 Hz), 4.40-4.30 (m, 1H), 4.25-4.10 (m, 1H), 3.83 (s, 3H), 2.88 (s, 3H).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][Si:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+].O>CN(C=O)C>[N:28]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][Si:22]([CH3:26])([CH3:25])[CH2:23][CH2:24]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)=[N+:29]=[N-:30]
Reactant: C[Si]1(C)CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si]1(C)CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To the Mesyl compound 18 (250 mg, 0.59 mmol) in DMF, NaN3 (78 mg, 1.20 mmol) is added and stirred at 60° C. for 2 h. Water (5 mL) is then added and extracted with DCM (2×5 mL), dried and concentrated. The crude (220 mg) is used for further steps without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Li+].[CH3:10][CH:11]([N-]C(C)C)[CH3:12].C(Br)C=C.[NH4+].[Cl-]>C1COCC1>[CH2:12]([C:7]1[C:6]([Br:8])=[CH:5][N:4]=[CH:3][C:2]=1[Br:1])[CH:11]=[CH2:10]
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1c(Br)cncc1Br
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A THF (100 mL) solution of 3,5-dibromopyridine (5 g, 21.1 mmol) at −78° C. was added via cannula to a solution of LDA (22.2 mmol) in THF (700 mL) at −78° C. keeping the temperature <60° C. After stirring for 10 min. at −78° C., allyl bromide (2.56 mL, 29.5 mmol) was added via syringe and the reaction mixture was stirred for 2 hr at −78° C. Saturated NH4Cl (100 mL) was added slowly to quench the reaction. The organic layer was separated, washed with brine and dried (MgSO4). Filtration and concentration in vacuo gave the title compound as an oil which was purified by chromatography on silica gel with hexane:ethyl acetate 9:1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[C:19]([O:26][CH2:27][CH2:28][OH:29])[N:18]=[C:17]([C:30]3[N:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:38][C:39]1[CH:40]=[N:41][C:42](Cl)=[N:43][CH:44]=1.Cl>O1CCCC1.CC(N(C)C)=O>[Br:38][C:39]1[CH:40]=[N:41][C:42]([O:29][CH2:28][CH2:27][O:26][C:19]2[N:18]=[C:17]([C:30]3[N:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:16]=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[C:20]=2[C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[N:43][CH:44]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2nc(-c3ncccn3)nc(OCCO)c2-c2cccs2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2nc(-c3ncccn3)nc(OCCOc3ncc(Br)cn3)c2-c2cccs2)cc1
Reaction time: 0.33 h
Yield: 26.4 %

Procedure:
To a solution of 4-tert-butyl-N-{6-(2-hydroxyethoxy)-5-(2-thienyl)-2-(2-pyrimidinyl)-pyrimidin-4-yl}benzenesulfonamide (1790 mg) in tetrahydrofuran (20 ml) is added sodium hydride (60% dispersion, 413 mg) at room temperature, and thereto is added dimethylacetamide (4 ml), and the mixture is stirred for 20 minutes. To the reaction mixture is added 5-bromo-2-chloro-pyrimidine (952 mg), and the mixture is stirred at room temperature for 46 hours. The mixture is acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=4:1) to give the title compound (617 mg) as a crystal.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1.Cl>O>[CH2:2]([O:9][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1ccccc1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: Cl
Agent: [Na]
Solvent: O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 148 °C
Yield: 88.2 %

Procedure:
Sodium (368 mg, 16 mmol) was added to benzyl alcohol (10 ml, 96 mmol) and the mixture was heated at 148° C. for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol), (J. Chem. Soc. section B 1967, 449), was added and the mixture maintained at 148° C. for 24 hours. The reaction mixture was allowed to cool, the solution was poured on to water (170 ml) and the aqueous mixture adjusted to pH3 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, ether and dried under vacuum to give 7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 89%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCBr)ccc21
Reactant: CCNCC
Product: CCN(CC)CCCCOc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C

Procedure:
In analogy to example 2.9, 6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and diethylamine were converted to yield 6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:8]1[C:9](=[O:21])[CH2:10][CH:11]([CH:15]2[CH2:20][CH2:19][CH2:18][S:17][CH2:16]2)[CH2:12][C:13]=1[OH:14])(=[O:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([C:8]1[C:9](=[O:21])[CH2:10][CH:11]([CH:15]2[CH2:20][CH2:19][CH2:18][S:17][CH2:16]2)[CH2:12][C:13]=1[O:14][C:1](=[O:3])[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(=O)C1=C(O)CC(C2CCCSC2)CC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1=C(C(C)=O)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.82 g (10.5 mmol) of acetyl chloride is added dropwise to a stirred solution of 2.54 g (10.0 mmol) of 2-acetyl-3-hydroxy-5-(tetrahydro-2H-thiopyran-3-yl)-cyclohex-2-en-1-one and 1.06 g (10.5 mmol) of triethylamine in 50 ml of dichloromethane. The mixture is stirred overnight at room temperature, and then is poured into 100 ml of ice-cold water. The organic layer is separated and washed with 20 ml of dilute sodium bicarbonate solution, followed by 50 ml of saturated sodium chloride solution. The washed extract is then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product can be purified by column chromatography employing tetrahydrofuran-hexane (1:2 by volume) as eluent to afford the title compound.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([C:31]1[CH:39]=[CH:38][C:34]2[O:35][CH2:36][O:37][C:33]=2[CH:32]=1)=[O:30]>>[O:35]1[C:34]2[CH:38]=[CH:39][C:31]([C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:19]3[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:4]4[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=4[C:6]([OH:8])=[O:7])(=[O:14])=[O:15])=[CH:21][CH:20]=3)=[O:30])=[CH:32][C:33]=2[O:37][CH2:36]1
Reactant: O=C(NCCCO)c1ccc2c(c1)OCO2
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCNC(=O)c2ccc3c(c2)OCO3)cc1
Yield: 49 %

Procedure:
The product of Example 2 (0.30 g, 0.92 mmol) was coupled to N-(3-hydroxypropyl)-1,3-benzodioxole-5-carboxamide, prepared according to Example 20, (0.205 g, 0.92 mmol) using the procedure of Example 3 to provide 0.23 g (49% yield) of yellow solid. MP 120° C.; 1H NMR (DMSO-d6): δ 1.63 (m, CH2) 1.9 (s, CH3), 3.20 (s, CH3), 3.6 (m, CH2), 4.1 (m, CH2), 6.07 (s, CH2), 6.9-7.1 (m, 5 Ar H), 7.3-7.5 (m, 3 Ar H), 7.88-7.94 (m, 2 Ar H), 8.52 (br s, NH). Electrospray Mass Spec: m/z 527.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[N:25]=[CH:24][C:23]4[C:18](=[C:19]([F:30])[CH:20]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:31])[C:11]=2[CH2:32][OH:33])[CH:3]=1.[F:34][C@H:35]1[CH2:37][C@H:36]1[C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:26]([C:21]1[CH:22]=[C:23]2[C:18](=[C:19]([F:30])[CH:20]=1)[C:17](=[O:31])[N:16]([C:12]1[C:11]([CH2:32][OH:33])=[C:10]([C:4]3[CH:3]=[C:2]([NH:1][C:38]([C@@H:36]4[CH2:37][C@@H:35]4[F:34])=[O:39])[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=3)[CH:15]=[CH:14][N:13]=1)[N:25]=[CH:24]2)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(N)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(NC(=O)[C@@H]2C[C@@H]2F)c1=O
Yield: 73 %

Procedure:
A solution of 123d, (1S,2S)-2-fluorocyclopropanecarboxylic acid (15 mg, 0.14 mmol, 1.3 equiv), HATU (65 mg, 0.17 mmol, 1.5 equiv) and N,N-diisopropylethylamine (60 uL, 0.33 mmol, 3.0 equiv) in DMF (1.0 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC (Column, Sunfire C18 19×150; mobile phase, CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV 254 nm) to give 43 mg (73%) of 123 as an off white solid. LC-MS m/z: 536.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.89 (d, J=1.7 Hz, 1H), 7.80-7.72 (m, 2H), 7.49 (d, J=5.0 Hz, 1H), 5.03-4.73 (m, 1H), 4.89 (t, J=5.2 Hz, 1H), 4.43-4.36 (m, 2H), 3.60 (s, 3H), 2.50-2.41 (m, 1H), 1.68-1.52 (m, 1H), 1.39 (s, 9H), 1.20-1.08 (m, 1H).
Reaction SMILES: N1C=CC=CC=1.O=[Si]=O.[CH2:10]([O:12][CH:13]([O:29][CH2:30][CH3:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[OH:21])[CH3:11]>[O-2].[O-2].[O-2].[Cr+6].ClCCl>[CH2:30]([O:29][CH:13]([O:12][CH2:10][CH3:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])=[O:21])[CH3:31]
Reactant: CCOC(OCC)c1ccccc1C(O)c1ccccc1F
Agent: [Cr+6]
Agent: O=[Si]=O
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(OCC)c1ccccc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Under a nitrogen atmosphere, 758 ml of pyridine and 469 g of dicalite were added to 6 l of dry dichloromethane. In one portion 469 g of chromium trioxide were added under vigorous stirring. The resulting mixture was stirred at room temperature for 0.5 h, after which a solution of 238 g of 2-(diethoxymethyl)-α-(2-fluorophenyl)-benzenemethanol in 600 ml dry dichloromethane was added. After stirring at room temperature for 2 h, the mixture was filtered. The filtrate was washed with 3×1 l of 1N sodium hydroxide in water and 1 l of water, dried over magnesium sulphate and evaporated to dryness under reduced pressure to yield 224 g of [2-(diethoxymethyl)phenyl](2-fluorophenyl)-methanone as an oil, M.S. (C.I.) (M/Z): 303 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH2:12])=O)=[CH:4][CH:3]=1.Cl[C:14]1[N:15]=[N:16][C:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:15]3[N:16]=[C:17]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=[CH:19][C:14]3=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cc1ccc(F)cc1
Reactant: Clc1ccc(-c2cccs2)nn1
Product: Fc1ccc(Cc2nnc3ccc(-c4cccs4)nn23)cc1

Procedure:
The title compound was prepared as described in Example 17 from 4-fluorophenylacetic acid hydrazide (1.04 mmol) and 3-chloro-6-thiophen-2-yl-pyridazine (0.52 mmol) as a pale beige solid. 1H NMR (CD3OD) δ 8.19 (1H, d, J=9.9 Hz), 7.93 (1H, dd, J=3.8 Hz, 0.9 Hz), 7.90 (1H, d, J =9.9 Hz), 7.75 (1H, dd, J=5.0 Hz, 1.0 Hz), 7.50 (2H, dd, J=9.0 Hz, 5.3 Hz), 7.24 (1H, dd, J=5.3 Hz, 3.8 Hz), 7.06 (2H, t, J=8.8 Hz), 4.59 (2H, s). ESI-MS (m/z): Calcd for C16H11FN4S: 310.1; found 311.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][CH2:20][CH:21]([OH:50])[CH2:22][NH:23][C:24](=[O:49])[C@H:25]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:26]C(OCC1C=CC=CC=1)=O)=[O:18].[H][H]>COCCOC.CN(C)C=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][CH2:20][CH:21]([OH:50])[CH2:22][NH:23][C:24](=[O:49])[C@H:25]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[NH2:26])=[O:18]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(O)CNC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)NCC(O)CNC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl

Procedure:
1.80 g (2.46 mmol) of Nα -benzyloxycarbonyl-Nε -tert.-butoxycarbonyl-L-lysine-3-{2-[2-(2,6-dichlorophenylamino)-phenyl]-acetylamino}-2-hydroxypropylamide are dissolved in 100 ml of 1,2-dimethoxyethane/dimethylformamide (9:1) and after the addition of 0.40 g of palladium-on-carbon (10%) the whole is treated for 11/4 hours with hydrogen. The catalyst is filtered off, the filtrate is concentrated by evaporation at 30° in a rotary evaporator and the residue is lyophilised after being taken up in 100 ml of dioxan/water (7:3). Nε -tert.-butoxycarbonyl-L-lysine-3-{2-[2-(2,6-dichlorophenylamino)-phenyl]-acetylamino}-2hydroxypropylamide is obtained in the form of a colourless powder which is immediately processed further; Rf =0.52 (acetonitrile:water=3:1), Rf =0.66 (ethyl acetate:n-butanol:pyridine:acetic acid:water=42:21:21:6:10).
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([C:14]([O:16]CC)=[O:15])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:19](O)[CH3:20]>>[Br:1][C:2]1[C:3]([C:4]([O:6][CH2:19][CH3:20])=[O:5])=[C:7]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:14]([OH:16])=[O:15]
Reactant: CCO
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(Br)c1C(=O)O
Product: CCOC(=O)c1c(C(=O)O)ccc([N+](=O)[O-])c1Br

Procedure:
By boiling with ethanol, a mixture of 2-bromo-6-ethoxycarbonyl-3-nitro-benzoic acid and 3-bromo-2-ethoxycarbonyl-4-nitro-benzoic acid is obtained from the above.