Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=O)[NH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]cc(OC)c2c1
Product: COc1ccc2c(Cl)ncc(OC)c2c1
Yield: 27.5 %

Procedure:
A solution of 4,6-dimethoxyisoquinolin-1(2H)-one (4 g, 19.49 mmol) in POCl3 (40 mL) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (1.2 g, 27.5%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.16-8.13 (d, J=12 Hz, 1H), 7.74 (s, 1H), 7.44-7.43 (d, J=4 Hz, 1H), 7.30-7.27 (d, J=12 Hz, 1H), 7.26 (s, 1H), 4.05 (s, 3H), 3.97 (s, 3H); MS: MS m/z 224.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12](O)=[O:13].[H]1[BH2][H][BH2]1.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: N#Cc1ccc(CCC(=O)O)c(Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCCO)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(2-chloro-4-cyanophenyl)-propanoic acid (14.3 g, 0.068 mol) in 70 mL of dry THF at -18° C. was added B2H6 (72 ml, 0.068 mol) in THF. The mixture was stirred at room temperature overnight. After addition of water, the layers were separated and the aqueous phase was extracted with ether. Evaporation and distillation gave 3-(2-chloro-4-cyanophenyl)propanol as an oil: 11.0 g; bp 55°-60° C. (0.005 mm Hg). Anal. calcd for C10H10ClNO: C, 61.39; H, 5.15; N, 7.16. Found: C, 61.02; H, 5.19; N, 6.76. ##STR31##
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH2:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][OH:51]>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([NH:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][OH:51])=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: NCCOCCO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NCCOCCO)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (46.5 mg, 0.074 mmol; Example 6A) was reacted with 2-(2-aminoethoxy)ethanol (23.4 mg, 0.223 mmol) in acetonitrile (1 ml) to give the target compound (30 mg, 68% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:11][C:12]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][N:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[O:17])[CH2:19][CH2:20]3)[CH:26]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: NCc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Temperature: 150 °C
Yield: 198.2 %

Procedure:
To two vials which each contained a solution of [(3-bromo-4-fluorophenyl)methyl]amine hydrochloric salt (0.601 g, 2.5 mmol) in p-dioxane/H2O (15/5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.2 g, 3.75 mmol), Pd(PPh3)4 (145 mg, 0.125 mmol), and K2CO3 (1.38 g, 10 mmol). The mixture was heated with a microwave at 150° C. for 15 min. The organic layer of both vials was separated, combined, concentrated and purified by CombiFlash chromatograph to afford the title compound 1.98 g (99%). LC-MS m/z 400 (M+H)+.
Reaction SMILES: C(OC(=O)[CH2:5][N:6]1[C:10]([CH:11]=[O:12])=[N:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7]1)C.C(OC(=O)CNN)C.C1(C2OCC(=O)N=2)C=CC=CC=1>>[CH3:5][N:6]1[C:10]([CH:11]=[O:12])=[N:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7]1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)nc1C=O
Agent: CCOC(=O)CNN
Agent: O=C1COC(c2ccccc2)=N1
Product: Cn1nc(-c2ccccc2)nc1C=O

Procedure:
(5-Formyl-3-phenyl-1,2,4-triazol-1-yl)-acetic acid ethyl ester, from Hydrazino-acetic acid ethyl ester and 2-Phenyl-oxazol-4-one. H-NMR: (CDCl3) δ 10.05 (s, 1H), 8.15 (d, 2H), 7.50 (m, 3H), 5.38 (s, 2H), 4.28 (m, 2H), 1.32 (t, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[N:18]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O)(=O)C.C(O)(=O)C.C(N)CN.S([O-])(O)=O.[Na+]>CO>[N:18]1([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[O:34][C:33](/[CH:35]=[C:6]4\[C:2](=[O:1])[N:3]([NH:8][C:9]5[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=5[C:11]([OH:13])=[O:12])[C:4](=[S:7])[S:5]\4)=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Reactant: O=Cc1ccc(-c2ccc(N3CCOCC3)cc2)o1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Solvent: NCCN
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1NN1C(=O)/C(=C\c2ccc(-c3ccc(N4CCOCC4)cc3)o2)SC1=S
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
A mixture of 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (0.089 g, 0.33 mmol), 5-(4-morpholin-4-yl-phenyl)-furan-2-carbaldehyde (0.091 g, 0.35 mmol) and ethylenediamine diacetate (0.063 g, 0.035 mmol) in methanol (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into stirred 0.6 N aq sodium hydrogensulfite (50 mL). The mixture was vigorously stirred for 30 mm. The solid product was filtered off and washed on funnel successively with 0.6 N aq sodium hydrogensulfite (1 mL), water (2×2 mL), ether (2×1 mL) and hexanes (2 mL). The material was dried in a vacuum oven at 65° C. for 17 h to afford 2-{5-[1-[5-(4-morpholin-4-yl-phenyl)-furan-2-yl]-meth-(E)-ylidene]-4-oxo-2-thioxo-thiazolidin-3-ylamino}-benzoic acid (147 mg, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6): 3.26 (2H, m), 3.76 (2H, m), 6.53 (1H, d, J=8.4 Hz), 6.87 (1H, m), 7.14 (2H, m), 7.17 (1H, d, J=3.6 Hz), 7.31 (1H, m), 7.40 (1H, d, J=4.0 Hz), 7.71 (1H, s), 7.76 (2H, m), 7.91 (1H, m), 10.4 (1H, bs). LC/MS: APCI 506.1, HPLC 92%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].I[CH2:17][CH2:18][CH2:19][F:20]>CN1C(=O)N(C)CC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][CH2:19][F:20])=[C:4]([F:9])[CH:3]=1
Reactant: FCCCI
Reactant: Oc1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: FCCCOc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
4-Bromo-2-fluorophenol (382 mg, 2.0 mmol) was dissolved in DMI (0.5 mL), and potassium tert-butoxide (224 mg, 2.0 mmol) was added at room temperature. 1-Iodo-3-fluoropropane (376 mg, 2.0 mmol) was added to the reaction solution, and the mixture was heated to 60° C. and stirred for six hours. The reaction solution was purified by silica gel column chromatography to give 4-bromo-2-fluoro-1-(3-fluoro-propoxy)-benzene (410 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26]
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(Cl)c([N+](=O)[O-])c1)N2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c([N+](=O)[O-])c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.2 %

Procedure:
To a solution of methyl 2-(4-chloro-3-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (8.2 g, 21 mmol) in dichloromethane (150 mL), which was cooled to −10° C. under a nitrogen atmosphere, was added triethylsilane (7.08 g, 60.9 mmol) and trifluoroacetic acid (9.82 g, 86.1 mmol). The resulting reaction mixture was stirred overnight at room temperature. The mixture was neutralized with 20 g of Sodium bicarbonate. The solid was filtered and the filtrate was evaporated to remove the solvent. The residue was dissolved in methanol, and insoluble solid was the crude product (3.0 g). The filtrate was purified on silica gel to afford 170 mg of methyl 2-(4-chloro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH:20](C(O)=O)[CH2:19][C:18]2[CH:17]=[C:16]3[C:11]([O:12][C@@H:13]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[C:14](=[O:24])[NH:15]3)=[CH:10][C:9]=2[CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.COC(=O)[C@@H](N)CC1C=CC(C2C=CC=CC=2)=CC=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:20][CH2:19][C:18]2[CH:17]=[C:16]3[C:11]([O:12][CH:13]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:29][CH:30]=4)[C:14](=[O:24])[NH:15]3)=[CH:10][C:9]=2[CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Product: CC(C)OC(=O)N1CCc2cc3c(cc2C1)OC(c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Yield: 136.1 %

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-isopropyl ester (120 mg) was coupled with (S)-2-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochloride according to general procedure A to provide (S)-74(S)-2-biphenyl-4-yl-1-methoxycarbonyl-ethylcarbamoyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid isopropyl ester (151 mg, LC/MS: m/z 825).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:33]>>[NH2:12][C@H:7]1[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:20]3[CH:19]=[C:18]4[C:23](=[CH:22][CH:21]=3)[N:14]([CH3:13])[C:15](=[O:33])[CH2:16][CH2:17]4)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: N[C@@H]1CCCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-2 [E], Suzuki reaction of (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate B-3b) with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave the title compound as light yellow amorphous solid. MS: 308.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 60 h
Yield: 54.3 %

Procedure:
4-(trifluoromethyl)phenylboronic acid (263 mg, 1.39 mmol) was suspended in water (2 mL). 4-bromophenol (0.200 g, 1.16 mmol), potassium carbonate (484 mg, 3.47 mmol), and palladium(II) acetate (13.3 mg, 0.0580 mmol) were added. The reaction was allowed to stir open to ambient atmosphere for 60 hours. The reaction was filtered through Celite and extracted three times with ethyl acetate. The combined organics were washed with 1N HCl, water, and brine, dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-20% ethyl acetate in heptanes) gave 4′-(trifluoromethyl) biphenyl-4-ol (150 mg, 55%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 7.63-7.70 (m, 4H), 7.50-7.54 (m, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.81 (s, 1H). MS (M−1): 237.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[C:6]=1[CH3:16])[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[C:6]=1[CH3:16])[CH3:2]
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1C
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1C

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-Methyl-3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].O>CO.[Pd]>[NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)NCCCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)NCCCCC(=O)O
Reaction time: 8 h

Procedure:
Boc-Gly-Gly-Phe-Gly-OH (SEQ ID NO. 1) (575 mg), HOSu (182 mg), and DCC (326 mg) were dissolved in DMF (20 ml), and the solution was stirred for 30 minutes. The resulting solution was added with a solution of p-toluenesulfonic acid salt of 5-aminopentanoic acid benzyl ester (500 mg) and triethylamine (0.184 ml) dissolved in DMF (10 ml), and the mixture was stirred at room temperature for three days. The reaction mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to obtain 560 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1). The Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1) (560 mg) was dissolved in methanol (60 ml) containing 50% of water, and the solution was added with 5% Pd—C (water content; 50%, 1.5 g) and stirred overnight under hydrogen at ordinary pressure. After the catalyst was removed from the reaction mixture by filtration, the mixture was concentrated to dryness to obtain 300 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOH (SEQ ID NO. 1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:28])([F:27])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[NH:14][C:13]2=[O:26])=[CH:8][CH:7]=1.Cl[CH2:30][O:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:32]([O:31][CH2:30][N:14]1[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:16][C:17](=[O:18])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][C:4]([F:3])([F:27])[F:28])=[CH:7][CH:8]=2)[C:13]1=[O:26])[CH3:33]
Reactant: O=c1cc(-c2ccccc2Cl)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCn1c(-c2ccccc2Cl)cc(=O)n(-c2ccc(OC(F)(F)F)cc2)c1=O
Temperature: 0 °C
Yield: 73.1 %

Procedure:
0.5 g of sodium hydride (purity: 55%) was added to 50 ml of dimethylformamide, and then 3.8 g of 3-(4-trifluoromethoxyphenyl)-6-(2-chlorophenyl)-2,4(1H,3H)-pyrimidinedione was added to the solution with stirring at 0° C. The resulting solution was stirred at room temperature for 15 minutes, then added dropwise with 1.3 g of chloromethylethyl ether and further stirred at room temperature for 3 hours. The reaction mixture was added into 200 ml of ice water and extracted with 200 ml of ethyl acetate. The organic layer was washed with water and dried, and then the solvent was distilled away under reduced pressure to obtain 3.8 g of a crude product. This crude product was recrystallized from diisopropyl ether to obtain 3.2 g of the objective compound.
Reaction SMILES: [NH:1]([C:3](=[O:23])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5])[NH2:2].[F:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[N:33]=[C:34]=S>>[F:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[NH:33][C:34]1[O:23][C:3]([C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C@H:13]3[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)=[O:5])=[N:1][N:2]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: Fc1cc(F)c(N=C=S)cc1F
Product: COC(=O)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1

Procedure:
Following the procedure of Example 105 except that methyl trans-4-(4-{[hydrazino(oxo) acetyl]amino}phenyl)cyclohexanecarboxylate (Intermediate 44) and 2,4,5-trifluorophenylisothiocyanate were used as starting materials the title compound was obtained as solid; 1H NMR δ 1.47 (1H, s), 1.49 (2H, d), 1.52 (1H, s), 1.85 (2H, d), 2.01 (2H, d), 2.45 (1H+DMSO, m), 2.53-2.56 (1H, m), 3.62 (3H, s), 7.22-7.24 (2H, m), 7.68 (1H, s), 7.71 (2H, q), 8.15-8.18 (1H, m), 10.96 (1H, s), 11.04 (1H, s) MS m/e MH+ 475.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=3)=[CH:13][C:12]([C:23]([OH:25])=O)=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:59]3[CH2:63][C:62](=[O:64])[NH:61][CH2:60]3)=O)=N2)C=CC=1>C(O)=O>[C:21]([C:17]1[CH:16]=[C:15]([C:14]2[N:10]([C:5]3[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[CH:4]=3)[N:11]=[C:12]([C:23]([N:59]3[CH2:63][C:62](=[O:64])[NH:61][CH2:60]3)=[O:25])[CH:13]=2)[CH:20]=[CH:19][CH:18]=1)#[N:22]
Reactant: N#Cc1cccc(-c2cc(C(=O)O)nn2-c2ccc(F)c(C#N)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccc(F)c(C#N)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 112A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. In order to remove the 1,1′,1″-phosphoryltripyrrolidine the product is taken up in a little tetrahydrofuran, water is added to the mixture until a precipitate forms, the tetrahydrofuran is removed in vacuo, and the precipitate is collected by suction filtration, and dried under high vacuum. 25 mg (48% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)[OH:9])=[CH:4][C:3]=1[O:24][CH3:25]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:21])([F:22])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc(C(O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of (4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol (0.58 g, 1.57 mmol) in CH2Cl2 (5 mL) was added activated manganese dioxide (0.80 g, 7.86 mmol). The reaction mixture was stirred overnight at rt. Additional manganese dioxide (0.80 g, 7.86 mmol) was added and the reaction stirred at rt for another overnight. The reaction mixture was diluted with CH2Cl2 and filtered through celite and the solid was washed with CH2Cl2. The filtrate was concentrated under reduced pressure to yield (4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone (0.56 g, 98% yield). HPLC: RT=4.048 minutes (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient, flow rate 4 mL/min, monitoring at 220 nm); LCMS: [M+H] 365.2 (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous methanol containing 0.1% TFA over a 2 minute gradient, flow rate 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3): 7.5-7.1 (m, 6H), 5.92 (tt, J=2.2, 53.6 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:18][O:17][C@@H:16]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH2:15][C@H:14]1[CH2:23][OH:24]>ClCCl>[CH:20]1([CH2:19][C@@H:16]2[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[C@H:14]([CH2:23][OH:24])[CH2:15]2)[CH2:21][CH2:22]1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](CC2CC2)C[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](CC2CC2)C[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Benzoyl isothiocyanate (0.6 g, 3.7 mmol) was added drop-wise to a solution of rel-[(2S,4R,5S)-5-amino-2-(cyclopropylmethyl)-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C71) (1.10 g, 3.7 mmol) in dichloromethane (30 mL). After the reaction mixture had stirred at room temperature for 15 hours, it was concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) provided the product as a brown solid. Yield: 1.14 g, 2.47 mmol, 67%. LCMS m/z 461 [M+H+].